Open access peer-reviewed chapter

Metabolic Features of Neurofibromatosis Type 1-Associated Tumors

Written By

Ionica Masgras and Andrea Rasola

Submitted: May 21st, 2021Reviewed: June 1st, 2021Published: August 16th, 2021

DOI: 10.5772/intechopen.98661

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Rewiring cellular metabolism is a key hallmark of cancer. Multiple evidences show that alterations in various metabolic circuits directly contribute to the tumorigenic process at different levels (e.g. cancer initiation, metastasis, resistance). However, the characterization of the metabolic profile of Neurofibromatosis type 1 (NF1)-related neoplastic cells has been only partially elucidated both in benign neurofibromas and in malignant peripheral nerve sheath tumors (MPNSTs). Here, we illustrate the state of the art on the knowledge of the metabolic features of tumors related to NF1 and discuss their potential implications for the development of novel therapeutic perspectives.


  • NF1
  • metabolism
  • mitochondria
  • chaperones
  • sirtuins
  • neurofibroma
  • glucose
  • glutamine
  • PET

1. Introduction

Neurofibromatosis type 1 (NF1) is a genetic multisystem disorder that predisposes to the onset of several tumor types and is characterized by a number of clinical manifestations encompassing café au lait macules in the skin, iris hamartomas (Lisch nodules), cognitive deficits, axillary or groin freckles, bone deformities, optic gliomas and Schwann cell neoplasms called neurofibromas. The presence of two or more of these clinical features is used as consensus diagnostic criteria for NF1 [1].

NF1 is inherited in an autosomal dominant way when inactivating mutations occur at the NF1locus that encodes for the Ras-GTPase activating protein (Ras-GAP) neurofibromin. Complete loss of neurofibromin activity, caused by second hit mutations, leads to hyperactivation of Ras signaling and tumor onset. The tumor type that hallmarks this genetic disease is neurofibroma, a benign neoplasm affecting peripheral nerves. Plexiform neurofibromas (PNs) involve perineural sheaths of nerve bundles and may occasionally transform into malignant peripheral nerve sheath tumors (MPNSTs), highly aggressive sarcomas endowed with a dismal prognosis. MPNSTs are currently untreatable, while only recently an inhibitor of MEK, a downstream effector of Ras signaling, has been approved for pediatric inoperable neurofibromas [2].

PN monitoring is critical for managing tumor progression and early malignancy diagnosis. To this purpose, imaging tools are extremely important in identifying suspicious lesions, and an increase in the avidity for the radioactive tracer 18F-fluorodeoxyglucose (FDG) during Positron Emission Tomography (PET) scans is a critical indication of malignant progression [3, 4, 5]. This increase in glucose uptake denotes that some neoplastic cells inside the PN mass are undergoing a metabolic rewiring. Glucose is used by various intracellular metabolic pathways for the overall energetic and anabolic needs of highly proliferative cells, as it provides them with several advantages, such as induction of nucleotide and amino acid biosynthetic pathways that stem from glycolysis intermediates, as well as enhancement of anti-oxidant defenses by boosting the pentose phosphate pathway [6]. Moreover, glycolysis induction is often accompanied by a repression in cellular respiration, akaoxidative phosphorylation (OXPHOS), making neoplastic cells less dependent on oxygen, as its availability can often be scarce in a growing neoplastic mass that is poorly vascularized [7]. The characterization of tumor metabolic features has gained increased attention in the attempt of identifying crucial regulators of metabolism that could be exploited as pharmacological targets.


2. Metabolic features of NF1 patients

Several indications suggest that dysregulation of Ras signaling in NF1 has metabolic effects. Indeed, metabolic alterations have been identified in NF1 patients at the systemic level (Figure 1). For instance, in fasting conditions they show a glucose level in the blood that is lower than in control people [8] and display an increased insulin sensitivity [9] that makes them less prone to diabetes mellitus development [10]. This could be caused by a general imbalance in the levels of several hormones, including lower levels of leptin and visfatin and higher adiponectin in NF1 patients with respect to control subjects. It remains to be explained the mechanistic connection between heterozygous loss of neurofibromin and these metabolic changes, confirmed in a large cohort of patients [11]. Moreover, NF1 individuals show reduced cerebral glucose metabolism, specifically in the thalamus [12]. Altogether, these observations put forward the hypothesis that neurofibromin haploinsufficiency may have systemic effects in overall glucose utilization. Thalamic glucose hypometabolism could be related to the neurological symptoms of NF1 (e.g. cognitive impairment). By using NF1 animal models it was also proposed that other dysmetabolic traits, such as disarrangements in neuronal usage of glutamate, γ-amino butyric acid (GABA) and dopamine, could be connected to the deficits in spatial learning, memory and attention observed in patients [13, 14, 15].

Figure 1.

The multisystem metabolic phenotype of NF1 disease. A NF1 patient is depicted with the most common metabolic-related features.

Changes in the levels of these neurotransmitters could affect the activity of several ion channels linked to the neurologic phenotype of NF1. For instance, augmented activity of voltage-gated sodium and calcium channels in sensory neurons dictates increased excitability and firing properties and underlies heightened pain sensations in NF1 patients [16]. In addition, changes in ion channel properties have repercussions on non-neuronal cells in NF1 and may participate in the overall alteration of ion homeostasis, as for Ca2+ signaling, which is altered in NF1 keratinocytes [17]. Ca2+ is a highly compartmentalized ion, and its mobilization has the capability of tuning a variety of cellular processes connected to mitochondrial metabolism and cell death pathways. Whether these Ca2+ alterations in neurofibromin haploinsufficient cells install adaptations that are relevant also in NF1-related tumors is an intriguing possibility.

At the muscular level, NF1 children may display reduced muscle function, which has been related to a role of neurofibromin in regulating fatty acid metabolism in this tissue [18]. Muscle specimens from limb-specific Nf1Prx1−/− conditional knockout mice show a 10-fold increase in muscle triglyceride content, upregulation in the activity of oxidative metabolism enzymes and increased expression of fatty acid synthase and of the hormone leptin, whereas the expression of a number of fatty acid transporters is decreased. This genetic NF1 mouse models has shown that a lipid storage disease phenotype may underlie muscle weakness in NF1, thus displaying commonalities with the lipid storage myopathies (LSMs), which also present with progressive muscle weakness and muscle lipid accumulation, and may occasionally be treated with high dose L-carnitine supplementation [19]. Nf1 null muscle specimens are enriched in long chain fatty acid (LCFA) containing neutral lipids, such as cholesterol esters and triacyl glycerides, suggesting impaired LCFA metabolism [20]. Thus, Nf1Prx1−/− mice recapitulate the human NF1 myopathy and lipid storage excess inside muscle fibers, and a dietary intervention of reduced LCFAs and enrichment of medium-chain fatty acids with L-carnitine effectively rescues lipid accumulation and muscle weakness in knockout mice. These data link NF1 deficiency to fundamental shifts in muscle metabolism, and provide strong proof of principle that a dietary intervention can ameliorate muscle symptoms. On the same path, pharmacological intervention with the MEK inhibitor PD0325901 in pregnant mice is able to rescue body weight loss and lipid accumulation in the Nf1MyoD−/− progeny, suggesting a potential mechanism underlying the NF1-Ras-MAPK dependency of altered fatty acid metabolism [21]. Furthermore, a recent work has highlighted the requirement of neurofibromin for postnatal muscle growth and metabolic homeostasis [22].

In NF1 patients, skeletal problems including scoliosis, tibial pseudo-arthrosis and short stature are also common. Bone dysplasia is considered linked to mineralization defects and is a generalized metabolic bone disease [23]. Indeed, NF1 patients display a decreased bone mineral density, low levels of serum 25-hydroxy vitamin D3, increased osteoporosis and fracture risk [24]. Whether these systemic metabolic characteristics (i.e. increased glucose utilization and reduced fat depot mass) could affect the timing and type of tumor manifestations remains a puzzling issue. Neurofibroma onset and growth are accelerated by the heterozygous condition of the tumor microenvironment. Similarly, it could be envisioned that circulating factors determined by the peculiar metabolism of NF1 also participate in determining the extent of cancer predisposition. Moreover, given the sophisticated regulation and adaptability of human metabolism to external factors, the understanding of its potential involvement in NF1-related tumorigenesis may shed light on the patient-to-patient variability in the tumor burden of this disease.

Take home message.Altogether, these reports underline that NF1 has multisystem effects from the metabolic point of view. Recently, some of the metabolic and morphologic features of humans with NF1 have been fully recapitulated by Nf1 heterozygous mouse models of the disease [25].


3. Metabolic adaptations of NF1-related tumors

One of the most worrisome features of NF1 disease is the increased susceptibility of patients to several neoplasms. Beside the presence of neurofibromas, benign tumors that hallmark this disorder, gliomas, hematological neoplasms, breast cancer, pheochromocytomas, gastrointestinal tumors (GISTs) and MPNSTs may develop throughout lifetime. Following the loss of the tumor suppressor gene neurofibromin and the subsequent activation of the Ras pathway, several intracellular signaling cascades are rearranged and impact on cellular processes relevant to cancer progression (e.g. survival, growth, cell death, metabolism). Beside this network of deregulated pathways inside the tumor cell, a variety of inter-cellular signals are altered by neurofibromin haploinsufficiency. Neurofibromas show a highly heterotypic microenvironment composed mainly by mast cells, macrophages and fibroblasts, and neoplastic growth depends on the complex interplay between these cell types (Figure 2). For instance, the KIT growth factor is secreted by NF1 null Schwann cells and acts as a chemo-attractant for NF1 heterozygous mast cells. In turn, mast cells produce TGFβ, stimulating heterozygous fibroblasts to increase production of collagen and of other extracellular matrix (ECM) proteins. Mast cells also produce heparin, vascular endothelial growth factor (VEGF) and matrix metalloproteases (MMPs), which promote tumor vascularization and invasiveness. Aberrantly proliferating Schwann cells secrete colony-stimulating factor (CSF1), thereby recruiting macrophages that sustain tumor progression.

Figure 2.

Impact of neurofibromin loss on intra/intercellular signaling and metabolic pathways. Signaling cascades within Schwann cells and in the heterozygous microenvironment are highlighted in black. Metabolic pathways altered following neurofibromin loss are depicted in red.

Apart from regulating survival and proliferation, some of these alterations in signal transduction can also directly affect cellular metabolism. Indeed, RAS signaling promotes oncogenic metabolism by coordinating numerous metabolic processes including lipid, nucleotide, and glycolytic pathways (Figure 2). Specifically, upregulation of the Ras pathway sustains a glycolytic and glutaminolytic metabolism by MYC induction, allowing cancer cells to preferentially use glucose and glutamine for anabolic purposes. This is accompanied by a decrease in OXPHOS that is characterized by blunted TCA cycle and reduced mitochondrial respiration. Ras downstream pathways, such as the mTOR signaling, also affect lipid and nucleotide synthesis for anabolic demands [26, 27].

