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Metabolic reprogramming enables cancer cell growth, proliferation, and survival. This reprogramming is driven by the combined actions of oncogenic alterations in cancer cells and host cell factors acting on cancer cells in the tumor microenvironment. Cancer cell-intrinsic mechanisms activate signal transduction components that either directly enhance metabolic enzyme activity or upregulate transcription factors that in turn increase expression of metabolic regulators. Extrinsic signaling mechanisms involve host-derived factors that further promote and amplify metabolic reprogramming in cancer cells. This review describes intrinsic and extrinsic mechanisms driving cancer metabolism in the tumor microenvironment and how such mechanisms may be targeted therapeutically. SIGNIFICANCE: Cancer cell metabolic reprogramming is a consequence of the converging signals originating from both intrinsic and extrinsic factors. Intrinsic signaling maintains the baseline metabolic state, whereas extrinsic signals fine-tune the metabolic processes based on the availability of metabolites and the requirements of the cells. Therefore, successful targeting of metabolic pathways will require a nuanced approach based on the cancer's genotype, tumor microenvironment composition, and tissue location., (©2021 American Association for Cancer Research.)

Cancer immunotherapy has made remarkable advances with over 50 separate Food and Drug Administration (FDA) approvals as first- or second-line indications since 2015. These include immune checkpoint blocking antibodies, chimeric antigen receptor-transduced T cells, and bispecific T-cell-engaging antibodies. While multiple cancer types now benefit from these immunotherapies, notable exceptions thus far include brain tumors, such as glioblastoma. As such, it seems critical to gain a better understanding of unique mechanistic challenges underlying the resistance of malignant gliomas to immunotherapy, as well as to acquire insights into the development of future strategies. An Immuno-Oncology Think Tank Meeting was held during the 2019 Annual Society for Neuro-Oncology Scientific Conference. Discussants in the fields of neuro-oncology, neurosurgery, neuro-imaging, medical oncology, and cancer immunology participated in the meeting. Sessions focused on topics such as the tumor microenvironment, myeloid cells, T-cell dysfunction, cellular engineering, and translational aspects that are critical and unique challenges inherent with primary brain tumors. In this review, we summarize the discussions and the key messages from the meeting, which may potentially serve as a basis for advancing the field of immune neuro-oncology in a collaborative manner., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Cancer stem cells (CSCs) are self-renewing cells that facilitate tumor initiation, promote metastasis, and enhance cancer therapy resistance. Transcriptomic analyses across many cancer types have revealed a prominent association between stemness and immune signatures, potentially implying a biological interaction between such hallmark features of cancer. Emerging experimental evidence has substantiated the influence of CSCs on immune cells, including tumor-associated macrophages, myeloid-derived suppressor cells, and T cells, in the tumor microenvironment and, reciprocally, the importance of such immune cells in sustaining CSC stemness and its survival niche. This review covers the cellular and molecular mechanisms underlying the symbiotic interactions between CSCs and immune cells and how such heterotypic signaling maintains a tumor-promoting ecosystem and informs therapeutic strategies intercepting this co-dependency., Competing Interests: Declaration of Interests R.A.D. is a co-founder, advisor, and director of Tvardi Therapeutics focused on the development of STAT3 inhibitors. R.A.D. is also co-founder and advisor of Asylia Therapeutics, Nirogy Therapeutics, and Stellanova Therapeutics. The other authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Inhibiting glycolysis remains an aspirational approach for the treatment of cancer. We have previously identified a subset of cancers harbouring homozygous deletion of the glycolytic enzyme enolase (ENO1) that have exceptional sensitivity to inhibition of its redundant paralogue, ENO2, through a therapeutic strategy known as collateral lethality. Here, we show that a small-molecule enolase inhibitor, POMHEX, can selectively kill ENO1-deleted glioma cells at low-nanomolar concentrations and eradicate intracranial orthotopic ENO1-deleted tumours in mice at doses well-tolerated in non-human primates. Our data provide an in vivo proof of principle of the power of collateral lethality in precision oncology and demonstrate the utility of POMHEX for glycolysis inhibition with potential use across a range of therapeutic settings.

