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The CD58-CD2 axis regulates T cell-mediated cancer immunity, but little is known about the regulation of CD58. In two recent papers pubished in Cancer Cell , Miao et al. and Ho et al. define a mechanism of CD58 regulation by CMTM6 and show an unexpected yin-yang link between PD-L1 and CD58. The CD58-CD2 axis regulates T cell-mediated cancer immunity, but little is known about the regulation of CD58. In two recent papers published in Cancer Cell , Miao et al. and Ho et al. define a mechanism of CD58 regulation by CMTM6 and show an unexpected yin-yang link between PD-L1 and CD58. [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocytes recognize and kill cancer cells when the latter present antigenic epitopes complexed with MHC class I molecules on their surface. In a recent Science paper, Mangalhara et al. show that alterations of the mitochondrial electron flow upregulate multiple factors involved in antigen presentation via a succinate-dependent epigenetic mechanism. Cytotoxic T lymphocytes recognize and kill cancer cells when the latter present antigenic epitopes complexed with MHC class I molecules on their surface. In a Science paper, Mangalhara et al. show that alterations of the mitochondrial electron flow upregulate multiple factors involved in antigen presentation via a succinate-dependent epigenetic mechanism. [ABSTRACT FROM AUTHOR]

In this Q&A, Cell Press Community Review Scientific Editor Leia Judge talks to Dr. Clint Allen and Dr. Sandro Santagata about their new papers "Phenotypic plasticity and reduced tissue retention of exhausted tumor-infiltrating T cells following neoadjuvant immunotherapy in head and neck cancer" and "Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma" and their experiences with publishing through Cell Press Community Review. [ABSTRACT FROM AUTHOR]

Two papers published in this edition of Cancer Cell (Zheng et al., 2022 and Veatch et al., 2022) provide an elegant illustration of how single-cell sequencing can be used to define a molecular phenotype which identifies tumor-specific T cells. Two papers published in this edition of Cancer Cell (Zheng et al., 2022 and Veatch et al., 2022) provide an elegant illustration of how single-cell sequencing can be used to define a molecular phenotype which identifies tumor-specific T cells. [ABSTRACT FROM AUTHOR]

The immune system employs complex tolerance mechanisms in order to avoid harmful autoimmunity, yet autoantibodies are frequently observed in cancer. In a paper in Cell , Mazor et al. report that autoantibodies produced by tumor-infiltrating B cells in human ovarian cancer frequently recognize the self-protein matrix metalloproteinase 14 (MMP14) through two distinct mechanisms of tolerance disruption. [ABSTRACT FROM AUTHOR]

Discrete tissue niches are emerging as essential prerequisites enabling cell communication and function in both homeostasis and disease. In a recent Cell paper, Di Pilato et al. identify a unique dendritic cell-cytotoxic T cell crosstalk within the perivascular space that facilitates T cell survival and proliferation and drives anti-tumor activity. [ABSTRACT FROM AUTHOR]

Eligibility criteria restrict patient enrollment in clinical trials. A Nature paper applied a machine-learning algorithm in a real-world database to show that relaxing some criteria may not jeopardize efficacy and safety. This may enable more patients to have earlier access to new therapies and make results more generalizable to clinical practice. [ABSTRACT FROM AUTHOR]

The functional repertoire of intratumoral microorganisms and their local effects on the host remain poorly characterized. By revealing potentially immunogenic bacterial peptides on melanoma cells, a Nature paper provides evidence that intratumoral bacteria can directly modulate antitumor immune responses, and it details a new class of therapeutically relevant, non-human tumor antigens. [ABSTRACT FROM AUTHOR]

Two recent Lancet and Lancet Oncology papers report that cancer patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection have higher mortality rates. Common independent factors associated with increased risk of death were older age, history of smoking status, number of comorbidities, more advanced performance status, and active cancer. [ABSTRACT FROM AUTHOR]

A paper published in Science probes over 1500 tumor samples from multiple cancer types for markers of a tumor microbiome and viable bacteria. Unique intertumoral and intracellular signatures associated with clinical biomarkers and metabolic pathways provide clues to the roles bacteria play in carcinogenesis. [ABSTRACT FROM AUTHOR]

Reprogramming the tumor microenvironment may be a key strategy to broaden the efficacy of current cancer immunotherapies. In a recent Nature paper, Canale et al. use synthetic biology to alter intratumoral arginine levels via engineered bacteria, leading to improved responsiveness to anti-PD-L1 checkpoint blockade in a murine model of cancer. [ABSTRACT FROM AUTHOR]

