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Table of Contents
Year : 2020  |  Volume : 3  |  Issue : 4  |  Page : 154-161

Mechanisms of cell competition in glioblastoma: A narrative review

1 Department of Molecular Reproduction Development and Genetics, Indian Institute of Science, Bengaluru, Karnataka, India
2 Department of Neuropathology, National Institute of Mental Health and Sciences, Bengaluru, Karnataka, India

Date of Submission02-Dec-2020
Date of Decision16-Dec-2020
Date of Acceptance30-Dec-2020
Date of Web Publication1-Feb-2021

Correspondence Address:
Prof. Paturu Kondaiah
Department of Molecular Reproduction Development and Genetics, Indian Institute of Science, Bengaluru, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_29_20

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Cell competition among neighboring cells in a tissue gauges relative fitness in terms of growth and proliferation, which results in the death of cells with suboptimal fitness and the dominance of optimally or supraoptimally fit cells. It is conserved across multiple taxa and has indispensable functions in development, homeostasis, aging, and prevention of neoplastic growth, both in Drosophila and mammals. However, similar to how several key developmental pathways are subverted in cancer, cell competition mechanisms are often co-opted in the oncogenic transformation of cells in homeostatically stable tissues, and the role of this phenomenon in human cancer is attracting increasing interest. Grade IV glioblastomas (GBMs) are the most aggressive brain tumors that occur in adults. GBMs arise from glial cells and invariably result in tumor recurrence and death. Treatment of GBMs is complicated by the unique features of the anatomical context, including the dura, blood–brain barrier, glioma stem cells, necrosis, and extensive genetic and epigenetic heterogeneity. In this review, we discuss the evidence for cell competition elicited by genomic alterations in several key genes involved in early or late gliomagenesis, as well as activation of specific signaling pathways that aid competitive interactions with nonglial cell types like neurons to gain leverage in the colonization of brain niches. The role of intratumoral heterogeneity in conferring clonal dominance or cooperation resulting in therapeutic resistance in GBMs is also discussed.

Keywords: Cellular-fitness, chemoresistance, glioma stem cells, radioresistance, tumoral heterogeneity

How to cite this article:
Kundu P, Santosh V, Kondaiah P. Mechanisms of cell competition in glioblastoma: A narrative review. Glioma 2020;3:154-61

How to cite this URL:
Kundu P, Santosh V, Kondaiah P. Mechanisms of cell competition in glioblastoma: A narrative review. Glioma [serial online] 2020 [cited 2023 Feb 3];3:154-61. Available from: http://www.jglioma.com/text.asp?2020/3/4/154/308487

  Introduction Top

Cell competition is an intriguing phenomenon that occurs in multicellular organisms in microenvironments containing cells with different levels of relative fitness. First discovered in 1975 by Morata and Ripoll in Drosophila melanogaster,[1] cell competition has since been shown to be conserved from insects to mammals and is indispensable in normal development, homeostasis, and the repair and regeneration of differentiated tissues. Cell competition is an important means of quality control and can eliminate cells that are neoplastic through induction of apoptosis; it, therefore, plays a major role in preventing neoplastic transformation, especially in epithelial cells. However, cell competition can also give rise to super-competitor cells with high relative fitness that have a proliferative advantage over wild-type cells, which results in their rapid spread throughout a tissue, while less-fit cells are eliminated by programmed cell death mechanisms such as apoptosis. Since the discovery of cell competition over 40 years ago, many genes have been identified that confer competitive advantages or disadvantages in complex tissue systems,[2] and Drosophila models have shown that aberrations in some key driver genes may initiate early events in tumorigenesis by exploiting competitive mechanisms.