Metabolic reprograming is an emerging hallmark of tumor biology and an actively pursued opportunity in discovery of oncology drugs. Extensive efforts have focused on therapeutic targeting of glycolysis, whereas drugging mitochondrial oxidative phosphorylation (OXPHOS) has remained largely unexplored, partly owing to an incomplete understanding of tumor contexts in which OXPHOS is essential. Here, we report the discovery of IACS-010759, a clinical-grade small-molecule inhibitor of complex I of the mitochondrial electron transport chain. Treatment with IACS-010759 robustly inhibited proliferation and induced apoptosis in models of brain cancer and acute myeloid leukemia (AML) reliant on OXPHOS, likely owing to a combination of energy depletion and reduced aspartate production that leads to impaired nucleotide biosynthesis. In models of brain cancer and AML, tumor growth was potently inhibited in vivo following IACS-010759 treatment at well-tolerated doses. IACS-010759 is currently being evaluated in phase 1 clinical trials in relapsed/refractory AML and solid tumors.

We are in the midst of a technological revolution that is providing new insights into human biology and cancer. In this era of big data, we are amassing large amounts of information that is transforming how we approach cancer treatment and prevention. Enactment of the Cancer Moonshot within the 21st Century Cures Act in the USA arrived at a propitious moment in the advancement of knowledge, providing nearly US$2 billion of funding for cancer research and precision medicine. In 2016, the Blue Ribbon Panel (BRP) set out a roadmap of recommendations designed to exploit new advances in cancer diagnosis, prevention, and treatment. Those recommendations provided a high-level view of how to accelerate the conversion of new scientific discoveries into effective treatments and prevention for cancer. The US National Cancer Institute is already implementing some of those recommendations. As experts in the priority areas identified by the BRP, we bolster those recommendations to implement this important scientific roadmap. In this Commission, we examine the BRP recommendations in greater detail and expand the discussion to include additional priority areas, including surgical oncology, radiation oncology, imaging, health systems and health disparities, regulation and financing, population science, and oncopolicy. We prioritise areas of research in the USA that we believe would accelerate efforts to benefit patients with cancer. Finally, we hope the recommendations in this report will facilitate new international collaborations to further enhance global efforts in cancer control., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Synthetic lethality and collateral lethality are two well-validated conceptual strategies for identifying therapeutic targets in cancers with tumour-suppressor gene deletions. Here, we explore an approach to identify potential synthetic-lethal interactions by screening mutually exclusive deletion patterns in cancer genomes. We sought to identify 'synthetic-essential' genes: those that are occasionally deleted in some cancers but are almost always retained in the context of a specific tumour-suppressor deficiency. We also posited that such synthetic-essential genes would be therapeutic targets in cancers that harbour specific tumour-suppressor deficiencies. In addition to known synthetic-lethal interactions, this approach uncovered the chromatin helicase DNA-binding factor CHD1 as a putative synthetic-essential gene in PTEN-deficient cancers. In PTEN-deficient prostate and breast cancers, CHD1 depletion profoundly and specifically suppressed cell proliferation, cell survival and tumorigenic potential. Mechanistically, functional PTEN stimulates the GSK3β-mediated phosphorylation of CHD1 degron domains, which promotes CHD1 degradation via the β-TrCP-mediated ubiquitination-proteasome pathway. Conversely, PTEN deficiency results in stabilization of CHD1, which in turn engages the trimethyl lysine-4 histone H3 modification to activate transcription of the pro-tumorigenic TNF-NF-κB gene network. This study identifies a novel PTEN pathway in cancer and provides a framework for the discovery of 'trackable' targets in cancers that harbour specific tumour-suppressor deficiencies.