Reprogramming the tumor microenvironment may be a key strategy to broaden the efficacy of current cancer immunotherapies. In a recent Nature paper, Canale et al. use synthetic biology to alter intratumoral arginine levels via engineered bacteria, leading to improved responsiveness to anti-PD-L1 checkpoint blockade in a murine model of cancer. [ABSTRACT FROM AUTHOR]

Two papers published recently in the New England Journal of Medicine describe the utility of abiraterone acetate, an androgen biosynthesis inhibitor, in the early treatment of metastatic prostate cancer. In addition to establishing a new standard of care, these two articles pose a number of important questions for future investigation. [ABSTRACT FROM AUTHOR]

Effective cancer therapy requires that a cancer be more susceptible to a treatment than are the essential tissues in the body. A paper by Sarosiek et al. in this issue now shows that, unlike those of cancer cells, mitochondria in many tissues in adults are in an apoptosis-resistant state. [ABSTRACT FROM AUTHOR]

Rapamycin analogs that inhibit mTOR signaling have antitumor activity against certain lymphomas, but treatment of solid tumors has been less encouraging despite inhibition of mTOR function. Two recent papers give insight into the potential use of mTOR inhibitors. O''Reilly et al. provide evidence that poor tumor response to rapamycins is the result of relieving mTOR-mediated feedback inhibition of insulin receptor substrate 1, and activation of Akt-mediated survival. In the second paper, Kaper et al. address the impact of pathway activation on hypoxia-mediated downregulation of mTOR signaling, raising the possibility that rapalogs could selectively inhibit hypoxic cells. [Copyright &y& Elsevier]

Two recent papers published in Nature demonstrate the power of systematic high-throughput pharmacologic profiling of very large, diverse, molecularly-characterized human cancer cell line panels to reveal linkages between genetic profile and targeted-drug sensitivity. Known oncogene addictions are confirmed while surprising complexities and biomarker relationships with clinical potential are revealed. [Copyright &y& Elsevier]

Despite the promise of the new generation of molecularly targeted drugs, intrinsic and acquired resistance is proving to be as problematic as with cytotoxic drugs. Two recent papers have identified novel ways by which non-small cell lung cancers can exhibit resistance to EGFR inhibitors and suggest new therapeutic workarounds. [ABSTRACT FROM AUTHOR]

RAF inhibitors have the unique property of transactivating RAS-dependent RAF dimers in most cells but inhibit RAF/MEK/ERK signaling in cells expressing mutant BRAF, in which RAS activity is too low to support this process. These drugs thus selectively inhibit ERK signaling in tumors with BRAF mutation. RAF inhibitors have remarkable clinical activity in melanomas with BRAFV600E mutations; however, resistance invariably develops. Three recent papers reveal that acquired resistance may be due to mechanisms that cause ERK signaling to become insensitive to RAF inhibitors, or that reduce the dependence of the tumor on ERK signaling through activation of other pathways. [ABSTRACT FROM AUTHOR]

Clinical practice reveals that therapy with angiogenesis inhibitors often does not prolong survival of cancer patients for more than months, because tumors elicit evasive resistance. In this issue of Cancer Cell, two papers report that VEGF inhibitors reduce primary tumor growth but promote tumor invasiveness and metastasis. These perplexing findings help to explain resistance to these drugs but raise pertinent questions of how to best treat cancer patients with antiangiogenic medicine in the future. We discuss here how VEGF inhibitors can induce such divergent effects on primary tumor growth and metastasis. [Copyright &y& Elsevier]

In a recent Nature paper, Yamamoto et al. demonstrate that, in the particular context of pancreatic carcinoma, autophagy causes the continuous destruction of major histocompatibility complex class I (MHC-I) proteins. Suppression of autophagy favors MHC-I re-appearance on the surface of malignant cells, facilitating their clearance by cytotoxic T lymphocytes. [ABSTRACT FROM AUTHOR]

RAF research is booming since the discovery of mutant B-RAF in ∼8% of human cancer. One reason for the excitement is the availability of RAF-targeted therapies. RAF inhibitors have been developed because RAF functions at a convergence point of signal transduction. Two recent papers by the groups of Rosen and Marais dramatically advance our understanding of RAF oncogenes in human tumors. The results confirm that the mitogenic cascade (RAF-MEK-ERK) is essential for RAF transformation, that RAF kinases work in concert, and that RAF-transformed cells are hooked on MEK, making them sensitive to growth inhibition by kinase inhibitors. [Copyright &y& Elsevier]

