TGF-β reduces DNA ds-break repair mechanisms to heighten genetic diversity and adaptability of CD44+/CD24− cancer cells

Abstract

Many lines of evidence have indicated that both genetic and non-genetic determinants can contribute to intra-tumor heterogeneity and influence cancer outcomes. Among the best described sub-population of cancer cells generated by non-genetic mechanisms are cells characterized by a CD44+/CD24− cell surface marker profile. Here, we report that human CD44+/CD24− cancer cells are genetically highly unstable because of intrinsic defects in their DNA-repair capabilities. In fact, in CD44+/CD24− cells, constitutive activation of the TGF-beta axis was both necessary and sufficient to reduce the expression of genes that are crucial in coordinating DNA damage repair mechanisms. Consequently, we observed that cancer cells that reside in a CD44+/CD24− state are characterized by increased accumulation of DNA copy number alterations, greater genetic diversity and improved adaptability to drug treatment. Together, these data suggest that the transition into a CD44+/CD24− cell state can promote intra-tumor genetic heterogeneity, spur tumor evolution and increase tumor fitness.DOI: http://dx.doi.org/10.7554/eLife.21615.001

Deciphering the Molecular Mechanism of Spontaneous Senescence in Primary Epithelial Ovarian Cancer Cells

“…Particularly intriguing activity was recently observed in ovarian cancer cell-derived HGF, which appeared capable of inducing accelerated senescence in HPMCs, actively contributing to the formation of a metastatic niche by these cells within the peritoneum [51]. It is also possible that exogenous pro-senescence stimuli may interfere with intracellular senescence machinery, as evidenced by TGF-β1, which has the ability to generate ROS [52], suppress hTERT [53], reduce the efficiency of DNA repair mechanisms [54], and deteriorate telomeres [55].…”

Cancer metastasis through the prism of epithelial‐to‐mesenchymal transition in circulating tumor cells

“…These findings that are consistent with developmental models (Murakami et al ., ; Seher and Leptin, ) might explain the drug resistance associated with EMT (Maheswaran and Haber, ; Nieto et al ., ). In fact, TGF‐β activation in the CD44+/CD24− stem‐like cells increases DNA copy number alterations and contributes to changes in drug responses (Pal et al ., ). Taken together, these findings suggest that EMT in proliferating cancer cells could be a major contributor to the molecular evolution and heterogeneity of tumors during disease progression.…”

Methods for Copy Number Aberration Detection from Single-cell DNA Sequencing Data

“…Moreover, HMMcopy was designed for aCGH data originally, and thus does not take into account the specific error profiles that characterize single-cell sequencing data, such as low and uneven coverage, or the computational challenges that arise due to biological processes such as aneuploidy in a tumor single cell. While these three methods have been widely applied to analyze single-cell data [27,[31][32][33][34][37][38][39][40][41][42][43][44][45][46][47][48], a comprehensive study of their performance is currently lacking. While Knouse et al [32] assessed the performance of CBS and HMM-based methods on single-cell DNA sequencing data, their evaluation is limited to CNVs in brain and skin cells.…”