Critically short telomeres activate cellular senescence or apoptosis, as mediated by the tumor suppressor p53, but in the absence of this checkpoint response, telomere dysfunction engenders chromosomal aberrations and cancer. Here, analysis of p53-regulated genes activated in the setting of telomere dysfunction identified Zfp365 (ZNF365 in humans) as a direct p53 target that promotes genome stability. Germline polymorphisms in the ZNF365 locus are associated with increased cancer risk, including those associated with telomere dysfunction. On the mechanistic level, ZNF365 suppresses expression of a subset of common fragile sites, including telomeres. In the absence of ZNF365, defective telomeres engage in aberrant recombination of telomere ends, leading to increased telomere sister chromatid exchange and formation of anaphase DNA bridges, including ultra-fine DNA bridges, and ultimately increased cytokinesis failure and aneuploidy. Thus, the p53-ZNF365 axis contributes to genomic stability in the setting of telomere dysfunction.

The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.

Myriad genetic and epigenetic alterations are required to drive normal cells toward malignant transformation. These somatic events commandeer many signaling pathways that cooperate to endow aspiring cancer cells with a full range of biological capabilities needed to grow, disseminate and ultimately kill its host. Cancer genomes are highly rearranged and are characterized by complex translocations and regional copy number alterations that target loci harboring cancer-relevant genes. Efforts to uncover the underlying mechanisms driving genome instability in cancer have revealed a prominent role for telomeres. Telomeres are nucleoprotein structures that protect the ends of eukaryotic chromosomes and are particularly vulnerable due to progressive shortening during each round of DNA replication and, thus, a lifetime of tissue renewal places the organism at risk for increasing chromosomal instability. Indeed, telomere erosion has been documented in aging tissues and hyperproliferative disease states-conditions strongly associated with increased cancer risk. Telomere dysfunction can produce the opposing pathophysiological states of degenerative aging or cancer with the specific outcome dictated by the integrity of DNA damage checkpoint responses. In most advanced cancers, telomerase is reactivated and serves to maintain telomere length and emerging data have also documented the capacity of telomerase to directly regulate cancer-promoting pathways. This review covers the role of telomeres and telomerase in the biology of normal tissue stem/progenitor cells and in the development of cancer.

Somatically acquired epigenetic changes are present in many cancers. Epigenetic regulation is maintained via post-translational modifications of core histones. Here, we describe inactivating somatic mutations in the histone lysine demethylase gene UTX, pointing to histone H3 lysine methylation deregulation in multiple tumor types. UTX reintroduction into cancer cells with inactivating UTX mutations resulted in slowing of proliferation and marked transcriptional changes. These data identify UTX as a new human cancer gene.

Activating mutations in the ras oncogene are not considered sufficient to induce abnormal cellular proliferation in the absence of cooperating oncogenes. We demonstrate that the conditional expression of an endogenous K-ras(G12D) allele in murine embryonic fibroblasts causes enhanced proliferation and partial transformation in the absence of further genetic abnormalities. Interestingly, K-ras(G12D)-expressing fibroblasts demonstrate attenuation and altered regulation of canonical Ras effector signaling pathways. Widespread expression of endogenous K-ras(G12D) is not tolerated during embryonic development, and directed expression in the lung and GI tract induces preneoplastic epithelial hyperplasias. Our results suggest that endogenous oncogenic ras is sufficient to initiate transformation by stimulating proliferation, while further genetic lesions may be necessary for progression to frank malignancy.

Mounting genetic evidence suggests that each product of the Ink4a/Arf locus, p16(INK4a) and p19(ARF), possesses tumor-suppressor activity (Kamijo et al., 1997; Krimpenfort et al., 2001; Sharpless et al., 2001a). We report the generation and characterization of a p19(ARF)-specific knockout allele (p19(ARF)-/-) and direct comparison with mice and derivative cells deficient for p16(INK4a), both p16(INK4a) and p19(ARF), and p53. Like Ink4a/Arf-/- murine embryo fibroblasts (MEFs), p19(ARF)-/- MEFs were highly susceptible to oncogenic transformation, exhibited enhanced subcloning efficiency at low density, and resisted both RAS- and culture-induced growth arrest. In contrast, the biological profile of p16(INK4a)-/- MEFs in these assays more closely resembled that of wild-type cells. In vivo, however, both p19(ARF)-/- and p16(INK4a)-/- animals were significantly more tumor prone than wild-type animals, but each less so than p53-/- or Ink4a/Arf-/- animals, and with differing tumor spectra. These data confirm the predominant role of p19(ARF) over p16(INK4a) in cell culture-based assays of MEFs, yet also underscore the importance of the analysis of tumor suppressors across many cell types within the organism. The cancer-prone conditions of mice singly deficient for either p16(INK4a) or p19(ARF) agree with data derived from human cancer genetics, and reinforce the view that both gene products play significant and nonredundant roles in suppressing malignant transformation in vivo.