Activation of the phosphatidylinositol 3′ kinase-Akt pathway has long been associated with malignant transformation and antiapoptotic signaling. Mutations downstream of Akt that activate the TOR kinase are found in tumor-prone syndromes, while overexpression of translation initiation complex components, such as eIF4E, occurs frequently in human cancer. However, direct roles for TOR signaling or eIF4E overexpression, in the genesis of cancer, have been lacking. Recent papers, including one by in this issue of Cancer Cell, clearly establish that dysregulation of cap-dependent translation confers malignant characteristics and induces cancer by suppressing apoptosis, underscoring the potential of therapeutics that selectively target the Akt-TOR-eIF4E pathway. [Copyright &y& Elsevier]

A recent paper in Cell (Fujita et al., 2003) demonstrates that MTA3, a novel component of the Mi-2/NuRD transcriptional repression complex, is an estrogen receptor-regulated inhibitor of the Snail zinc finger transcription factor in breast cancer. Given the important role of Snail in repressing E-cadherin transcription and the function of E-cadherin as a tumor suppressor protein and regulator of epithelial architecture, the findings offer potentially significant new insights into cancer pathogenesis. [Copyright &y& Elsevier]

The mechanisms through which tumor antigen-specific T cells are elicited in natural or chemotherapy-induced immunosurveillance have been elusive. In this issue of Cancer Cell , two papers by Broz and colleagues and Ruffell and colleagues delineate an important role for a specific dendritic cell subset characterized by CD103 expression, dependence on transcription factors Batf3 and Irf8, and interleukin-12 production. [ABSTRACT FROM AUTHOR]

Focal amplifications in 6p21 containing the VEGFA locus occur in 7%–10% of hepatocellular carcinoma (HCC). A recent paper describes how VEGF-A stimulates paracrine secretion of hepatocyte growth factor by stromal cells, which induces tumor progression. HCC patients with VEGFA amplification are distinctly sensitive to sorafenib. [ABSTRACT FROM AUTHOR]

An elegant paper by Anchoori and colleagues in this issue of Cancer Cell describes an irreversible inhibitor of Rpn13, one of the ubiquitin receptors on the 26S proteasome that is nonessential for proteasome function in most normal tissues, but is overexpressed in many solid tumors. [Copyright &y& Elsevier]

Hotspot mutations in IDH1 and IDH2 cause a differentiation block that can promote tumorigenesis. Two recent papers reported that small molecules targeting mutant IDH1 or mutant IDH2 release this differentiation block and/or impede tumor growth, providing a proof-of-concept that mutant IDHs are therapeutically targetable and that their effects are reversible. [Copyright &y& Elsevier]

WNT/β-catenin signaling is critical to the development of many cancer types. A paper by Mo and colleagues in a recent issue of Cell shows that autocrine CXCL12/CXCR4 chemokine signaling activates β-catenin signaling in a rare peripheral nerve sarcoma. Together with the availability of small molecules targeting CXCR4, this finding suggests new avenues for cancer therapy. [Copyright &y& Elsevier]

Normal and neoplastic tissues display cellular hierarchies that integrate extracellular cues to maintain tissue function through bidirectional signals mediated via cell surface proteins. Two papers in Cancer Cell, one in this issue (Day and colleagues) and one in a recent issue (Binda and colleagues), describe how Eph receptor tyrosine kinases critically define and regulate the growth of cancer stem cells. [ABSTRACT FROM AUTHOR]

Activation of epithelial-mesenchymal transition (EMT) is important for cancer cell dissemination. Two papers in this issue of Cancer Cell (Ocaña and colleagues and Tsai and colleagues) support the concept that the reversal of EMT is necessary for efficient metastatic colonization. Moreover, although EMT has been associated with stemness properties, one study indicates that they are not necessarily linked. [ABSTRACT FROM AUTHOR]

MYCN is an oncogenic driver of childhood neuroblastoma, a frequently lethal pediatric tumor. In a recent paper in Science Translational Medicine, Chanthery and colleagues demonstrate that PI3K inhibition leads to the dual therapeutic benefits of enhanced MYCN degradation and loss of a paracrine angiogenic signal mediated by MYCN. [Copyright &y& Elsevier]

In a recent paper, Poulikakos et al. describe a new and potentially common mechanism whereby melanomas develop resistance to the BRAF inhibitor vemurafenib by expressing truncated forms of BRAF(V600E) that can dimerize in the absence of activated RAS. Will it be possible to block this with improved BRAF inhibitor design? [Copyright &y& Elsevier]