Several metabolic circuits converge on mitochondria, which are considered the powerhouse of the cell. They are in charge of energy supply and actively sustain biosynthetic pathways mandatory for cell replication. Moreover, mitochondria are involved in cell death signaling and contribute to oxidative stress regulation. Changes in several mitochondrial functions have been linked to the pro-neoplastic dysregulation of many fundamental biological processes, including a variety of bioenergetic circuities [28].

Tumor metabolism refers to a plethora of cancer features, spanning from the way neoplastic cells take up and utilize nutrients for growth and replication, to the diverse communication modes they establish with the neighboring cells. Altogether, these metabolic adaptations during cancer initiation and progression render aberrant cells capable of circumventing nutrient and oxygen shortage conditions that they may encounter, and often affect and constrain the behavior of the surrounding microenvironment [29].

So far, targeting strategies against cancer mainly rely on specifically blocking molecular signals that promote cell proliferation, hinder cell death, modulate the immune response or enhance angiogenesis and cell survival. However, most of these signaling pathways are either redundant or essential in healthy tissue making these types of target therapies challenging. A further strategy is to hit key metabolic transformations that occur in cancer cells, whereby the metabolic adaptations to hypoxic conditions seem to be specific for cancer cells, shared in many tumor types and required for neoplastic growth.

3.1 Mitochondrial respiration

Although the metabolic scenario of NF1 mutant cells is poorly defined, some bioenergetic alterations are starting to surface. For instance, respiratory complex II, akasuccinate dehydrogenase (SDH), is a crucial metabolic enzyme at the crossroad between OXPHOS and Krebs cycle that is repressed in NF1-related tumor cells in an ERK-dependent manner following neurofibromin loss; this metabolic rewiring is compensated by an increased glycolytic pathway [30]. In detail, hyperactivation of the mitochondrial branch of Ras/ERK signaling causes phosphorylation of the mitochondrial chaperone TRAP1. Its consequent activation inhibits SDH enzymatic activity, triggering intracellular accumulation of the oncometabolite succinate that in turn stabilizes the pro-neoplastic transcription factor HIF1α. Importantly, genetic ablation of TRAP1 inhibits tumor growth [31]. Taken together, these data indicate that TRAP1 mediates a pseudo-hypoxic signaling, as it orchestrates a HIF1α-dependent program that is crucial in the neoplastic process and boosts tumor growth independently of environmental oxygen tension. Moreover, it was recently demonstrated that TRAP1 also executes the hypoxic response, as it is a transcriptional target of HIF1α induced in KRAS-dependent models of carcinogenesis, such as pancreatic adenocarcinoma, with a crucial role in handling the cell bioenergetic response to oxygen paucity [32]. In specific cases of familiar cancers (i.e. in the hereditary paraganglioma-phaeochromocytoma syndrome, HPGL/PCC), succinate increases following inactivating mutations of SDH subunits. In these settings, in addition to inducing HIF1α, high levels of succinate can impinge on cell epigenetics by inhibiting α-ketoglutarate dependent dioxygenases, such as histone and DNA demethylases, further contributing to neoplastic growth [33]. Therefore, it can be envisioned that similar complex changes in the epigenome landscape occur upon TRAP1-mediated SDH inhibition in NF1-related tumor cells.

As a consequence, pharmacological inhibition of TRAP1 has been proposed as an anti-neoplastic approach for MPNST and other tumor types. Recently, the identification of highly selective TRAP1 allosteric inhibitors has shown promising results, ablating in vitrotumorigenesis [34, 35]. Previous targeting of the HSP90 family of chaperones, to which TRAP1 belongs, has been pursued with the drug IPI-504 which, in combination with the mTOR inhibitor rapamycin, cooperates in the growth repression of NF1 mutant cancer cells [36]. Here, strong ER stress drastically represses cancer growth. Given the intense molecular crosstalk between ER and mitochondria and their coordinated regulation of Ca2+ homeostasis, it could be envisaged that the interplay between ER and mitochondria is crucial in the growth of NF1 deficient cells. Indeed, yeast synthetic lethality screens have identified Y100 as a molecule capable of interfering with mito-ER homeostasis, thus revealing crucial metabolic vulnerabilities of the yeast cells null for the homolog of NF1, called IRA2 [37].

Another report describes that neurofibromin-deficient cells display a decrease in the activity of NADH dehydrogenase, akathe first respiratory complex, with a consequent unbalance in NAD+/NADH ratio [38]. This metabolic alteration negatively impacts on the activity of mitochondrial sirtuins, specifically SIRT3. SIRT3 reactivation through NAD+ precursor supply or genetic manipulation impairs tumorigenesis of neurofibromin-deficient cells and synergize with TRAP1 ablation in repressing MPNST growth in xenografts by preventing HIF1α stabilization. Furthermore, the repressed expression of several subunits of the NADH dehydrogenase respiratory complex I, one of the main ROS producers in mitochondria, renders neurofibromin-deficient cells more resistant to pro-oxidant drugs acting through complex I-mediated ROS increase.

Take home message.Altogether, these data indicate that NF1-related tumors display a pseudo-hypoxic signature that contributes to tumor proliferation and transition towards malignancy. Indeed, neurofibromin inactivation occurs in certain cancers through hypoxia-induced degradation, independently of NF1gene mutations [39]. These data suggest that the hypoxic response might affect the Ras/ERK signaling pathways downstream to neurofibromin loss and its genetic inactivation installs a hypoxic-like response that may provide cells with an equipped and prompt response to any possible drop in oxygen availability.