Mammalian aging occurs in part because of a decline in the restorative capacity of tissue stem cells. These self-renewing cells are rendered malignant by a small number of oncogenic mutations, and overlapping tumor suppressor mechanisms (e.g., p16(INK4a)-Rb, ARF-p53, and the telomere) have evolved to ward against this possibility. These beneficial antitumor pathways, however, appear also to limit the stem cell life span, thereby contributing to aging.

The analysis of compound mouse mutants for nonhomologous end-joining DNA double-strand break repair and those deficient for the p53 checkpoint pathway has provided a fascinating look at the carcinogenic consequences of the failure to properly repair DNA damage and to elicit appropriate checkpoints.

We have used large-scale insertional mutagenesis to identify functional landmarks relevant to cancer in the recently completed mouse genome sequence. We infected Cdkn2a(-/-) mice with Moloney murine leukemia virus (MoMuLV) to screen for loci that can participate in tumorigenesis in collaboration with loss of the Cdkn2a-encoded tumor suppressors p16INK4a and p19ARF. Insertional mutagenesis by the latent retrovirus was synergistic with loss of Cdkn2a expression, as indicated by a marked acceleration in the development of both myeloid and lymphoid tumors. We isolated 747 unique sequences flanking retroviral integration sites and mapped them against the mouse genome sequence databases from Celera and Ensembl. In addition to 17 insertions targeting gene loci known to be cancer-related, we identified a total of 37 new common insertion sites (CISs), of which 8 encode components of signaling pathways that are involved in cancer. The effectiveness of large-scale insertional mutagenesis in a sensitized genetic background is demonstrated by the preference for activation of MAP kinase signaling, collaborating with Cdkn2a loss in generating the lymphoid and myeloid tumors. Collectively, our results show that large-scale retroviral insertional mutagenesis in genetically predisposed mice is useful both as a system for identifying genes underlying cancer and as a genetic framework for the assignment of such genes to specific oncogenic pathways.

Telomere dysfunction and associated fusion-breakage in the mouse encourages epithelial carcinogenesis and a more humanized genomic profile that includes nonreciprocal translocations (NRTs). Here, array comparative genomic hybridization was used to determine the pathogenic significance of NRTs and to determine whether telomere dysfunction also drives amplifications and deletions of cancer-relevant loci. Compared to tumors arising in mice with intact telomeres, tumors with telomere dysfunction possessed higher levels of genomic instability and showed numerous amplifications and deletions in regions syntenic to human cancer hotspots. These observations suggest that telomere-based crisis provides a mechanism of chromosomal instability, including regional amplifications and deletions, that drives carcinogenesis. This model provides a platform for discovery of genes responsible for the major cancers affecting aged humans.

Cancer is a disease of impaired genome stability. The molecular forces that maintain genome integrity and sense altered chromosome structure are invariably subverted in cancer cells. Here, we explore the contrasting contributions of telomeres in the initiation and suppression of cancer and review the evidence supporting a role for telomere dysfunction as a mechanism driving the radical chromosomal aberrations that typify cancer genomes. Recent work suggests that passage of cells through crisis in the setting of deactivated DNA damage checkpoints provides a mutational mechanism that can generate the diverse genetic alterations required for cancer initiation. A greater understanding of telomere-induced crisis and the cell's crisis management mechanisms should guide the rational development of new therapeutics for cancer and other disorders.

