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

Cellular plasticity is critical for the development of a persister phenotype in a rare cancer cell population after targeted therapy. Persistence allows for the eventual development of stable resistance, however, pathways required for developing persistence are poorly understood. Torre and colleagues utilized a CRISPR-Cas9 screen to identify modulators of persistence after BRAF inhibitor treatment. They identified multiple genes that increased persistence through inducing cellular differentiation. Targeting genes that reduced differentiation, such as DOT1L, prior to BRAF inhibition led to increased persistence and resistance in vitro and in vivo.Expert Commentary: This study suggests targeting the key pathways for drug-induced persistence as a novel strategy to prevent drug resistance.Torre EA, Arai E, Bayatpour S, Jiang CL, Beck LE, Emert BL, et al. Genetic screening for single-cell variability modulators driving therapy resistance. Nature Genetics 2021;53:76–85.Garofano and colleagues developed a computational strategy to extract core tumor cell-intrinsic biological states of individual glioblastoma cells from single-cell and bulk sequencing information. They identified four glioblastoma developmental and metabolic cell states, dubbed proliferative/progenitor, neuronal, mitochondrial, and glycolytic/plurimetabolic. The mitochondrial subtype relied solely on oxidative phosphorylation, and patients exhibited improved survival. The glycolytic/plurimetabolic subtype was dependent on aerobic glycolysis, and amino acid and lipid metabolism for energy production. The authors found that the glucose-proton symporter SLC45A1 on chromosome 1p36.23 was deleted and functioned as a tumor suppressor in mitochondrial glioblastoma. Reintroduction of SLC45A1 into mitochondrial glioma cells induced acidification and loss of proliferation. As expected, mitochondrial glioblastoma responded to inhibitors of oxidative phosphorylation, while glycolytic/plurimetabolic glioblastoma were resistant.Expert Commentary: These data suggest that pathway-based classification can be used for classification and potentially for treatment of glioblastoma.Garofano L, Migliozzi S, Oh Y-T, D'Angelo F, Najac RD, Ko A, et al. Pathway-based classification of glioblastoma uncovers a mitochondrial subtype with therapeutic vulnerabilities. Nature Cancer; Published online January 11, 2021; DOI: 10.1038/s43018-020-00159-4.Metastasis accounts for the great majority of breast cancer deaths, however, mechanisms underlying metastasis remain largely elusive. Liu and colleagues investigated roles for splice variants of methyl-CpG–binding proteins MBDs, transcriptional regulators, and readers of methylated CpG dinucleotides in regulating breast cancer metastasis. Suppressing alternative splicing of MBD2 promoted breast cancer metastasis under hypoxic conditions. Hypoxia-induced miR-222 inhibited expression of splicing factor SRSF2, increasing expression of MBD2a and decreasing that of MBD2c. Elevated MBD2a outcompeted MBD2c for binding to promoter CpG islands to activate expression of the Wnt receptor FZD1, promoting epithelial-to-mesenchymal transition and metastasis. Interestingly, expression of MBD2a and MBD2c correlated with invasiveness clinically, indicating opposing roles for MBD2 splice variants in regulating human breast cancer metastasis.Expert Commentary: This study describes a novel link and the underlying mechanisms by which MBD2 switches to breast cancer metastasis under hypoxic conditions. These findings suggest targeting MBD2 switching together with HIF inhibitors as potential therapies for metastatic breast cancer, particularly as mediated by hypoxia and HIF1.Liu Z, Sun L, Cai Y, Shen S, Zhang T, Wang N, et al. Hypoxia-induced suppression of alternative splicing of MBD2 promotes breast cancer metastasis via activation of FZD1. Cancer Res 2021;81:1265-78.Cancer cells from a diverse array of tumors can enter a reversible, drug-tolerant persister state (DTP) in response to chemotherapy or targeted agents. Such cells represent less than 5% of the tumor. Rehman and colleagues used cellular barcoding and modeling in patient-derived colorectal cancer models to track DTPs during and after chemotherapy treatment. Unexpectedly, tumors that entered DTP had the same heterogenous complexity as those that exited this state, suggesting that all cancer cells, rather than a small subset, are capable of becoming DTPs. They further showed that tumors undergoing DTP behaved similarly to the reversible embryonic survival program termed diapause, a response to unfavorable environmental conditions. Mechanistically, DTP resulted from decreased mTOR activity and increased autophagy. Tumors exposed to chemotherapy and an autophagy inhibitor failed to enter a DTP state.Expert Commentary: This paper identified mechanisms underlying DTP that could be targeted to enhance chemotherapy.Rehman SK, Haynes J, Collignon E., Brown KR, Wang Y, Nixon AML, et al. Colorectal cancer cells enter a diapause-like DTP state to survive chemotherapy. Cell 2021;184:226–42.e21. DOI: 10.1016/j.cell.2020.11.018.Fatty acid 2-hydroxylase (FA2H) alters their chirality and subsequent biological properties, inducing metabolomic reprogramming and driving progression in colorectal cancer via poorly understood mechanisms. Sun and colleagues performed bioinformatic analyses of published colorectal cancer data and showed that FA2H expression was downregulated commonly in colorectal cancer, marking unfavorable outcome. Modulating FA2H expression altered colorectal cancer growth in vitro and in vivo. Knockdown of FA2H drove tumor growth, and overexpression of FA2H attenuated growth. Moreover, they showed that the FA2H product (R)-2-hydroxy palmitic acid, but not a similar (S)-hydroxylated fatty acid, could also attenuate the tumorigenic properties of colorectal cancer cells. They further identified and validated AMPK/YAP signaling as the relevant effectors of FA2H-modified fatty acids.Expert Commentary: FA2H functions as a tumor suppressor in colorectal cancer, altering fatty acid hydroxylation and subsequent YAP signaling via AMPK activity.Sun L, Yang X, Huang X, Yao Y, Wei X, Yang S, et al. 2-Hydroxylation of fatty acids represses colorectal tumorigenesis and metastasis via the YAP transcriptional axis. Cancer Res 2021;81:289–302.In order to allow for rapid proliferation, cancer cells accumulate metabolic alterations to secure nutrient consumption for biomass production. These metabolic alterations affect the fate of cancer cells as well as other types of cells in the tumor microenvironment. Gong and colleagues analyzed metabolic programming and heterogeneity of 465 triple-negative breast cancers (TNBC). The authors identified three different metabolic pathway subtypes: MPS1 with upregulated lipid metabolism, MPS2 with increased glycolysis and upregulated carbohydrate metabolism, and MSP3, with a mixed population. The three subtypes had distinct genomic alterations and prognoses and demonstrated differential sensitivity to metabolic inhibitors. Fatty acid inhibitors affected the MPS1 lipogenic population, while inhibitors of glycolysis targeted the MPS2 subtype. Importantly, the authors found that inhibition of lactate dehydrogenase could increase the anti-PD-1immunotherapy response in the MPS2 population of TNBCs.Expert Commentary: This work shows that the metabolic subtypes of TNBCs can be the basis for precision medicine using specific metabolic inhibitors.Gong Y, Ji P, Yang YS, Xie S, Yu TJ, Xiao Y, et al. Metabolic-pathway-based subtyping of triple-negative breast cancer reveals potential therapeutic targets. Cell Metab 2021;33:51–64.e9. DOI: 10.1016/j.cmet.2020.10.012.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.