3.2 Glutamine metabolism

As already shown for several cancers, NF1 null cells are highly sensitive to glutamine deprivation, and glutaminase (GLS) inhibitors such as BPTES (bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide 3) or CB-839 have been proposed as antineoplastic agents in the context of NF1-associated neoplasms [40]. Glutamine is one of the most abundant intracellular amino acids and fuels several biosynthetic pathways by providing carbons to TCA cycle intermediates, glutathione, fatty acids, and nucleotides. Pharmacological GLS inhibition causes a shortage in multiple TCA cycle intermediates, among which α-ketoglutarate, succinate and fumarate.

Phase II Basket Trial of Glutaminase Inhibitor (BeGIN) CB-839 HCl in patients with metastatic or unresectable MPNST is ongoing ( Still, CB-839 resistance has been observed in vitro,whereby c-Myc induction takes place through epigenetic changes mediated by bromodomain-containing protein 4 (BRD4), which promotes transcription by recognizing acetylated lysines on histones. Indeed, CB-839 resistant cells are more sensitive to JQ1, a small molecule inhibitor of BRD4 [41]. Furthermore, glutamine dependency has been identified in lung adenocarcinomas where KRAS mutations coexist with Nf1 loss [42]. This work suggests that oncologic patient stratification for NF1 loss may uncover crucial targetable metabolic adaptations.

Similarly, the glutamine antagonist JHU395, a novel orally bioavailable prodrug designed to circulate in an inert form in plasma and to permeate and release the active drug within target tissues, is able to inhibit tumor growth in a murine flank MPNST model [43]. One of the major outcomes of JHU395 administration is the reduced usage of glutamine-dependent metabolites with a prominent effect on purine synthesis. Interestingly, glutamine utilization for anaplerotic purposes ( of TCA intermediates such as glutamate, α-ketoglutarate and succinate) is not limited by JHU395. The different modes of action of drugs targeting glutamine metabolism indicate that multiple metabolic pathways in glutamine utilization might be critical for MPNST growth.

3.3 Lipid metabolism

During cancer growth, transformed cells experience nutrient and glucose shortage and must install metabolic adaptations to overcome these potentially harmful circumstances. Metabolic stress factors such as hypoxia and glucose deprivation increase expression of carnitine palmitoyltransferase 1C (CPT1C), member of a family of mitochondria-associated enzymes that regulate fatty acid metabolism. Its genetic ablation in a NF1 murine model delays tumor growth [44]. This finding exposes a susceptibility of NF1-related cancers to drugs targeting lipid metabolism when stressful conditions occur, as in the case of active chemotherapeutic regimens.

Lipid droplet accumulation has been reported in MPNSTs, which utilize both exogenous and endogenous lipids as a source of energy [45]. Indeed, either disruption of fatty acid oxidation and the use of the fatty acid synthase (FASN) inhibitors C75, orlistat and Irgasan reduce MPNST survival.

MPNSTs have been reported to secrete elevated levels of prostaglandin E2 (PGE2), an active lipid compound with hormone-like effects in animals [46]. It usually acts as an endocrine mediator of metabolic processes in homeostasis but also in inflammatory and neoplastic conditions. Remarkably, PGE2 receptor antagonists decreased the proliferation of MPNST cell lines. Prostaglandin administration has also been linked to aberrant cAMP metabolism in MPNSTs that display two-fold increased cAMP levels compared to normal Schwann cells [47].

3.4 Connections between genetic mutations and metabolic changes

The HPGL/PCC syndrome, where loss-of-function mutations affect SDH and increase intracellular levels of the oncometabolite succinate, thus causing onset of pheochromocytoma and paraganglioma, is a proof-of-concept that metabolic changes can drive tumorigenesis. It is of note that NF1 patients can develop this kind of tumors in 5% of cases, whereas in non-NF1 related patients with HPGL/PCC history NF1 mutations have been reported in tumor cells [48]. This information, even though only correlative, is in accord with the observation that TRAP1 exerts a pro-neoplastic role in NF1 by inhibiting SDH, and suggests a possible overlapping path of metabolic adaptations existing between inactivation of NF1 and SDH components. Moreover, it must be highlighted that dysregulated signaling cascades can impinge on metabolic circuits, thus leading to neoplastic metabolic alterations either in the absence or in addition to specific mutations in metabolic enzymes.

Another interesting line of investigation links gene mutations to pro-neoplastic metabolic adaptations during neurofibroma growth. Indeed, it was reported that somatic mutations in mitochondrial DNA (mtDNA), which encodes 13 proteins of the OXPHOS machinery, are acquired and maintained by a high percentage of cutaneous and plexiform neurofibromas [49]. This suggests a possible positive selection in neoplastic cells for mutated mitochondrial genes, in keeping with observations that an aberrant mitochondrial respiration confers adaptive advantages to neurofibroma cells.

Take home message.Although the metabolic landscape of neurofibromin-deficient cells and MPNST has been only partially investigated, uncovering the adaptations in the metabolic circuits of these tumor cells may shed light on novel targetable actors. Furthermore, despite the genetic variability in MPNSTs characterized by different acquired mutations (e.g. TP53, p16, PRC, SUZ12, CDKN2A,etc.), there is the possibility of conserved derangements in metabolic pathways that may render MPNST vulnerable to selective targeting.

Perspectives.Beside cell autonomous changes in metabolism of neurofibromin-deficient tumor cells, their metabolic phenotype can be determined by alterations in intercellular communication within the tumor microenvironment. Recently it has been reported that fibroblast metabolic rewiring can promote growth of neural tumors [50]. Furthermore, beside the mitochondria to nucleus signaling mediated by succinate-dependent regulation of HIF1α and of epigenetic changes, this oncometabolite can exit tumor cells affecting immune cell responses. Thus, metabolic changes within neurofibromin null cells can affect the behavior of neighboring cells within the tumor microenvironment. Recent advances in immunotherapy approaches against MPNST growth have highlighted how these cancers might evade immune recognition and hijack immunological functions (e.g. tissue healing, angiogenesis, etc.) to their advantage. Whether the metabolic status of NF1-related tumors mediate the relationship between transformed cells and immune system is an exciting matter of investigation.