Dual inactivation of PTEN and INK4a/ARF tumor suppressor genes is a common feature observed in a broad spectrum of human cancer types. To validate functional collaboration between these genes in tumor suppression, we examined the biological consequences of Pten and/or Ink4a/Arf deficiency in cells and mice. Relative to single mutant controls, Ink4a/Arf-/-Pten+/- mouse embryonic fibroblast cultures exhibited faster rates of growth in reduced serum, grew to higher saturation densities, produced more colonies upon low density seeding, and showed increased susceptibility to transformation by oncogenic H-Ras. Ink4a/Arf deficiency reduced tumor-free survival and shortened the latency of neoplasias associated with Pten heterozygosity, specifically pheochromocytoma, prostatic intraepithelial neoplasia, and endometrial hyperplasia. Compound mutant mice also exhibited an expanded spectrum of tumor types including melanoma and squamous cell carcinoma. Functional synergy between Ink4a/Arf and Pten manifested most prominently in the development of pheochromocytoma, prompting an analysis of genes and loci implicated in this rare human neoplasm. The classical pheochromocytoma genes Ret, Vhl, and Nf-1 remained intact, a finding consistent with the intersection of these genes with pathways engaged by Pten and Ink4a/Arf. Notably, conventional and array-comparative genomic hybridization revealed frequent loss of distal mouse chromosome 4 in a region syntenic to human chromosome 1p that is implicated in human pheochromocytoma. This study provides genetic evidence of collaboration between Pten and Ink4a/Arf in constraining the growth and oncogenic transformation of cultured cells and in suppressing a wide spectrum of tumors in vivo.

The cyclin-dependent kinase inhibitor p16INK4a can induce senescence of human cells, and its loss by deletion, mutation or epigenetic silencing is among the most frequently observed molecular lesions in human cancer. Overlapping reading frames in the INK4A/ARF gene encode p16INK4a and a distinct tumour-suppressor protein, p19ARF (ref. 3). Here we describe the generation and characterization of a p16Ink4a-specific knockout mouse that retains normal p19Arf function. Mice lacking p16Ink4a were born with the expected mendelian distribution and exhibited normal development except for thymic hyperplasia. T cells deficient in p16Ink4a exhibited enhanced mitogenic responsiveness, consistent with the established role of p16Ink4a in constraining cellular proliferation. In contrast to mouse embryo fibroblasts (MEFs) deficient in p19Arf (ref. 4), p16Ink4a-null MEFs possessed normal growth characteristics and remained susceptible to Ras-induced senescence. Compared with wild-type MEFs, p16Ink4a-null MEFs exhibited an increased rate of immortalization, although this rate was less than that observed previously for cells null for Ink4a/Arf, p19Arf or p53 (refs 4, 5). Furthermore, p16Ink4a deficiency was associated with an increased incidence of spontaneous and carcinogen-induced cancers. These data establish that p16Ink4a, along with p19Arf, functions as a tumour suppressor in mice.

Telomerase inhibition has been touted as a novel cancer-selective therapeutic goal based on the observation of high telomerase levels in most cancers and the importance of telomere maintenance in long-term cellular growth and survival. Here, the impact of telomere dysfunction on chemotherapeutic responses was assessed in normal and neoplastic cells derived from telomerase RNA null (mTERC(-/-)) mice. Telomere dysfunction, rather than telomerase per se, was found to be the principal determinant governing chemosensitivity specifically to agents that induced double-stranded DNA breaks (DSB). Enhanced chemosensitivity in telomere dysfunctional cells was linked to therapy-induced fragmentation and multichromosomal fusions, whereas telomerase reconstitution restored genomic integrity and chemoresistance. Loss of p53 function muted the cytotoxic effects of DSB-inducing agents in cells with telomere dysfunction. Together, these results point to the combined use of DSB-inducing agents and telomere maintenance inhibition as an effective anticancer therapeutic approach particularly in cells with intact p53-dependent checkpoint responses.

A striking link exists between advanced age and increased incidence of cancer. Here I review how several of the age-related molecular and physiological changes might act in concert to promote cancer, and in particular epithelial carcinogenesis. Experimental data indicate that the aged, cancer-prone phenotype might represent the combined pathogenetic effects of mutation load, epigenetic regulation, telomere dysfunction and altered stromal milieu. Further verification of the role of these effects should in turn lead to the design of effective therapeutics for the treatment and prevention of cancer in the aged.