The Minute gene, which encodes ribosomal proteins in Drosophila, influences cell competition. Homozygous Minute-/-mutants are nonviable, but heterozygotes are viable and characterized by delayed growth and small bristles, hence, the name “Minute.” In a mosaic background, wild-type cells with intact translation capability overtake heterozygotes and induce apoptosis in these cells, effectively “out-competing” them and undergoing compensatory proliferation to maintain near-normal tissue size [Figure 1]A. Thus, the mutant cells (“loser cells”) may survive if surrounded by other mutant cells but are eliminated in the presence of wild-type cells (“winner cells”). The proto-oncogene Drosophila myc (dMyc) is a core cell competition gene. dMyc-overexpressing clones proliferate quickly, at the expense of wild-type clones expressing basal levels of dMyc.[3],[4] This phenomenon is referred to as “super-competition,” as the mutant cells are the “winners,” while the wild-type cells are relatively less fit, and therefore, the “losers.” Super-competition is conferred by genes that have a positive impact on cellular anabolism, and dMyc was one of the first genes discovered to do so [Figure 1]B. Cell competition is, therefore, a type of cell–cell interaction that depends on the relative fitness of neighboring cells, rather than absolute fitness; its outcome is thus context dependent. In nonepithelial cells, this has interesting consequences. While single mutations are insufficient for complete oncogenic transformation, they may predispose cells to gain subsequent hits on their path to neoplastic transformation. This may confer a growth advantage to host cells at the expense of nearby cells and create “field cancerization.” Super-competitor cells offer fertile grounds for accumulating pro-proliferative aberrations and can be considered early events in carcinogenesis.[5]
Figure 1: Basics of cell competition. (A) Viable cells with suboptimal levels of fitness conferred by genetic or epigenetic anomalies may be eliminated through apoptosis or other cell death mechanisms. (B) A “super-competitor” phenotype results when wild-type cells are relatively less fit

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Glioblastomas (GBMs) are the most aggressive central nervous system tumors. Despite the application of multimodal treatment, the tumor almost always recurs. The median overall survival of patients undergoing therapy is 15 months, with a 2-year survival rate of 26%,[6] despite a huge surge in targeted therapies. GBMs are highly invasive locally but metastasize only rarely. They are characterized by extensive intratumoral heterogeneity (ITH), as the tumor undergoes nonneutral evolution[7] from its genesis to treatment, which means the tumor cells are under continuous clonal selection that enables them to adapt to the tumor microenvironment. During this rapid growth period, tumor cells rapidly outgrow the existing blood supply and start forming necrotic cores, which is another hallmark of GBMs. Necrosis is not only a consequence of tumor growth but also an active contributor to the disease's aggressiveness.[8],[9] Apart from the metabolic competition that leads to the rapid growth of specific tumor subclones, GBMs also face crucial space constraints inside the brain because of the presence of other cell types, particularly neurons and nontransformed glial cells. Therefore, there are two forces that promote cell competition during early gliomagenesis: First, metabolic demand and second, competition for space elicited by rapid tumor growth. Recurrent GBMs are typically chemo- and radiation-resistant. In this second phase of the disease, unresectable tumor cells resist chemotherapy and ionizing radiation directed at the tumor bed. Several lines of evidence suggest that temozolomide and γ-irradiation induce differentiation and de-differentiation of glioma stem cells (GSCs), and thus promote tumor relapse by exerting a selective pressure that leads to therapeutic resistance.[10],[11],[12] Therefore, GBMs typically do not stop evolving, and in the late stages of gliomagenesis, somatic mutations and genetic aberrations at the subclonal level mediate cell competition and promote the clonal dominance of tumor cells that are equipped with the most effective resistance and salvage mechanisms.

In this review, we discuss relevant examples of cell competition in a central nervous system cancer, glioblastoma, an intractable form of malignant and aggressive brain tumor in adults that has very few effective treatment options and is associated with poor survival. We discuss how the unique nature of GBMs confers novel opportunities in terms of cell competition throughout the course of disease progression.

  Database Search Strategy Top

We performed an electronic literature search in Google Scholar and PubMed. For initially screening the articles we searched the databases using the terms “competition + glioblastoma,” “competitive advantage + glioblastoma,” or “proliferative advantage + glioblastoma,” as well as “competition + glioblastoma + gene name” where gene name is the gene of interest, for genes which are already known to mediate cell competition in either Drosophila or other human cancers. Next, we evaluated the suitability and context of the evidence in GBMs. We also scanned the reference lists of the important articles for identifying other relevant and potentially useful studies. While ~65% of articles date from 2010 to 2020, we have included older, pioneering articles on cell competition and articles describing cell competition mediated by glioblastoma driver genes such as p53 or epidermal growth factor receptor (EGFR) based on their relevance.