4. Conclusions

For a long time, pharmacological treatments suited for NF1-related neoplasms have been lacking. Only recently the first therapeutic approaches have been translated from NF1 mouse models to patient bedside and further clinical trials are currently ongoing. Altogether, the major efforts in managing NF1-related neoplasms have been based on drugs targeting signaling transduction cascades such as RTK, RAS- RAF–MEK–ERK and PI3K-AKT–mTOR inhibitors. Selumetinib was the first drug approved in 2019 by the US FDA for pediatric NF1 patients with symptomatic and inoperable PN [51, 52] after a phase 2 clinical trial started a decade ago ( Results indicate that 74% of patients display a partial response in terms of tumor volume shrinkage, and this is durable in 56% of patients. Albeit extremely positive, these results demand the urgent development of additional treatments. Previous attempts of targeting signaling cascades in neurofibroma microenvironment through imatinib mesylate administration, a dual SCF/cKIT inhibitor, have shown modest response rates limited only to small tumors [53] ( Cabozantinib, an inhibitor of multiple tyrosine kinases among which c-Kit, vascular endothelial growth factor (VEGF) receptor (VEGFR)2, MET, RET, FMS-related RTK 3 (FLT3) and TAM family receptors (tyrosine kinases AXL, TYRO3 and MERTK) is now under study in a phase II trial against progressive or symptomatic, inoperable PN ( as it has shown promising results in Nf1-mutant mice [54].

As for glioma, chemotherapy remains the first line treatment. More recently, epigenetic-based approaches in fighting MPNST growth have emerged [55] and drugs targeting the immune checkpoints are considered the emerging therapeutic option with ongoing clinical trials [56, 57] (

In this scenario, beside the recently reviewed pharmacological options for MPNST treatment [58, 59, 60], targeting the metabolic features of NF1-related tumors constitutes an additional, promising therapeutic option. Although multiple metabolic routes have been shown to be affected in NF1 tumorigenesis, metabolic based anti-neoplastic approaches are limited in the field (BeGIN clinical trial) and others are at the preclinical stage (Figure 3). A recent report has resumed the idea of targeting the glycolytic pathway [61]; however, the drug employed, i.e. 3-bromopyruvate, has already been dismissed from past clinical trials for excessive and life-threatening toxicity.

Figure 3.

Treatment options against NF1-related neoplasms. Drugs under clinical (green) and preclinical (violet) evaluation against NF1-related tumors are reported.

As for MPNST, complete surgical excision with clear margins remains the only treatment in the case of a localized cancer. Given the lack of efficacy in targeting unique aspects of MPNST disease biology, some benefits could hopefully come from combinatorial therapeutic designs that consider and include innovative rational therapies, such as targeting bioenergetic circuities.

In this direction, despite the genetically heterogeneous phenotype of NF1-related malignancies, the annotation of conserved metabolic adaptations in the progression towards MPNST might open space for innovative therapeutic interventions [62].

Perspectives.Advancements in animal modeling of NF1-related neoplasms are meant to refine the understanding of PN tumorigenesis and put the basis for testing multi-targeted drug therapies and adaptive tumor response. For instance, atypical neurofibromas with an uncertain transforming potential have been recapitulated by Cdkn2aloss [63]. Uncovering the potential metabolic adaptations of the transitional stages of NF1 tumors from the benign to the malignant ones may equip clinicians with metabolic biomarkers to be monitored during NF1 patient surveillance.

Furthermore, the understanding of the metabolic interplay between cancer cells that have lost neurofibromin and other cell types present in the tumor microenvironment might uncover metabolic susceptibility of these cancers. For instance, MPNSTs display an increased number of macrophages with respect to PNs and are highly glutamine-addicted. It is known that macrophages sense the lack of glutamine and install a synthetic pathway for glutamine supply based on glutamine synthetase induction. This metabolic rewiring characterizes the pro-tumorigenic polarization towards a tumor-associated macrophage phenotype. Given these tight and crucial metabolic crosstalks between tumor cells and the immunologic compartment, it can be envisioned that targeted therapies are accompanied by metabolic-based treatments hitting both neoplastic and environmental cells in order to overcome potential cancer resistance (e.g. CB-839 and JQ1, which combines metabolic and epigenetic treatments).

PET scans with labeled glucose uptake evaluation can provide an extremely useful tool for monitoring lesions at high potential for growth and at risk for malignant transformation; regular imaging is suggested especially in symptomatic neurofibromas [64]. We expect that metabolic tracking of additional nutrients such as glutamine could be employed in NF1 patients for the unraveling of metabolically active lesions. Imaging of labeled glutamine is currently under evaluations in cancer patients and has the potential of predicting cancer response to metabolic targeted therapies, thus helping the guidance of therapeutic decision-making [65, 66].



This work was supported by grants from University of Padova, Neurofibromatosis Therapeutic Acceleration Program and Associazione Italiana Ricerca Cancro (AIRC grant IG 2017/20749).


Conflict of interest

The authors declare no conflict of interest.