Unicellular organisms, human cells and mice have provided insights into the processes of senescence, crisis, genomic instability and cancer in humans. Here, Artandi and DePinho discuss how studies in mice have uncovered a complex interplay between the ARF-p53 pathway, genomic instability due to telomere dysfunction, and the suppression or promotion of cancer.

Progressive telomere shortening occurs with the division of primary human cells and activates tumor suppressor pathways, triggering senescence and inhibiting tumorigenesis. Loss of p53 function, however, allows continued cell division despite increasing telomere dysfunction and entry into telomere crisis. Recent data suggest that the severe chromosomal instability of telomere crisis promotes secondary genetic changes that facilitate carcinogenesis. Reactivation of telomerase stabilizes telomere ends and allows continued tumor growth.

Maintenance of telomere length is predicted to be essential for bypass of senescence and crisis checkpoints in cancer cells. The impact of telomere dysfunction on tumorigenesis was assessed in successive generations of mice doubly null for the telomerase RNA (mTR) and the INK4a tumor suppressor genes. Significant reductions in tumor formation in vivo and oncogenic potential in vitro were observed in late generations of telomerase deficiency, coincident with severe telomere shortening and associated dysfunction. Reintroduction of mTR into cells significantly restored the oncogenic potential, indicating telomerase activation is a cooperating event in the malignant transformation of cells containing critically short telomeres. The results described here demonstrate that loss of telomere function in a cancer-prone mouse model possessing intact DNA damage responses impairs, but does not prevent, tumor formation.

Maintenance of telomere length and function is critical for the efficient proliferation of eukaryotic cells. Here, we examine the interactions between telomere dysfunction and p53 in cells and organs of telomerase-deficient mice. Coincident with severe telomere shortening and associated genomic instability, p53 is activated, leading to growth arrest and/or apoptosis. Deletion of p53 significantly attenuated the adverse cellular and organismal effects of telomere dysfunction, but only during the earliest stages of genetic crisis. Correspondingly, the loss of telomere function and p53 deficiency cooperated to initiate the transformation process. Together, these studies establish a key role for p53 in the cellular response to telomere dysfunction in both normal and neoplastic cells, question the significance of crisis as a tumor suppressor mechanism, and identify a biologically relevant stage of advanced crisis, termed genetic catastrophe.

Functional inactivation of the retinoblastoma (RB) and p53 pathways appears to be a rite of passage for all cancerous cells and results in disruption of cell-cycle regulation and deactivation of the apoptotic response that normally ensues. The INK4a/ARF locus sits at the nexus of these two growth-control pathways, by virtue of its ability to generate two distinct products: the p16INK4a protein, a cyclin-dependent kinase inhibitor that functions upstream of RB; and the p19ARF protein, which blocks MDM2 inhibition of p53 activity. This 'one gene--two products--two pathways' arrangement provides a basis for the prominence of INK4a/ARF in tumorigenesis.

Mxi1 belongs to the Mad (Mxi1) family of proteins, which function as potent antagonists of Myc oncoproteins. This antagonism relates partly to their ability to compete with Myc for the protein Max and for consensus DNA binding sites and to recruit transcriptional co-repressors. Mad(Mxi1) proteins have been suggested to be essential in cellular growth control and/or in the induction and maintenance of the differentiated state. Consistent with these roles, mxi1 may be the tumour-suppressor gene that resides at region 24-26 of the long arm of chromosome 10. This region is a cancer hotspot, and mutations here may be involved in several cancers, including prostate adenocarcinoma. Here we show that mice lacking Mxi1 exhibit progressive, multisystem abnormalities. These mice also show increased susceptibility to tumorigenesis either following carcinogen treatment or when also deficient in Ink4a. This cancer-prone phenotype may correlate with the enhanced ability of several mxi1-deficient cell types, including prostatic epithelium, to proliferate. Our results show that Mxi1 is involved in the homeostasis of differentiated organ systems, acts as a tumour suppressor in vivo, and engages the Myc network in a functionally relevant manner.