  Dysregulation of Key Genetic Pathways Confers Competitive Advantages to Aberrant Cells Top

Competitive regulation of cellular fitness that translates into a growth advantage in a particular cellular milieu can be achieved through either transcriptional control or metabolic control [Figure 2]A.[13] Transcriptional reprogramming and metabolic regulation of fitness are commonly achieved through accelerating the rates of glycolysis, protein synthesis, and mitochondrial activity, often at the expense of cells that fail to activate such pathways.[13] In the following section, the evidence for such mechanisms in gliomagenesis is discussed.
Figure 2: Cell competition at different stages of gliomagenesis. (A) I - In the early stages of liomagenesis, aberrations in driver genes can also confer a "super-competitor" phenotype that mediates key stages of transformation by enabling these cells to outcompete wild-type cells. Such semi-transformed cells with proliferative advantages form a small pool of premalignant cells. II - Super-competitor cells with enhanced metabolic control may outcompete nontransformed cells of similar or different types to leverage tumor growth.
(B) A well-formed heterogeneous tumor contains several clonal populations with different levels of fitness. Clones that exhibit maximal fitness in response to the genotoxic environment created by therapeutic insults are selected and subsequently expanded on therapy withdrawal. EGFR: Epidermal growth factor receptor, TERT: Telomerase reverse transcriptase, YAP: Yes-associated protein

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The role of P53 in cell competition is as diverse and context dependent as it is in cancer. P53 regulates a myriad of genes that are involved in cell-autonomous control of cell death and cell-extrinsic mechanisms of cell competition.[14] In multipotent neural stem cells, deletion of the DNA-binding domain of wild-type p53 does not confer a significant growth advantage per se, but stimulates a cascade of genetic aberrations, as the accumulation of mutant p53 protein leads to oncogenic events such as receptor tyrosine kinase (RTK)/MAPK mutation, activation of PDGFR signaling, and PTEN deletion. Cells that have been altered in these ways, which are referred to as nestin+-transformed cells, are found abutting the subventricular zone (SVZ) and give rise to high-grade gliomas.[15] The “guardian” effect of p53 can be nullified by amplification/deletion of ARF/MDM2/MDM4 or by inactivating/gain-of-function mutations in its DNA-binding domain. Deletion of tumor-suppressor genes (like PTEN) in a p53null background confers a distinct growth advantage and a super-competitor phenotype to cells that is sufficient to induce high-grade gliomas.[16],[17] In gliomas, p53 dysregulation primarily occurs because of missense or gain-of-function mutations, instead of extensive gene deletion. Clonal expansion of p53 mutant cells during progression from low-grade GBM to high-grade GBM has been documented.[18],[19] In one patient, 8% of cells in low-grade GBM had one mutant and one wild-type allele, while both alleles were mutated in 95% of cells in high-grade GBM, which suggests that the critical growth advantage of the mutant subpopulation was conferred by mutation of p53 codon 273, making this the dominant cell type.[18] Different mutated forms of p53 can be constitutively active, exhibit loss of function or gain of function, or act as a dominant negative over wild-type p53, and have an overwhelming impact on oncogenesis by upregulating c-myc, EGFR, multidrug resistance 1, insulin growth factor receptors, and other pro-oncogenic factors.[14] Among these, the roles of c-myc and EGFR in mediating super-competition are well documented and are discussed below.


The proto-oncogene c-myc is a master regulator of cell competition.[3],[20] In GBMs, RNA in situ hybridization indicated large amounts of c-myc RNA along tumor margins bordering necrotic areas,[21] and in a transgenic mouse model of astrocytoma c-myc-overexpressing astroglia formed foci of neoplastic cells mixed with slower-growing bystander cells.[22] c-myc is also commonly amplified in GBM cells carrying double-minute chromosomes[23] and lies downstream of Yes-associated protein (YAP) (Yki in Drosophila),[24] another key gene regulating cellular fitness. Such evidence suggests that super-competition induced by c-myc overexpression plays a vital role in glial transformation. Apart from promoting increased growth by accelerating anabolism, c-myc also dictates metabolic reprogramming in GBMs by increasing glycolytic flux.[25] c-myc transactivates the lactate dehydrogenase-A gene,[26] enabling hypoxic cells to engage in anaerobic glycolysis, and is highly expressed in glioblastoma tumor cores.[27] c-myc maintains CD133 + GSCs.[28] Brain tumor-initiating cells, a term that is used interchangeably with GSCs, are characterized by CD15 + CD133 + cells and also deploy c-myc to activate de novo purine biosynthesis[29] and meet DNA and RNA synthesis demands. Brain tumor-initiating cells depend on the mevalonate pathway for the synthesis of cholesterol and coenzyme Q synthesis, as well as metabolites essential for activation of the Ras pathway. cMyc and mevalonate transactivate each other through a positive feedback loop;[30] therefore, mevalonate connects the Myc and Ras pathways. Thus, cMyc is a central regulator of metabolism that can impart survival advantages in various ways.


