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

The impact of dietary changes on tumor progression has emerged as an area of interest in cancer research, with many strategies being proposed to improve patient outcomes. Lien and colleagues compared two low glycemic diets, caloric restriction (CR) and ketogenic diet (KD), in mouse models of pancreatic cancer and non-small cell lung cancer to interrogate the metabolic changes that impact tumor progression. Interestingly, only CR reduced tumor growth and was unique from KD by exhibiting marked decreases in fatty acid levels. Tumor cells are able to utilize stearoyl-CoA desaturase (SCD) to synthesize fatty acids in nutrient-depleted conditions to sustain proliferation, however, both low glycemic diets reduced SCD activity in tumor cells. Both forced expression of SCD and exogenous supplementation of unsaturated fatty acids reverted the effects of CR on tumor growth inhibition. In the context of KD, the authors showed supplementation of dietary saturated fatty acids synergized with the reduced SCD activity to reduce tumor growth.Expert Commentary: This study implies that alterations in lipid metabolism dictate the outcome of low glucose diets on tumor growth, suggesting dietary interventions as a therapeutic approach.Lien EC, Westermark AM, Zhang Y, Yuan C, Li Z, Lau AN, et al. Low glycaemic diets alter lipid metabolism to influence tumor growth. Nature 2021;599:302–7.Metastatic disease upon recurrence, driven in part by proliferation of disseminated, dormant cancer cells, contributes significantly to cancer-related deaths. Using paired proliferative/dormant mouse and human tumor cell lines coupled with quantitative microscopy, Di Martino and colleagues identified a potential new regulator of dormancy within the extracellular matrix (ECM). Dormant cancer cells are surrounded by ECM enriched in type III collagen, and knockdown/overexpression experiments showed that type III collagen was necessary and sufficient for cancer cell dormancy. Interestingly, production of type III collagen by the cancer cells, as opposed to stroma-derived, appeared to be the most critical source in the tumor microenvironment. Discoidin domain receptor tyrosine kinase 1 (DDR1) was identified as the key collagen receptor and was linked to a feedback loop activating the transcription factor STAT1, driving further production of type III collagen.Expert Commentary: This work highlights an avenue to inhibit tumor cell reactivation at resected tumor margins and other sites, either by introduction of type III collagen (as tested in the models presented) or via modulation of non-kinase functions of DDR1.Di Martino JS, Nobre AR, Mondal C, Taha I, Farias EF, Fertig EJ, et al. A tumor-derived type III collagen-rich ECM niche regulates tumor cell dormancy. Nat Cancer 2022;3:90–107.The design of T cells expressing chimeric antigen receptors (CAR T cells) against solid tumors like neuroblastoma is hampered by many issues including off-target effects on normal tissue. To overcome this limitation, Heitzeneder and colleagues evaluated a previously identified surface target in neuroblastoma, GPC2, which was identified to be expressed in the fetal brain and neuroblastoma, making it a good candidate for reducing toxicity to healthy tissue. The authors found across neuroblastoma cell lines that potency of GPC2 CAR T cells was highly dependent on antigen density. Flow cytometry of bone marrow aspirates from patients showed consistently low GPC2 antigen density in metastatic neuroblastoma xenografts. Incorporating a CD28 transmembrane domain and expression of c-Jun using a bicistronic construct into the CAR T cells led to highly potent effects against metastatic neuroblastoma and antigen-low tumor cells, improving in vivo efficacy and abrogating late relapses.Expert Commentary: Recapitulating the success of CD19 and CD22 CAR T–cell therapy in leukemia has so far proved elusive in solid tumors. The strategy employed here, to design immunotherapy effective against a fetal antigen with low levels of expression, opens up an array of possibilities to safely target pediatric and other solid tumors.Heitzeneder S, Bosse KR, Zhu Z, Zhelev D, Majzner RG, Radosevich MT, et al. GPC2-CAR T cells tuned for low antigen density mediate potent activity against neuroblastoma without toxicity. Cancer Cell 2022;40:53–69.e9. doi: 10.1016/j.ccell.2021.12.005.Although a large percentage of approved oncology drugs target cell surface proteins, this only represents 2.5% of the tumor cell surfaceome. Hu and colleagues annotated genes encoding cell surface proteins (GESP) by integrating data from independent resources, including experimentally and in silico–derived protein and gene ontology databases. Analysis of single cell and bulk mRNA sequencing data was used to determine which GESPs were specifically expressed in cancers, while genome-wide CRISPR screening data was used to infer cancer growth dependency. This approach identified new potential targetable receptor ligand interactions, with many involved in communication between tumor and immune cells in the tumor microenvironment.Expert Commentary: This systems biology approach provides a valuable resource for the prioritization and study of potential new cell surface targets and has been made available through the Functional Cancer Genome data portal (http://fcgportal.org/TCSA).Hu Z, Yuan J, Long M, Jiang J, Zhang Y, Zhang T, et al. The Cancer Surfaceome Atlas integrates genomic, functional and drug response data to identify actionable targets. Nat Cancer 2021;2:1406–22.There is substantial evidence that the gut microbiome has a substantial impact on colorectal cancer progression and chemoresistance, but the precise mechanisms by which species such as Fusobacterium nucleatum regulate this disease are underappreciated. Zheng and colleagues describe a novel mechanism by which F. nucleatum infection of colorectal cancer cells promotes its own bacterial colonization. They showed that F. nucleatum infection increased expression of angiopoietin-like 4 (ANGPTL4) and that ANGPTL4 in turn promoted glucose uptake (via Glut1 upregulation) and glycolysis in colorectal cancer cells in vitro and in vivo. This metabolic change provided a hypoxic environment for F. nucleatum colonization and subsequently increased carcinogenesis of the colon. Further, they showed that F. nucleatum regulates ANGPTL4 expression via increased acetylation of histone H3 lysine 27 in colorectal cancer cells and patient tumor samples, resulting from decreased histone deacetylase activity.Expert Commentary: This study provides a druggable target to attenuate F. nucleatum–mediated effects on colorectal cancer progression.Zheng X, Liu R, Zhou C, Yu H, Luo W, Zhu J, et al. ANGPTL4-mediated promotion of glycolysis facilitates the colonization of Fusobacterium nucleatum in colorectal cancer. Cancer Res 2021;81:6157–70.Nearly 50 years ago, Richard Peto proposed a paradox for the ontology of cancer. Because cancer was propelled by an accumulation of genetic mutations, it seemed logical that with more cellular divisions in larger or older animals, cancer incidence would increase. However, this was not true comparing large versus small mammalian species. Reporting in Nature, Vincze and colleagues assessed cancer mortality risk (CMR) and the incidence of cancer mortality in 191 mammalian species from 11,840 individual animals that had postmortem records, generating three conclusions. First, cancer was pervasive across nearly all species. Variability ranged from 0% to 57%, with strong concordance within related species. Second, carnivorous mammals had the highest cancer risk, tracking strongly with animals that ate other vertebrate mammals, which may be due to jumping pathogens. Third, life expectancy correlated with CMR across species, a finding shown previously only within species.Expert Commentary: An evolutionary perspective supports Peto's paradox that body size, and thereby total cell divisions, in mammalian species does not correlate with cancer risk. This diversity in cancer risk across mammalian species could reveal anticancer mechanisms.Vincze O, Colchero F, Lemaître JF, Conde DA, Pavard S, Bieuville M, et al. Cancer risk across mammals. Nature 2022;601:263–7.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.