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

The rigid tumor stroma in pancreatic ductal adenocarcinoma (PDAC) is thought to limit access to chemotherapy. Type 1 collagen (Col1) is a major component of this stroma and underlies the stiffness of PDAC. Chen and colleagues deleted Col1a1, which encodes the major component of Col1, in αSMA+ myofibroblasts in a mouse model of PDAC to directly evaluate its role in tumor progression. Tumors in mice harboring Col1a1-deleted myofibroblasts displayed a more flexible stroma, associated with enhanced tumorigenesis and decreased survival. Deletion of Col1a1 also resulted in SOX9-mediated upregulation of Cxcl5 in cancer cells. This enhanced CXCL5 production resulted in recruitment of myeloid-derived suppressor cells and attenuation of CD8+ T-cells, resulting in immune suppression. Importantly, combined inhibition of the CXCL5 receptor, CXCR2, and the cytokine CCR2 was able to reverse the enhanced tumorigenesis observed upon Col1a1 deletion.Expert Commentary: These results highlight a fundamental role for stroma-produced collagen in regulating tumor immunity and attenuating PDAC progression.Chen Y, Kim J, Yang S., Wang H, Wu CJ, Sugimoto H, et al. Type I collagen deletion in αSMA+ myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer. Cancer Cell 2021;39:548–65.e6. DOI: 10.1016/j.ccell.2021.02.007.The incidence of obesity-induced hepatocellular carcinoma (HCC) is rising in the world. Broadfield and colleagues analyzed metabolic effects of high-fat diets (HFD) in mouse livers before disease development. Healthy mice fed a HFD demonstrated increased hepatic glucose uptake in comparison to mice receiving control diet (CD), and HFD mice showed elevated lactate levels upon challenge with glucose. Addition of palmitate to hepatocytes and liver cancer cells resulted in formation of reactive oxygen species, followed by glucose uptake and secretion of lactate. Furthermore, a correlation between waist dimension and secretion of lactate was observed when a cohort of healthy humans received oral glucose. Treatment of mice with a hepatic carcinogen led to increased rates of HCC in HFD mice compared with CD mice. The changes in glucose metabolism induced by HFD in nontransformed livers were similar to the metabolic alterations observed in all mouse HCC tumors independent of diet.Expert Commentary: Fat induces metabolic changes in nontransformed liver cells that are related to the metabolic state of HCC.Broadfield LA, Duarte JAG, Scmieder R., Broekaert D, Veys K, Planque M, et al. Fat induces glucose metabolism in nontransformed liver cells and promotes liver tumorigenesis. Cancer Res 2021;81:1988–2001.Homologous recombination (HR) repair consists of end resection, strand invasion, and subsequent DNA synthesis, followed by resolution of Holliday junctions. End resection requires removal of several kilobases of DNA from the 5′ strand of double strand-breaks (DSB) while leaving the 3′ strand intact. Liu and colleagues demonstrated that RNA polymerase III is actively recruited to DSBs in a manner dependent on the MRN (Mre11, Rad50, and Nbs1) complex to enable the transcription of a hybrid RNA-DNA intermediate, which in turn, protects the single-stranded 3′ overhang during end resection. The absence of RNA polymerase III transcriptional activity led to a decrease in HR repair and end resection with subsequent genetic loss, implicating this polymerase as essential in DSB DNA repair.Expert Commentary: Liu and colleagues showed that HR repair depends on RNA polymerase III, suggesting that Pol III inhibitors may block tumor cells dependent on HR activity to control replicative stress.Liu S, Hua Y, Wang J, Li L, Yuan J, Zhang B, et al. RNA polymerase III is required for the repair of DNA double-strand breaks by homologous recombination. Cell 2021;184:1314–29.e10. DOI: 10.1016/j.cell.2021.01.048.Activating mutations of KRAS drive a majority of pancreatic adenocarcinomas and ∼25% of all cancers. Raf-Mek1/2-Erk1/2 signaling downstream of Ras is considered particularly relevant for cancer progression. This pathway can be targeted with highly specific Mek1/2 inhibitors. These inhibitors have shown mixed clinical activity, with efficacy against cancers driven by mutant BRAF but not KRAS. To shed light on this context-dependent efficacy, Bilal and colleagues generated pancreatic cancer cells co-resistant to inhibitors of Mek1/2, KRAS, and Erk1/2. Concurrent with the development of resistance, the cells acquired more mesenchymal-like phenotypes and became more highly metastatic. Slug was identified to be responsible for both the increased resistance to Mek1/2 inhibition and the increased metastatic ability of the cells. Targeting Slug resensitized pancreatic cancer cells to Mek1/2 inhibition.Expert Commentary: Slug mediates pancreatic cancer resistance to Mek1/2 inhibitors, indicating new therapeutic avenues for developing more effective pancreatic cancer treatment.Bilal F, Arenas EJ, Pederson K, Martinez-Sabadell A, Nabet B, Guruceaga E, et al. The transcription factor Slug uncouples pancreatic cancer progression from the Raf-Mek1/2-Erk1/2 pathway. Cancer Research; Published OnlineFirst April 26, 2021; DOI: 10.1158/0008-5472.CAN-20-4263.RAF dimer inhibitors are an emerging therapeutic class that can inhibit the growth of tumors harboring mutant RAF and RAS. Yen and colleagues described the preclinical and clinical activity of the RAF dimer inhibitor belvarafenib and identified the first reported resistance mechanism to these inhibitors. Belvarafenib had significant activity against both BRAF and NRAS mutant tumors. In both preclinical and clinical studies, recurrent acquired ARAFG387X mutations were identified at the time of resistance. ARAF mutant cells retained sensitivity to a MEK inhibitor. The combination of belvarafenib with a MEK inhibitor increased efficacy and response durability.Expert Commentary: This study demonstrates that acquired ARAF mutations mediate resistance to belvarafenib, which can be prevented by combining belvarafenib with a MEK inhibitor.Yen I, Shanahan F, Lee J, Hong YS, Shin SJ, Moore AR, et al. ARAF mutations confer resistance to the RAF inhibitor belvarafenib in melanoma. Nature; Published online May 5, 2021; DOI: 10.1038/s41586-021-03515-1.Activating molecule in BECN1-regulated autophagy protein 1 (AMBRA1) is a multifunctional adaptor protein with reported tumor suppressor activity. Di Leo and colleagues used mouse models to demonstrate that loss of Ambra1 accelerated growth and metastasis of melanoma in the context of Pten loss and mutated Braf. Ambra1-deficient tumors were enriched for genes involved in extracellular matrix organization and focal adhesion signaling. Loss of AMBRA1 binding to focal adhesion kinase (FAK) resulted in hyperactivation of FAK signaling. AMBRA1-deficient cells were sensitized to pharmacological inhibition of FAK, leading to decreased growth and invasion.Expert Commentary: Exploration of the potential use of FAK inhibitors in AMBRA1-low melanoma is supported by the reported association between low AMBRA1 expression and genes linked with invasive phenotypes in human melanoma and warrants further investigation.Di Leo L, Bodemeyer V, Bosisio FM, Claps G, Carretta M, Rizza S, et al. Loss of Ambra1 promotes melanoma growth and invasion. Nature Commun 2021;12:2550. DOI: 10.1038/s41467-021-22772-2.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.