Notes/thanks/other declarations

Images were obtained with BioRender software (


  1. 1.Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, et al. Guidelines for the diagnosis and management of individuals with neurofibromatosis 1. J Med Genet 2007 Feb;44(2):81-88
  2. 2.Mukhopadhyay S, Maitra A, Choudhury S. Selumetinib: the first ever approved drug for neurofibromatosis-1 related inoperable plexiform neurofibroma. Curr Med Res Opin 2021 Mar 23:1-6
  3. 3.Ahlawat S, Blakeley JO, Langmead S, Belzberg AJ, Fayad LM. Current status and recommendations for imaging in neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis. Skeletal Radiol 2020 Feb;49(2):199-219
  4. 4.Van Der Gucht A, Zehou O, Djelbani-Ahmed S, Valeyrie-Allanore L, Ortonne N, Brugières P, et al. Metabolic Tumour Burden Measured by 18F-FDG PET/CT Predicts Malignant Transformation in Patients with Neurofibromatosis Type-1. PLoS One 2016 Mar 17;11(3):e0151809
  5. 5.Urban T, Lim R, Merker VL, Muzikansky A, Harris GJ, Kassarjian A, et al. Anatomic and metabolic evaluation of peripheral nerve sheath tumors in patients with neurofibromatosis 1 using whole-body MRI and (18)F-FDG PET fusion. Clin Nucl Med 2014 May;39(5):e301-7
  6. 6.DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv 2016 May 27;2(5):e1600200
  7. 7.Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 2009 May 22;324(5930):1029-1033
  8. 8.Martins AS, Jansen AK, Rodrigues LO, Matos CM, Souza ML, de Souza JF, et al. Lower fasting blood glucose in neurofibromatosis type 1. Endocr Connect 2016 Jan;5(1):28-33
  9. 9.Martins AS, Jansen AK, Rodrigues LOC, Matos CM, Souza MLR, Miranda DM, et al. Increased insulin sensitivity in individuals with neurofibromatosis type 1. Arch Endocrinol Metab 2018 Feb;62(1):41-46
  10. 10.Ozhan B, Ozguven AA, Ersoy B. Neurofibromatosis type 1 and diabetes mellitus: an unusual association. Case Rep Endocrinol 2013;2013:689107
  11. 11.Kallionpää RA, Peltonen S, Leppävirta J, Pöyhönen M, Auranen K, Järveläinen H, et al. Haploinsufficiency of the NF1 gene is associated with protection against diabetes. J Med Genet 2020 Jun 22
  12. 12.Apostolova I, Derlin T, Salamon J, Amthauer H, Granström S, Brenner W, et al. Cerebral glucose metabolism in adults with neurofibromatosis type 1. Brain Res 2015 Nov 2;1625:97-101
  13. 13.Costa RM, Federov NB, Kogan JH, Murphy GG, Stern J, Ohno M, et al. Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature 2002 Jan 31;415(6871):526-530
  14. 14.Brown JA, Emnett RJ, White CR, Yuede CM, Conyers SB, O'Malley KL, et al. Reduced striatal dopamine underlies the attention system dysfunction in neurofibromatosis-1 mutant mice. Hum Mol Genet 2010 Nov 15;19(22):4515-4528
  15. 15.Ryu HH, Lee YS. Cell type-specific roles of RAS-MAPK signaling in learning and memory: Implications in neurodevelopmental disorders. Neurobiol Learn Mem 2016 Nov;135:13-21
  16. 16.Moutal A, Dustrude ET, Khanna R. Sensitization of Ion Channels Contributes to Central and Peripheral Dysfunction in Neurofibromatosis Type 1. Mol Neurobiol 2017 Jul;54(5):3342-3349
  17. 17.Korkiamäki T, Ylä-Outinen H, Koivunen J, Karvonen SL, Peltonen J. Altered calcium-mediated cell signaling in keratinocytes cultured from patients with neurofibromatosis type 1. Am J Pathol 2002 Jun;160(6):1981-1990
  18. 18.Sullivan K, El-Hoss J, Quinlan KG, Deo N, Garton F, Seto JT, et al. NF1 is a critical regulator of muscle development and metabolism. Hum Mol Genet 2014 Mar 1;23(5):1250-1259
  19. 19.Summers MA, Quinlan KG, Payne JM, Little DG, North KN, Schindeler A. Skeletal muscle and motor deficits in Neurofibromatosis Type 1. J Musculoskelet Neuronal Interact 2015 Jun;15(2):161-170
  20. 20.Summers MA, Rupasinghe T, Vasiljevski ER, Evesson FJ, Mikulec K, Peacock L, et al. Dietary intervention rescues myopathy associated with neurofibromatosis type 1. Hum Mol Genet 2018 Feb 15;27(4):577-588
  21. 21.Summers MA, Vasiljevski ER, Mikulec K, Peacock L, Little DG, Schindeler A. Developmental dosing with a MEK inhibitor (PD0325901) rescues myopathic features of the muscle-specific but not limb-specific Nf1 knockout mouse. Mol Genet Metab 2018 Apr;123(4):518-525
  22. 22.Wei X, Franke J, Ost M, Wardelmann K, Börno S, Timmermann B, et al. Cell autonomous requirement of neurofibromin (Nf1) for postnatal muscle hypertrophic growth and metabolic homeostasis. J Cachexia Sarcopenia Muscle 2020 Dec;11(6):1758-1778