BRCA1 is a crucial human breast and ovarian cancer tumor suppressor gene. The article by Drost et al. in this issue of Cancer Cell together with a recent paper in Science now provide a clearer picture of how this large and complex protein suppresses tumorigenesis. [ABSTRACT FROM AUTHOR]

In a recent paper in Cell, Oricchio et al. identify EPHA7 as a tumor suppressor gene residing in the 6q-deleted region in follicular lymphoma. A truncated EPHA7TR isoform is secreted by normal B cells, inhibits EPHA2 signaling, and, as a secreted tumor suppressor protein, has potential as a targeted therapeutic polypeptide. [ABSTRACT FROM AUTHOR]

Tumor-associated inflammation is a consequence and a driver of tumorigenesis. Three papers in this issue of Cancer Cell demonstrate the importance of tumor-elicited inflammation in the development and progression of pancreatic ductal adenocarcinoma and esophageal squamous carcinoma. Disruption of tissue homeostasis culminates in activation of STAT3, generating a pro-tumorigenic inflammatory microenvironment. [ABSTRACT FROM AUTHOR]

Mutations in BRCA1 predispose to tumorigenesis presumably from the inability to accurately repair DNA double-strand breaks by homologous recombination. Two new papers shed light on how loss of the DNA damage response protein 53BP1 reverses phenotypes of BRCA1 mutant cells, with potential clinical implications. [Copyright &y& Elsevier]

Three papers in Cell and Nature now report that dimeric RAF is a plastic enzyme: blocking one ATP-binding site paradoxically stimulates the kinase activity of the other protomer. This occurs only in “primed” cells bearing activated RAS and WT RAF, explaining the selective efficacy of RAF inhibitors for RAF mutant cells. [Copyright &y& Elsevier]

Expression of MCL-1 is frequently elevated in cancer and is implicated in the resistance to chemotherapy by the BCL-2 small molecule inhibitor ABT-737. A recent paper in Nature identified USP9X as an antagonist of MCL-1 ubiquitinylation and degradation. Often upregulated in tumor cells, USP9X activity influences the response to ABT-737. [Copyright &y& Elsevier]

Genetic alternations resulting in constitutive stabilization of β-catenin and altered transcription of β-catenin/TCF-regulated genes are found in many cancers. A recent Nature paper offers insights into the role of tankyrase in regulating the Wnt/β-catenin pathway and suggests that compounds targeting tankyrase''s poly-ADP-ribosylation (PARsylation) activity may hold promise for cancer therapy. [Copyright &y& Elsevier]

Recent papers published in Nature by Guardavaccaro et al. and Westbrook et al. describe a nexus of two masters of negative regulation of protein levels. Both of these studies establish that the transcriptional repressor REST/NRSF is regulated by the highly versatile ubiquitin protein ligase (E3) SCFβ-TrCP, adding a new dimension to the relationship between the ubiquitin-proteasome system and epigenetic regulation of transcription. These studies elucidate a critical means of regulation for REST, with implications for neuronal stem cell differentiation and the dual roles of this protein as a tumor suppressor and oncogene. These findings and their significance are discussed herein. [Copyright &y& Elsevier]

Loss of the VHL tumor suppressor gene promotes cancer in several ways, including activation of the HIF transcription factors. HIF overexpression is associated with increased malignancy in many tumor types. So why is the spectrum of tumors associated with VHL loss restricted only to a few specific organs? In a recent paper in the March issue of Nature Cell Biology, Kaelin and colleagues provide a possible explanation, suggesting that VHL loss can also trigger senescence, a potent tumor suppressor mechanism. [Copyright &y& Elsevier]

Small numbers of proangiogenic bone marrow-derived cells (BMDCs) can play pivotal roles in tumor progression. In this issue of Cancer Cell, two papers, utilizing different tumor angiogenesis models, both find that activated MMP-9 delivered by BMDCs modulates neovessel remodeling, thereby promoting tumor growth. The changes in microvascular anatomy induced by MMP-9-expressing BMDCs are strikingly different between the preirradiated tumor vascular bed model employed by Ahn and Brown and the invasive glioblastoma model utilized by Du et al., likely mirroring the complexity of the real tumor microenvironment and the intricacy of roles of different BMDC populations in mediating tumor neoangiogenesis. [Copyright &y& Elsevier]

