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

The retinoic acid inducible transcription factor AP-2α, encoded by TFAP2A, is required by migratory neural crest cells. There has been interest in defining the role of AP-2α in metastatic melanoma cells, which share many features of neural crest cells, however, the role of AP-2α remains controversial. Some findings suggest AP-2α functions as a tumor suppressor while others have reported high expression correlates with poor prognosis. White and colleagues demonstrated that AP-2α enhances melanoma metastasis through transcriptional activation of E2F pathway genes including EZH2, a methyltransferase with known oncogenic properties. Mechanistically, AP-2α promotes transcription of these target genes via inhibition of the NuRD repression complex, which regulates chromatin remodeling. Pharmacological inhibition of EZH2 with tazemetostat was effective at reducing anchorage-independent colony formation in vitro and metastasis in vivo, supporting the importance of this pathway in facilitating melanoma cell invasion.Expert Commentary: This study demonstrates that AP-2α enhances the invasiveness of melanoma cells and implicates EZH2 as a potential downstream therapeutic target for reducing the metastatic burden in melanoma patients.White JR, Thompson DT, Koch KE, Kiriazov BS, Beck AC, van der Heide DM, et al. AP-2α-mediated activation of E2F and EZH2 drives melanoma metastasis. Cancer Res 2021;81:4455–70.Enhancers engage target promoters to regulate gene transcription, which has important implications for cancer research, but what regulates promoter choice by enhancers remains unclear. Oh and colleagues introduced mutations at gene promoters that caused the loss of specific enhancer-promoter interactions. Cognate enhancers subsequently interacted with neighboring gene promoters and modulated gene expression. Such plasticity occurred preferentially at promoter regions with CTCF binding sites and was cohesin dependent, although CTCF binding at these promoters was distinct from its occupancy at chromatin domain boundaries. Analysis of published data sets suggested this mechanism to be instrumental in the aberrant expression of disease-related genes. In tumor cells, mutations in the PVT1 promoter induced the upregulation of the neighboring MYC gene, while in Parkinson's disease, mutations in the NUCKS1 promoter led to new enhancer interactions with the RAB7L1 promoter. The authors concluded that chromatin reorganization can promote the aberrant expression of disease-causing genes through “enhancer release and retargeting.”Expert Commentary: Oh and colleagues provide another mechanism by which chromatin modifications lead to disease-related aberrant gene expression. It would be interesting to determine the prevalence of this phenomenon in various diseases and whether specific mutations that lead to enhancer plasticity are tissue or cell specific.Oh S, Shao J, Mitra J, Xiong F, D'Antonio M, Wang R, et al. Enhancer release and retargeting activates disease-susceptibility genes. Nature 2021;595:735–40.Cancer patients develop more complications and show higher morbidity with SARS-CoV-2 infection than healthy individuals, yet it is unclear whether SARS-CoV-2 mRNA vaccines are as efficacious in cancer patients as they have been shown to be in the general population. To investigate this question, Addeo and colleagues performed an international prospective study examining seroconversion rates and anti-SARS-CoV-2 spike protein antibody titers in two cohorts of patients with solid and hematological malignancies after two doses of mRNA-1273 and BNT162b2 SARS-CoV-2 vaccines. While the majority of patients showed high seroconversion after the second vaccine dose, patients with solid tumors had significantly higher antibody titers and seroconversion rates than those with hematological disease. The type of treatment cancer patients received also influenced antibody titers. Notably, all patients who received anti-CD20 cancer therapy six months prior to vaccination failed to develop antibodies to SARS-CoV-2.Expert Commentary: This study presents potential risk factors, including type of tumor and therapy, which could influence the response of cancer patients to the SARS-CoV-2 vaccine in order to identify vulnerable populations where alternative strategies should be utilized.Addeo A, Shah