Highlights from Recent Cancer Literature
Journal: Cancer Research (2022)

Glioblastoma, a highly malignant brain tumor, has been extensively profiled at the genetic and transcriptomic levels, but the successful development of new drugs has been very limited, in part due to the impact of the tumor microenvironment on drug resistance. Comparing patient-derived glioblastoma stem cells between two conditions (spheroid culture and intracranial xenografts) in an RNAi-based screen, Dixit and colleagues identified DPY30, a component of an epigenetic regulatory complex, as required for tumor growth in vivo but not in vitro. Analyses of the downstream mechanism of DPY30 activity in tumors revealed that this protein modulated cell viability and angiogenesis in hypoxic conditions, at least partly through regulating the phosphodiesterase PDE4B. Consistent with these data, an existing phosphodiesterase inhibitor, rolipram, inhibited intracranial xenograft growth, while effects in culture were minimal.Expert Commentary: These data highlight the importance of drug screen designs that consider key features of the tumor microenvironment—in this case, angiogenesis and hypoxia—and reiterate the potential of modulating epigenetic regulators to alter transcriptional programs supporting tumor cell growth and survival.Dixit D, Prager BC, Gimple RC, Miller TE, Wu Q, Yomtoubian S, et al. Glioblastoma stem cells reprogram chromatin in vivo to generate selective therapeutic dependencies on DPY30 and phosphodiesterases. Sci Transl Med 2022;14:eabf3917. doi: 10.1126/scitranslmed.abf3917.Metastatic spread to the brain in patients with breast cancer is often fatal and little progress has been made in finding effective treatments. In a recent study, Dai and colleagues investigated the strategy of limiting the escape of disseminated tumor cells from dormancy as opposed to trying to block the early steps of metastasis. The authors used intravital imaging of triple-negative breast cancer cell lines and their metastatic counterparts to demonstrate that escape from dormancy was the rate-limiting step for the formation of metastases in the brain. They identified a critical role for astrocytes, and specifically their secretion of laminin-211, in driving breast cancer cell dormancy in the brain. Mechanistically, laminin-211 binds dystroglycan on breast cancer cells and impedes translocation of YAP to the nucleus, resulting in reduced proliferative cues in dormant cells.Expert Commentary: This elegant study provides insight into tissue-specific mechanisms that regulate metastatic dormancy and helps identify potential vulnerabilities that could be therapeutically targeted.Dai J, Cimino PJ, Gouin KH, Grzelak CA, Barrett A, Lim AR, et al. Astrocytic laminin-211 drives disseminated breast tumor cell dormancy in brain. Nat Cancer 2022;3:25–42.Chemoimmunotherapy is the most common first-line treatment for metastatic non-small cell lung cancer (NSCLC), however, a significant number of patients fail to benefit from chemoimmunotherapy. Limagne and colleagues found that despite the presence of immunogenic cell death in chemoimmunotherapy-resistant mouse lung cancer models, CXCL10 induction and CD8+ T-cell tumor infiltration were absent. A targeted kinase screen revealed that KRAS/MEK/ERK pathway inhibitors sensitized tumors to chemoimmunotherapy through restoration of CXCL10 expression and CD8+ T-cell recruitment in a mitophagy-dependent manner. This process was mediated by TLR9, which senses the release of mitochondrial DNA following mitophagy and triggers CXCL10 expression. Interestingly, high CXCL10 and mitophagy-associated gene expression correlated with efficacy of immunotherapy in NSCLC and melanoma patients.Expert Commentary: This study suggests that mitophagy activation through MEK inhibition may be an effective therapeutic strategy to improve outcomes with chemoimmunotherapy.Limagne E, Nuttin L, Thibaudin M, Jacquin E, Aucagne R, Bon M, et al. MEK inhibition overcomes chemoimmunotherapy resistance by inducing CXCL10 in cancer cells. Cancer Cell 2022;40:136–52.e12. doi: 10.1016/j.ccell.2021.12.009.Immunotherapy has shown a lot of promise for the treatment of cancer to date, however, there is an ongoing search for biomarkers to predict which patients may respond best to this therapy and improve outcomes. To better understand the cancer immune cell environment, Combes and colleagues set out to identify common tumor immune archetypes (collections of cell subsets and specific immune cell pairings linked with function) regardless of tissue of origin or tumor grade. Using bulk tumor cell sequencing to identify common functional pathways and flow cytometry analysis of the immune cell microenvironment, they examined this landscape across 364 tumors from 12 distinct cancer types. They identified 10 distinguishing criteria that allowed them to identify 12 unique tumor immune archetypes across all the analyzed cancer types, which could be validated in The Cancer Genome Atlas (TCGA) dataset. A number of these unique tumor archetypes were also significantly associated with patient outcome.Expert Commentary: These 12 pan-cancer tumor immune cell archetypes have the potential to provide predictive signatures for the rapid classification of many cancers, regardless of site of origin or tumor grade.Combes AJ, Samad B, Tsui J, Chew NW, Yan P, Reeder GC, et al. Discovering dominant tumor immune archetypes in a pan-cancer census. Cell 2022;185:184–203.e19. doi: 10.1016/j.cell.2021.12.004.The Goldilocks model of T-cell receptor (TCR) signal strength describes how TCR affinities control the development of T cells in the thymus, where intermediate TCR signal strength is required for the positive selection of T cells. Shakiba and colleagues showed that in mature T cells responding to tumor antigens, a similar paradigm exists. In their model, the TCR of tumor-specific T cells was kept constant but its affinity for tumor antigen was controlled by single point mutations in the peptide antigen recognized by the TCR in isogenic tumor clones. T cells with reduced TCR signal strength produced more cytokines when stimulated in vitro. Despite differences in functional capacity of the T cells with high and low affinities, there was no difference in tumor control. CRISPR editing of the coreceptor CD8 to tune overall TCR signal strength improved tumor control.Expert Commentary: Tuned T-cell receptor signal strength is required to mount effective cancer immunity without inducing T-cell dysfunction.Shakiba M, Zumbo P, Espinosa-Carrasco G, Menocal L, Dündar F, Carson SE, et al. TCR signal strength defines distinct mechanisms of T-cell dysfunction and cancer evasion. J Exp Med 2022;219:e20201966. doi: 10.1084/jem.20201966.Metastatic prostate cancer is a highly lethal disease for which there is a strong effort underway to identify improved therapies for patient. Docetaxel has been a long-standing first-line treatment for prostate cancer, however, patients with metastatic prostate cancer commonly develop resistance. Jiang and colleagues analyzed expression of circular RNAs (circRNA) in docataxel-resistant and -sensitive prostate cancer cells and identified a novel circular RNA, circARHGAP29, upregulated in docataxel-resistant prostate cancer cell lines and clinical samples. circARHGAP29 promoted docataxel resistance and glycolysis in prostate cancer in vitro and in vivo. circARHGAP29 interacted with the IGF2BP2 protein, promoting stability of LDHA mRNA. Moreover, circARHGAP29 also interacted with and stabilized MYC mRNA and protein, which promoted LDHA expression by facilitating its transcription.Expert Commentary: A novel circRNA, circARHGAP29, promotes docetaxel resistance and glycolytic metabolism in metastatic prostate cancer. circARHGAP29 is a promising prognostic biomarker and therapeutic target in docetaxel-resistant prostate cancer.Jiang X, Guoc S, Want S, Zhanga Y, Chen H, Wang Y, et al. EIF4A3-induced circARHGAP29 promotes aerobic glycolysis in docetaxel-resistant prostate cancer through IGF2BP2/c-Myc/LDHA signaling. Cancer Res 2022;82:831–45.Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.