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

eLife

Naishitha Anaparthy¹  Anja Pertot²  Kenneth Chang²  Jude Kendall³  Michael C Schatz³  Fred Rollins⁴  Gary C Stone⁴  Tyler Garvin⁴  Nitin H Shirole⁴  Vijay A Singh⁴  Zhan Yao⁴  James Hicks⁴  Debjani Pal⁴  Hilary Cox⁴  Leyla Edwards⁴  Raffaella Sordella⁵  Gregory J Hannon⁵ 

[1] Graduate Program in Genetics, Stony Brook University, Stony Brook, United States;Graduate Program in Molecular and Cellular Biology, Stony Brook University, Stony Brook, United States;Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States;Cold Spring Harbor Laboratory, Cold Spring Harbor, United States;Huntington Hospital, Northwell Health, Huntington, United States;

关键词: genetic diversity;    drug adaptability;    intra-tumor heterogeneity;    tumor evolution;    tumor fitness;    copy number alteration;   

DOI  :  10.7554/eLife.21615

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown