Highlights from Recent Cancer Literature
Journal: Cancer Research (2021)

The DREAM complex (dimerization partner, RB-like, E2F, and multivulval class B) is a master regulator of both quiescence and cell-cycle progression. However, how this delicate balance is disrupted in cancer remains unclear. Kim and colleagues demonstrated that PAF can remodel the DREAM complex leading to proliferation and lung tumorigenesis. PAF was found to be overexpressed in lung cancer and associated with a poor prognosis. PAF was both sufficient and required for bypass of quiescence and lung tumorigenesis through its modulation of the DREAM complex leading to transactivation of cell-cycle genes. Pharmacologic inhibition of the PAF-DREAM-associated transcriptional program prevented lung cancer growth.Expert Commentary: This study suggests that targeting the PAF-DREAM axis may be an effective therapy for lung cancer.Kim MJ, Cervantes C, Jung YS, Zhang X, Zhang J, Lee SH, et al. PAF remodels the DREAM complex to bypass cell quiescence and promote lung tumorigenesis. Molecular Cell; Published online February 17, 2021; DOI: 10.1016/j.molcel.2021.02.001.Development of drug resistance in response to therapy can be facilitated by a small population of treatment-persistent cells. Dhimolea and colleagues evaluated these treatment-persistent cells in 3D culture and in vivo models of breast and prostate cancer following prolonged exposure to cytotoxic agents, identifying a reversible, dormant state characterized by a transcriptional profile similar to that of the embryonic diapause. This state was driven by downregulation of Myc activity. Depletion of MYC, or BRD4 inhibition using JQ1, led to cellular drug persistence and dormancy, while MYC overexpression or CDK9 inhibition partially reversed the MYC-suppressed diapause-like cell state and restored sensitivity to chemotherapeutics. The addition of CDK9 inhibitors to chemotherapy potentiated the effects of the latter, suggesting the combination of transcriptional inhibitors and cytotoxic agents as an approach to residual disease.Expert Commentary: The seemingly opposing results of BRD4 inhibition driving cells into the dormant state through MYC suppression and their reversal with blocking transcriptional pause release—CDK9 inhibition—are somewhat unclear, as is the premise that JQ1 treatment in MYC-addicted cancer cells will promote persistent disease, aspects that merit further investigation.Dhimolea E, de Matos Simoes R, Kansara D, Al’Khafaji A, Bouyssou J, Weng X, et al. An embryonic diapause-like adaptation with suppressed Myc activity enables tumor treatment persistence. Cancer Cell 2021;39:240–256.e11. DOI: 10.1016/j.ccell.2020.12.002.The incidence and mortality of prostate cancer are greater in men of African ancestry than European ancestry. These racial disparities are due to multiple factors, but variations in genomic susceptibility such as single nucleotide polymorphisms (SNP) may play an important role in determining cancer aggressiveness and treatment outcome. Using public databases, Han and colleagues identified a prostate cancer susceptibility SNP at an intronic enhancer of the NEDD9 gene, which strongly associated with enhanced cancer risk in men with African ancestry. Mechanistically, this genetic variation altered the binding and activity of multiple transcription factors, including ERG and NANOG. Moreover, NEDD9 displayed oncogenic activity in prostate cancer cells, promoting tumor growth and metastasis in vitro and in vivo.Expert Commentary: A prostate cancer susceptibility SNP in NEDD9 was strongly associated with risk in patients of African ancestry, increasing expression of NEDD9 and promoting prostatic cancer. This study provides novel insights into genetic mechanisms driving racial disparities in prostate cancer.Han D, Owiredu JN, Healy BM, Li M, Labaf M, Steinfeld JS, et al. Susceptibility-associated genetic variation in NEDD9 contributes to prostate cancer initiation and progression. Cancer Research; Published OnlineFirst February 25, 2021; DOI: 10.1158/0008-5472.CAN-20-3042.Regulatory T cells aid tumors by dampening immune responses; targeting these cells would help overcome tumor immune evasion. Lim and colleagues reported that tumor-infiltrating immunosuppressive regulatory T cells (TI-Tregs) activate a sterol-regulatory-element-binding protein (SREBP) transcriptional program, revealing a tumor-specific vulnerability of Tregs. Analysis of transcriptional datasets in human and mouse cancers revealed increased SREBP activity in TI-Tregs. Mice with Treg-specific knockout of SREBP cleavage–activating protein (Scap-KO) did not suppress antitumor immunity, and tumors were rejected in mice. Importantly, Scap-KO in Tregs did not affect homeostatic immune control and could control multiple sclerosis in the EAE mouse model, revealing the remarkable specificity of the defect to cancers. Scap-KO Tregs in tumors showed reduced cholesterol homeostasis and fatty-acid metabolism. The authors showed that both pathways contributed to Treg dysfunction in tumors. HMG-CoA reductase and mevalonate production was required to upregulate PD-1 in Tregs to dampen improper IFNγ production. Fatty acid synthesis was required for complete activation of Tregs in the tumor microenvironment.Expert Commentary: SREBP activity distinguishes tumor-infiltrating Tregs and blocking SREBP pathway activity leads to tumor-specific immune activation that controls cancer without inciting autoimmunity.Lim SA, Wei J, Nguyen TM, Shi H, Su W, Palacios G, et al. Lipid signalling enforces functional specialization of Treg cells in tumours. Nature 2021;591:306–311.Malignant rhabdoid tumor (MRT) is a rare childhood tumor that commonly originates in the kidneys but can also occur in other soft tissues or in the brain. The molecular underpinnings of MRT are not well established. Custers and colleagues performed whole genome sequencing on two MRT and adjacent structures. Some somatic changes including SMARCB1 mutations of the tumor were also present in nearby neural cell precursor cells, but not in blood, kidney, or muscle. To understand how lack of differentiation of neural crest could result in MRT, they re-expressed SMARCB1 in patient-derived MRT organoids and performed single-cell mRNA sequencing. Cells with SMARCB1 reconstitution appeared more differentiated, resembling normal neural crest cells. Comparing bulk gene expression signatures to a drug perturbation database, they observed that HDAC and mTOR inhibition mimicked the differentiation signature observed upon SMARCB1 reconstitution, validated with combined HDAC and mTOR inhibition.Expert Commentary: MRTs are challenging to treat, with no clear therapeutic target. This study identified a putative cell of origin and leveraged normal expression patterns during differentiation to identify therapies that could be rapidly translated to the clinic.Custers L, Khabirova E, Coorens THH, Oliver TRW, Calandrini C, Young MD, et al. Somatic mutations and single-cell transcriptomes reveal the root of malignant rhabdoid tumours. Nat Commun 2021;12:1407. DOI: 10.1038/s41467-021-21675-6.Isocitrate dehydrogenase (IDH) mutations are closely related to the occurrence and development of glioma. Platten and colleagues reported a novel clinical trial of an IDH1(R132H)-specific peptide vaccine (IDH1-vac), which they previously showed to induce a T helper cell response in syngeneic MHC-humanized mice. They enrolled 33 patients newly diagnosed with IDH1 mutant high-grade glioma. The vaccine was safe and induced an immune response in over 90% of patients. Encouraging early response rates were observed. An explorative mutation-specificity score showed that peripheral T cells produced TNF, IFNγ, and IL17 when exposed to IDH1(R132H) in vitro. This response was associated with the degree of IDH1(R132H) antigen presentation in the primary tumor. Pseudoprogression was observed and correlated with peripheral IDH1-vac immune response, consistent with treatment-induced intratumoral inflammation. One patient underwent resection after pseudoprogression. Single-cell RNA-sequencing suggested clonal expansion of IDH1(R132H)-specific helper T cells.Expert Commentary: This study represents an exciting new therapeutic avenue to combat adult high-grade gliomas. In light of the resistance to immune checkpoint inhibitors, this approach should be prioritized for large randomized studies of newly diagnosed IDH1 mutant high-grade glioma.Platten M, Bunse L, Wick A. Bunse T, Le Cornet L, Harting I, et al. A vaccine targeting mutant IDH1 in newly diagnosed glioma. Nature; Published online March 24, 2021; DOI: 10.1038/s41586-021-03363-z.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.