  23. 23.Brunetti-Pierri N, Doty SB, Hicks J, Phan K, Mendoza-Londono R, Blazo M, et al. Generalized metabolic bone disease in Neurofibromatosis type I. Mol Genet Metab 2008 May;94(1):105-111
  24. 24.Filopanti M, Verga U, Ulivieri FM, Giavoli C, Rodari G, Arosio M, et al. Trabecular Bone Score (TBS) and Bone Metabolism in Patients Affected with Type 1 Neurofibromatosis (NF1). Calcif Tissue Int 2019 Feb;104(2):207-213
  25. 25.Tritz R, Benson T, Harris V, Hudson FZ, Mintz J, Zhang H, et al. Nf1 heterozygous mice recapitulate the anthropometric and metabolic features of human neurofibromatosis type 1. Transl Res 2021 Feb;228:52-63
  26. 26.Park JH, Pyun WY, Park HW. Cancer Metabolism: Phenotype, Signaling and Therapeutic Targets. Cells 2020 Oct 16;9(10):2308. doi: 10.3390/cells9102308
  27. 27.DeBerardinis RJ, Chandel NS. Fundamentals of cancer metabolism. Sci Adv 2016 May 27;2(5):e1600200
  28. 28.Cannino G, Ciscato F, Masgras I, Sánchez-Martín C, Rasola A. Metabolic Plasticity of Tumor Cell Mitochondria. Front Oncol 2018 Aug 24;8:333
  29. 29.Pavlova NN, Thompson CB. The Emerging Hallmarks of Cancer Metabolism. Cell Metab 2016 Jan 12;23(1):27-47
  30. 30.Masgras I, Ciscato F, Brunati AM, Tibaldi E, Indraccolo S, Curtarello M, et al. Absence of Neurofibromin Induces an Oncogenic Metabolic Switch via Mitochondrial ERK-Mediated Phosphorylation of the Chaperone TRAP1. Cell Rep 2017 Jan 17;18(3):659-672
  31. 31.Sciacovelli M, Guzzo G, Morello V, Frezza C, Zheng L, Nannini N, et al. The mitochondrial chaperone TRAP1 promotes neoplastic growth by inhibiting succinate dehydrogenase. Cell Metab 2013 Jun 4;17(6):988-999
  32. 32.Laquatra C, Sanchez-Martin C, Dinarello A, Cannino G, Minervini G, Moroni E, et al. HIF1α-dependent induction of the mitochondrial chaperone TRAP1 regulates bioenergetic adaptations to hypoxia. Cell Death Dis 2021 May 1;12(5):434-021-03716-6
  33. 33.Kaushik AK, DeBerardinis RJ. Applications of metabolomics to study cancer metabolism. Biochim Biophys Acta Rev Cancer 2018 Aug;1870(1):2-14
  34. 34.Sanchez-Martin C, Moroni E, Ferraro M, Laquatra C, Cannino G, Masgras I, et al. Rational Design of Allosteric and Selective Inhibitors of the Molecular Chaperone TRAP1. Cell Rep 2020 Apr 21;31(3):107531
  35. 35.Masgras I, Sanchez-Martin C, Colombo G, Rasola A. The Chaperone TRAP1 As a Modulator of the Mitochondrial Adaptations in Cancer Cells. Front Oncol 2017 Mar 29;7:58
  36. 36.De Raedt T, Walton Z, Yecies JL, Li D, Chen Y, Malone CF, et al. Exploiting cancer cell vulnerabilities to develop a combination therapy for ras-driven tumors. Cancer Cell 2011 Sep 13;20(3):400-413
  37. 37.Allaway RJ, Wood MD, Downey SL, Bouley SJ, Traphagen NA, Wells JD, et al. Exploiting mitochondrial and metabolic homeostasis as a vulnerability in NF1 deficient cells. Oncotarget 2017 Jul 18;9(22):15860-15875
  38. 38.Masgras I, Cannino G, Ciscato F, Sanchez-Martin C, Pizzi M, Menga A, et al. Tumor growth of neurofibromin-deficient cells is driven by decreased respiration and hampered by NAD+ and SIRT3. in press (2021)
  39. 39.Green YS, Sargis T, Reichert EC, Rudasi E, Fuja D, Jonasch E, et al. Hypoxia-Associated Factor (HAF) Mediates Neurofibromin Ubiquitination and Degradation Leading to Ras-ERK Pathway Activation in Hypoxia. Mol Cancer Res 2019 May;17(5):1220-1232
  40. 40.Sheikh TN, Patwardhan PP, Cremers S, Schwartz GK. Targeted inhibition of glutaminase as a potential new approach for the treatment of NF1 associated soft tissue malignancies. Oncotarget 2017 Oct 6;8(55):94054-94068
  41. 41.Sheikh TN, Lu C, Schwartz GK. Targeting compensatory metabolic pathways: Novel approaches to overcome resistance to glutaminase inhibition in NF1 driven malignant peripheral nerve sheath tumors. Proceedings of the American Association for Cancer Research Annual Meeting 2020 2020;80(16):Abstract nr 248
  42. 42.Wang X, Min S, Liu H, Wu N, Liu X, Wang T, et al. Nf1 loss promotes Kras-driven lung adenocarcinoma and results in Psat1-mediated glutamate dependence. EMBO Mol Med 2019 Jun;11(6):e9856. doi: 10.15252/emmm.201809856
  43. 43.Lemberg KM, Zhao L, Wu Y, Veeravalli V, Alt J, Aguilar JMH, et al. The Novel Glutamine Antagonist Prodrug JHU395 Has Antitumor Activity in Malignant Peripheral Nerve Sheath Tumor. Mol Cancer Ther 2020 Feb;19(2):397-408
  44. 44.Sanchez-Macedo N, Feng J, Faubert B, Chang N, Elia A, Rushing EJ, et al. Depletion of the novel p53-target gene carnitine palmitoyltransferase 1C delays tumor growth in the neurofibromatosis type I tumor model. Cell Death Differ 2013 Apr;20(4):659-668