Single-cell-based studies suggest that not only is wild-type EGFR often amplified in GBMs but that 89% of cells also carry mutually exclusive EGFRvII and EGFR vIII variants in different clonal populations.[31] Consistent with such reports, immunohistochemistry data have shown heterogeneous expression of EGFR deletion mutants such as EGFRvIII in cells adhering to the tumor vasculature in glioblastoma specimens.[32] EGFRvIII, unlike wild-type EGFR, is constitutively phosphorylated and is more tumorigenic than wild-type EGFR in vivo, leading to the rapid development of large intracranial tumors due to the dramatic growth advantage that it confers.[33] In a phenomenon reminiscent of cell competition, these mutant cells clonally expand and dominate the entire tumor, even when seeded at extremely limiting ratios of 1:50,000 with wild-type EGFR expressing cells.[34] These cells can proliferate during prolonged serum starvation and delay apoptosis by upregulating Bcl-xL.[34] Theoretically, this type of oncogene addiction could be targeted with specific inhibitors, though practically this approach does not work, as GBMs harbor mutant copies of EGFR on extrachromosomal double minute chromosomes[35] that can be shed into the cellular microenvironment and picked up by other cells, leading to the re-emergence of mutant EGFR clones and the rise of new resistant populations after drug withdrawal. EGFR variant heterogeneity in GBMs and its intricate relationship with drug resistance is well-documented.[31],[35] Given that EGFR activates the MAPK, PI3K/Akt, JAK/STAT, and PKC pathways and mitochondrial COXII, it is clear that EGFR influences all aspects of cell survival.[36] While EGFR dysregulation alone only leads to benign hyperplasia, when coupled with another oncogenic insult, it can transform cells into super competitors that induce apoptosis of wild-type cells through upregulation of c-myc.[37] Constitutive EGFR activation, therefore, enables genetically aberrant cells to proliferate unchecked, and later, telomerase reverse transcriptase (TERT) activation leads to immortalization.


Yorkie (Yki), the Drosophila homolog of YAP, induces cell competition in Drosophila imaginal discs by regulating dMyc transcription.[24] An intricate, codependent transcriptional and posttranscriptional negative feedback network involving dMyc and Yki has been reported to coordinate organ size and growth control in Drosophila.[38] Both c-myc and YAP are aberrantly expressed in cancer cells,[39] suggesting that this control is lost. In GBM, YAP expression differs significantly across different clones from the same tumor.[40] Monolayer and spheroid co-culture of clones expressing different levels of YAP showed that clones expressing more YAP consistently dominated and outgrew clones with lower/negligible YAP levels, which ultimately underwent apoptosis.[40]

Wnt pathway

Wnt pathway genes are not frequently mutated in GBM.[41] Instead, epigenetic dysregulation of soluble frizzled-related proteins has been reported in GBMs.[42] The Wnt pathway is activated in GBMs through various noncanonical pathways that utilize ROR2 as a coreceptor instead of LRP5/6.[43] GSCs isolated from primary GBMs have been documented to be a heterogeneous mix of Wnthigh and Wntlow cells, which differ in their clonogenic capacity.[44] c-myc is a crucial Wnt target gene that, when activated, can transform GBM cells into super-competitors despite the absence of Axin or APC mutations. Wnt ligands have been reported to be sequestered from the tumor microenvironment by glioma microtubes in Drosophila gliomas.[45] Therefore, Wnt pathway activation can confer clonal dominance through a variety of mechanisms.


Many rapidly growing tumors, including GBMs, require telomerase activity to achieve replicative immortality and delay senescence. TERT promoter mutations (C228T and C250T) are the most prevalent mutations associated with altered telomerase activity in GBMs and occur in 75%–83% of all de novo GBMs.[46] About 25% of GBMs also take advantage of the alternative lengthening of telomeres mechanism,[47] mediated by mutations in the ATRX/DAXX genes, to maintain telomere length. Either way, telomerase expansion increases the effective number of population doublings, creates proliferative advantage, and imparts both genomic and chromosomal instability to cells, which increases genetic and epigenetic heterogeneity. The mutual exclusivity of TERT promoter mutations and ATRX mutations in GBMs, coupled with the fact that neural stem/glial progenitor cells are slow-cycling cells, suggests that telomerase reactivation in these cells is a prerequisite for rapid growth and can be achieved functionally by such redundant mechanisms.[48] Recent studies have suggested an unexplored role for TERT promoter mutations in early gliomagenesis. In the tumor-free SVZ of the hippocampus in GBM patients, low-level TERT promoter driver mutations have been reported at a frequency ranging from 1% to 6%. In these patients, a high frequency of TERT mutation (22%–52%) was observed in the tumor mass, separate from the SVZ.[49] Thus, TERT mutation in slow-cycling neural stem cells of the SVZ could be an early genetic aberration that delays replicative senescence until other somatic driver mutations occur in genes such as EGFR, PTEN, or p53 genes.[49] This is corroborated by evidence suggesting that TERT promotes tumorigenesis in two distinct phases:[50] first, by repairing critically short telomeres enough to prevent replicative senescence, without preventing telomeric fusion; and second, increasing telomerase expression because of the genomic instability that results from maintaining these short telomeres, as well as begetting new driver mutations. Thus, the increased telomerase expression induced by TERT promoter mutation or other mechanisms could confer a competitive advantage to both IDH mutant and wild-type GBM cells when combined with predisposing driver mutations. In primary fibroblasts, a growth advantage was conferred by artificial overexpression of TER (the RNA component of TERT) or TERT.[51] Extratelomeric roles for telomerase include telomerase-mediated activation of Wnt signaling in embryonic stem cells through interaction with the β-catenin transcriptional complex.[52] Given the high prevalence of TERT promoter mutations and alternative lengthening of telomeres in GBMs, it is plausible that this type of mechanism gives telomerase-expressing cells an additional competitive advantage by activating the Wnt pathway.

Insulin growth factor binding proteins and signal transducer and activator of transcription

Insulin-like growth factor-binding proteins (IGFBPs) are proteins that bind IGFs 1 and 2 in a context-dependent manner in many cancers, based on the presence or absence of the canonical IGF ligands. IGFBPs also have noncanonical IGF-independent functions that are largely pro-tumorigenic in GBMs.[53],[54] IGFBP3 emerged as a strong predictor of survival in multivariate analyses, along with patient age. IGFBP3 was also found to regulate STAT1 protein expression in gliomas,[55] and immunohistochemistry data confirmed heterogeneous STAT1 expression in tumor cells, along with nuclear STAT1 positivity in perivascular tumor cells.[55] Palisading perinecrotic cells were found to stain strongly for IGFBP2, along with tumor cells.[56] In Drosophila, activated STAT has been documented to confer super-competitor status to cells, leading to the induction of apoptosis in cells with lower STAT expression levels.[57],[58] Unlike STAT1, whose functions are context dependent, STAT3 is uniformly pro-tumorigenic in GBMs.[59] Interestingly, IGFBP2 also regulates STAT3 through EGFR,[60] which suggests that the IGFBP-STAT nexus has uncharacterized roles in cell competition in perivascular and other zones in GBMs.

Cell competition between glioma cells and neurons or nontransformed astrocytes

GBMs face space constraints due to rapid growth and engage in metabolic competition with neurons. Astrocytes are adept at glutamate absorption, whereas glioma cells release large amounts of glutamate into their niche. The released glutamate is excitotoxic to neurons and microglial cells, and eliminates them,[61] freeing up space. In addition, AMPA receptors are activated by glutamate, thereby activating the pro-proliferative AKT/MAPK pathway.[62] Glioblastoma cells create glioma-to-neuron synapses that utilize potassium currents to enhance their growth,[63] which may explain the presence of perineuronal Scherer's structures in GBMs. TGFβ inhibits the protective activity of glutamine synthetase in peritumoral nontransformed astrocytes, thus affecting astrocytes as much as neurons.[64] In a Drosophila model of glioma, tumor microtubes enwrapped neurons in “peri-neuronal nests” and accumulate frizzled receptors, which sequester Wnt ligands from neurons, leading to enhanced glioma growth and neuronal death.[45] This process, causing neurodegeneration, has been aptly termed “vampirization,” and activates the JNK pathway to upregulate MMP1/2 in glioma cells, further promoting invasion in a positive feedback loop [Figure 2]B.[45]

