TGF-β reduces DNA ds-break repair mechanisms to heighten genetic diversity and adaptability of CD44+/CD24- cancer cells.
Debjani PalAnja PertotNitin H ShiroleZhan YaoNaishitha AnaparthyTyler GarvinHilary CoxKenneth ChangFred RollinsJude KendallLeyla EdwardsVijay A SinghGary C StoneMichael C SchatzJames HicksGregory J HannonRaffaella SordellaPublished in: eLife (2017)
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.
Keyphrases
- copy number
- genetic diversity
- genome wide
- dna damage
- dna repair
- mitochondrial dna
- induced apoptosis
- single cell
- dna methylation
- endothelial cells
- transforming growth factor
- circulating tumor
- emergency department
- stem cells
- cell free
- machine learning
- big data
- squamous cell carcinoma
- deep learning
- mesenchymal stem cells
- cell death
- data analysis
- dna damage response
- binding protein
- combination therapy
- circulating tumor cells
- smoking cessation
- nucleic acid