  45. 45.Patel AV, Johansson G, Colbert MC, Dasgupta B, Ratner N. Fatty acid synthase is a metabolic oncogene targetable in malignant peripheral nerve sheath tumors. Neuro Oncol 2015 Dec;17(12):1599-1608
  46. 46.Deadwyler GD, Dang I, Nelson J, Srikanth M, De Vries GH. Prostaglandin E(2) metabolism is activated in Schwann cell lines derived from human NF1 malignant peripheral nerve sheath tumors. Neuron Glia Biol 2004 May;1(2):149-155
  47. 47.Dang I, De Vries GH. Aberrant cAMP metabolism in NF1 malignant peripheral nerve sheath tumor cells. Neurochem Res 2011 Sep;36(9):1697-1705
  48. 48.Dahia PL. Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity. Nat Rev Cancer 2014 Feb;14(2):108-119
  49. 49.Kurtz A, Lueth M, Kluwe L, Zhang T, Foster R, Mautner VF, et al. Somatic mitochondrial DNA mutations in neurofibromatosis type 1-associated tumors. Mol Cancer Res 2004 Aug;2(8):433-441
  50. 50.Wei CJ, Gu YH, Wang W, Ren JY, Cui XW, Lian X, et al. A narrative review of the role of fibroblasts in the growth and development of neurogenic tumors. Ann Transl Med 2020 Nov;8(21):1462-20-3218
  51. 51.Gross AM, Wolters PL, Dombi E, Baldwin A, Whitcomb P, Fisher MJ, et al. Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med 2020 Apr 9;382(15):1430-1442
  52. 52.Dombi E, Baldwin A, Marcus LJ, Fisher MJ, Weiss B, Kim A, et al. Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas. N Engl J Med 2016 Dec 29;375(26):2550-2560
  53. 53.Robertson KA, Nalepa G, Yang FC, Bowers DC, Ho CY, Hutchins GD, et al. Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial. Lancet Oncol 2012 Dec;13(12):1218-1224
  54. 54.Fisher MJ, Shih CS, Rhodes SD, Armstrong AE, Wolters PL, Dombi E, et al. Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial. Nat Med 2021 Jan;27(1):165-173
  55. 55.Korfhage J, Lombard DB. Malignant Peripheral Nerve Sheath Tumors: From Epigenome to Bedside. Mol Cancer Res 2019 Jul;17(7):1417-1428
  56. 56.Farschtschi S, Kluwe L, Park SJ, Oh SJ, Mah N, Mautner VF, et al. Upregulated immuno-modulator PD-L1 in malignant peripheral nerve sheath tumors provides a potential biomarker and a therapeutic target. Cancer Immunol Immunother 2020 Jul;69(7):1307-1313
  57. 57.Wu LMN, Lu QR. Therapeutic targets for malignant peripheral nerve sheath tumors. Future Neurol 2019;14(1). doi: 10.2217/fnl-2018-0026
  58. 58.Hassan A, Pestana RC, Parkes A. Systemic Options for Malignant Peripheral Nerve Sheath Tumors. Curr Treat Options Oncol 2021 Feb 27;22(4):33-021-00830-7
  59. 59.Marjanska A, Galazka P, Wysocki M, Styczynski J. New Frontiers in Therapy of Peripheral Nerve Sheath Tumors in Patients With Neurofibromatosis Type 1: Latest Evidence and Clinical Implications. Anticancer Res 2020 Apr;40(4):1817-1831
  60. 60.Foiadelli T, Naso M, Licari A, Orsini A, Magistrali M, Trabatti C, et al. Advanced pharmacological therapies for neurofibromatosis type 1-related tumors. Acta Biomed 2020 Jun 30;91(7-S):101-114
  61. 61.Linke C, Wösle M, Harder A. Anti-cancer agent 3-bromopyruvate reduces growth of MPNST and inhibits metabolic pathways in a representative in-vitro model. BMC Cancer 2020 Sep 18;20(1):896-020-07397-w
  62. 62.Lemberg KM, Wang J, Pratilas CA. From Genes to -Omics: The Evolving Molecular Landscape of Malignant Peripheral Nerve Sheath Tumor. Genes (Basel) 2020 Jun 24;11(6):691. doi: 10.3390/genes11060691
  63. 63.Chaney KE, Perrino MR, Kershner LJ, Patel AV, Wu J, Choi K, et al. Cdkn2a Loss in a Model of Neurofibroma Demonstrates Stepwise Tumor Progression to Atypical Neurofibroma and MPNST. Cancer Res 2020 Nov 1;80(21):4720-4730
  64. 64.Reinert CP, Schuhmann MU, Bender B, Gugel I, la Fougère C, Schäfer J, et al. Comprehensive anatomical and functional imaging in patients with type I neurofibromatosis using simultaneous FDG-PET/MRI. Eur J Nucl Med Mol Imaging 2019 Mar;46(3):776-787
  65. 65.Grkovski M, Goel R, Krebs S, Staton KD, Harding JJ, Mellinghoff IK, et al. Pharmacokinetic Assessment of (18)F-(2S,4R)-4-Fluoroglutamine in Patients with Cancer. J Nucl Med 2020 Mar;61(3):357-366
  66. 66.Faubert B, Solmonson A, DeBerardinis RJ. Metabolic reprogramming and cancer progression. Science 2020 Apr 10;368(6487):eaaw5473. doi: 10.1126/science.aaw5473

Written By

Ionica Masgras and Andrea Rasola

Submitted: May 21st, 2021Reviewed: June 1st, 2021Published: August 16th, 2021