Intratumoral heterogeneity (ITH) in glioblastomas

ITH is a hallmark of aggressive solid tumors and provides a backdrop for tumor evolution to enable “survival of the fittest” clones, as well as a ready repertoire of clones that have varying fitness with regard to resisting the genotoxic insults inflicted by chemo- and radiotherapy [Figure 2]B. Super-competition among transformed clones increases tumor aggressiveness by maintaining a pool of cells that are intrinsically resistant to therapy. Therefore, therapeutic resistance and genomic instability/mutations are two sides of the same coin. Super-competition-induced ITH is an extension of clonal evolution of tumor theory, first proposed by Nowell,[65] which posited that Darwinian fitness at the cellular level selects cells with maximal fitness at each stage of cancer development and treatment. This is also consistent with the nonneutral mode of tumor evolution found in GBM.[7] Nonneutral malignancies are constantly under selective pressure that give rise to phenotypically and molecularly distinct subclones. Identification of multiple molecular subtypes in the same tumor mass supports this hypothesis.[66] Subclonal differences in driver alterations in RTK such as EGFR, PDGFRa, and MET have been reported in GBMs,[67] which hints at redundancy in RTK pathways and provides a possible explanation for targeted therapy failure. These subclones exist as a mixed population in the tumor core but are enriched (EGFR-amplified) in niches like the invasive edge. Near-identical fitness of such subclones[67] may explain their coexistence, and their heterogeneity could impart therapeutic resistance against a variety of specific RTK inhibitors. ITH in terms of wild-type EGFR and EGFRvIII (ΔEGFR) also activated the AKT, MAPK, and STAT pathways to potentiate tumor growth in a cellular cross-talk model.[68]

During the generation of therapeutic resistance, ITH elicits cell competition among different clonal populations of the same glial tumor. This is, however, distinct from competition between glial tumor cells and nontumor glial cells as well as neurons, which is primarily generated by space constraints faced by the rapidly growing mass of the tumor.

  Future Perspectives Top

The findings reviewed above suggest a previously unappreciated role for cell competition in gliomagenesis
Figure 3: Signaling pathways relevant to cell competition in glioblastoma. Key mitogenic pathways interact with each other to determine cell fitness-based outcomes. p53, c-myc, and EGFR act as hubs that integrate fitness-specific responses. AKT: Protein kinase B, AMPA: a-amino-3-hydroxy-5-meth yl-4-isoxazole propionic acid, COXII: Cyclooxygenase II, EGFR: Epidermal growth factor receptor, Glut: Glucose transporter, IGF: Insulin-like growth factor, IGFBP: Insulin-like growth factor binding protein, JNK/STAT: Janus kinase/signal transducer and activator of transcription, K+: Potassium, MAPK: Mitogen-activated protein kinase, MDR: Multidrug resistance, MMP: Matrix metalloproteinase, PI3K: Phosphoinositide 3-kinase, PKC: Protein kinase C, TCF/LEF: T-cell factor/lymphoid enhancer factor, TEAD: TEA domain family member, YAP/TAZ: Yes-associated protein/transcriptional coactivator with PDZ-binding motif

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[Figure 3]. Pioneering experiments in cell competition were performed in Drosophila models, which continue to be useful in vivo genetic system for studying the mechanisms of cell competition in brain tumors. In vitro cell culture models do not incorporate tissue-level heterogeneity in terms of fitness or genetic/epigenetic makeup. While these techniques allow researchers to quantify cell-autonomous behavior and are indispensable for identifying driver genes and pathways, noncell-autonomous interactions with the tumor microenvironment and stroma are not addressed by such approaches. To address this, co-culture systems of fluorophore-tagged clones expressing different amounts of gene-of-interest or mutated versions of genes should be utilized to investigate competitive outgrowth conferred by pro-tumorigenic genes. Approaches as these would accommodate the inherent heterogeneity of GBMs and hence are better disease models as they reveal variants (like extrachromosomal mutant EGFR) that have difficult-to-predict roles in tumor progression and therapeutic resistance.{Figure 3}

Financial support and sponsorship

P. Kundu received fellowship from the Indian Institute of Science. P. Kondaiah is a recipient of fellowship from the Indian National Science Academy. P. Kondaiah and V. Santosh received grants from the Department of Biotechnology, Government of India.

Conflicts of interest

There are no conflicts of interest.

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