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

• DOI: 10.7554/elife.21615
• Publication Date: 2017-01-16T13:02:33Z
• Authors: Debjani Pal; Anja Pertot; Nitin H Shirole; Zhan Yao; Naishitha Anaparthy; Tyler Garvin; Hilary Cox; Kenneth Chang; Fred Rollins; Jude Kendall; Leyla Edwards; Vijay A Singh; Gary C Stone; Michael C Schatz; James Hicks; Gregory J Hannon; Raffaella Sordella
• Keywords: 0301 basic medicine; tumor evolution; copy number alteration; DNA Repair; QH301-705.5; Science; Gene Dosage; DNA repair; 03 medical and health sciences; Transforming Growth Factor beta; Cell Line, Tumor; Neoplasms; cancer; drug adaptability; Humans; DNA Breaks, Double-Stranded; TGF-beta; Biology (General); Cancer Biology; Q; R; intra-tumor heterogeneity; CD24 Antigen; Genetic Variation; genetic diversity; tumor fitness; 3. Good health; Hyaluronan Receptors; Mutation; Medicine

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.