Tumorigenesis is a multistep process that requires constitutive cell division, growth, and survival. One strategy used by cancer cells to upregulate growth and survival pathways is through autocrine production of growth and survival factors. Two recent papers by Gao et al. and Sansone et al. published in The Journal of Clinical Investigation outline the importance of autocrine interleukin 6 (IL-6) in lung and breast cancers and implicate IL-6 as an important activator of oncogenic STAT3 in lung adenocarcinomas and of Jagged-1/Notch signaling in breast tumor mammospheres. [Copyright &y& Elsevier]

Members of the fibroblast growth factor (FGF) family are believed to play critical roles during organogenesis and carcinogenesis via signaling between epithelial and stromal compartments. Two new studies in this issue of Cancer Cell underscore the importance of FGF signaling in mediating epithelial-stromal interactions during prostate carcinogenesis. These papers show that deregulated FGF signaling in mouse models of prostate cancer leads to cancer progression and promotes an epithelial-mesenchymal transition, suggesting that FGF receptor inhibitors may have therapeutic value for prostate cancer treatment. [Copyright &y& Elsevier]

Multiple myeloma (MM) is a late-stage B cell malignancy that has received much attention recently because of its therapeutic susceptibility to proteasome inhibitors. Two papers in this issue of Cancer Cell show that primary MM samples and MM cell lines frequently have mutations in genes encoding regulators and effectors of NF-κB signaling, and that these mutations lead to chronic NF-κB target gene expression, which is required for the viability of these MM tumor cells. These results reveal the molecular basis for constitutive NF-κB activity in many MMs and further validate the NF-κB signaling pathway as an appropriate target for MM therapy. [Copyright &y& Elsevier]

Cell culture studies have established NF-κB''s critical role in cancer cell survival and proliferation and led to the clinical use of NF-κB inhibitors. However, a paper in this issue of Cancer Cell reveals an anticancer function for NF-κB in a mouse model where NF-κB activity is lost specifically in hepatocytes. These studies suggest careful examination of NF-κB inhibitors as a therapeutic modality for cancer. [Copyright &y& Elsevier]

Aneuploidy is a hallmark of most human cancers, but whether it is a cause or a consequence of cellular transformation remains a subject of debate. The spindle checkpoint functions to prevent aneuploidy and plays a central role in this discussion. The checkpoint gene Mad2 is activated by E2F1 and overexpressed in cells lacking a functional Rb pathway. In this issue of Cancer Cell, Sotillo and coworkers report that Mad2 overexpression leads to chromosomal instability and tumorigenesis, indicating that Mad2 contributes to cancer development after Rb mutation. In a second paper, Weaver et al. report that aneuploidy has both tumor-promoting and -suppressing properties. [Copyright &y& Elsevier]

The concepts of stem cells being resistant to therapy, stem-like cells existing in brain tumors, and these tumors initially responding to therapy followed by recurrence are well documented. On this foundation, a recent paper in Nature has demonstrated that CD133-expressing glioma cells in vivo and in culture are relatively resistant to radiation. The mechanism of resistance involves the cell-cycle-regulating proteins CHK1/CHK2. The data raise many questions about the details of radiobiology of stem-like cells in their native environment within tumors in vivo. These answers may lead to better optimization of radiation treatments and schedules for these patients. [Copyright &y& Elsevier]

One of the most exciting developments in recent cancer treatment has been the move away from crude cytotoxic agents toward drugs that inhibit specific targets in specific cellular pathways. One assumption of this strategy is that maintenance of human cancers is dependent upon a limited cadre of therapeutically tractable oncogenic lesions. In this issue of Cancer Cell, an intriguing paper from Sharma et al. endorses this approach by showing that evolution appears to be working for us. They show that an innate asymmetry in the dynamics of intracellular signaling biases pathway inhibition in favor of cell death. This bias may significantly potentiate targeted cancer therapies. [Copyright &y& Elsevier]

Adler et al., in a paper appearing in Nature Genetics, exploited the intersect of genetic information from expression profiles with that from array comparative genomic hybridization in human breast cancers to identify genes that may induce the transcription of the prognostic “wound response” expression signature. The amplification of two genes, MYC and CSN5, appeared to be correlated with the wound response cassette. In vitro validation showed that the wound signature could be induced in MCF10A cells only when MYC and CSN5 were coexpressed. This work shows that the intersect analysis of gene amplification and transcriptional expression on a genome-wide scale can uncover complex conditional interactions embedded in the systems map of transcriptional regulation. [Copyright &y& Elsevier]