PK, Bordry N, Hudson RD, Albracht B, Di Marco M, et al. Immunogenicity of SARS-CoV-2 messenger RNA vaccines in patients with cancer. Cancer Cell 2021:S1535-6108(21)00330-5. DOI: 10.1016/j.ccell.2021.06.009.YAP is a transcriptional coactivator with contrasting effects in different cancer contexts; it has been reported to function as an oncogenic driver in solid tumors and as a tumor suppressor in hematologic malignancies. Pearson and colleagues have defined a binary “on” or “off” state relating to YAP expression across different cancers. This pan-cancer state is regulated at the epigenetic level and is defined by different gene sets, allowing YAP to exert both pro- and antitumor effects. These opposing effects result from differential enhancer deployment. YAP loss is associated with loss of RB1, and YAPoff solid cancers represent neural/neuroendocrine tumors. Lineage switching between YAPoff and YAPon states is seen in these tumors and the authors suggest that this can be therapy induced.Expert Commentary: The observation that the binary YAP status can drive selective sensitivities to diverse classes of drugs across different cancer types is intriguing and could potentially have significant therapeutic implications.Pearson JD, Huang K, Pacal M, McCurdy SR, Lu S, Aubry A et al. Binary pan-cancer classes with distinct vulnerabilities defined by pro- or anti-cancer YAP/TEAD activity. Cancer Cell 2021:S1535-6108(21)00338-X. DOI: 10.1016/j.ccell.2021.06.016.World-wide vaccinations with the BNT162b2 SARS-CoV-2 vaccine have demonstrated efficacy and safety, yet cancer patients were not included in the initial clinical trials. Goshen-Lago and colleagues analyzed safety and serological status in 232 cancer patients receiving anticancer treatments and 261 health care workers as controls. All individuals received the BNT162b2 vaccine, a lipid nanoparticle formulation containing mRNA encoding the SARS-CoV-2 full-length spike, modified by two proline mutations to lock it in the prefusion conformation. After one dose, 29% of cancer patients showed seropositivity compared with 84% in the control group, and after the second dose, 86% of the patients demonstrated seroconversion. Even though antibodies were generated later in cancer patients compared with the control group, patients reached similar serological status after the second dose of vaccine and did not report more vaccine-related complications than in the healthy population.Expert Commentary: The BNT162b2 vaccine showed safety in cancer patients similar to the healthy population, and despite a lag-period before antibody production, the vaccine showed efficiency after the second dose, supporting advocacy of prioritization of cancer patients for vaccination.Goshen-Lago T, Waldhorn I, Holland R, Szarcwort-Cohen M, Reiner-Benaim A, Shachor-Meyouhas Y, et al. Serologic status and toxic effects of the SARS-CoV-2 BNT162b2 vaccine in patients undergoing treatment for cancer. JAMA Oncology; Published online July 8, 2021; DOI: 10.1001/jamaoncol.2021.2675.While biomarkers and novel therapeutic strategies have been developed for treating radiation-induced thymic lymphomas, underlying drivers remain largely unknown. Using whole-exome sequencing, Lee and colleagues compared lymphomas from three distinct cohorts of irradiated mice (WT, KrasLA1, and Trp53+/−) with nonirradiated mice lacking p53 (Trp53−/−). They identified mutations and copy number variations in Notch1 and Ikzf1, encoding a negative regulator of Notch, as potential drivers of irradiated WT p53 thymic lymphomas (WT and KrasLA1 mice). Importantly, these mutations clustered in hot spots within Notch1 previously shown to drive acute lymphoblastic leukemia. They validated these findings by showing increased activated Notch signaling in lymphomas from mice. Significantly, deletion of Rbpj, which encodes a Notch transcription complex DNA binding protein, attenuated radiation-induced thymic lymphoma development.Expert Commentary: This work establishes for the first time that Notch activation is a major driver of radiation-induced thymic lymphoma.Lee CL, Brock KD, Hasapis S, Zhang D, Sibley AB, Qin X, et al. Whole-exome sequencing of radiation-induced thymic lymphoma in mouse models identifies Notch1 activation as a driver of p53 wild-type lymphoma. Cancer Res 2021;81:3777–90.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.