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

Pal, D., Pertot, A., Shirole, N. H., Yao, Z., Anaparthy, N., Garvin, T., Cox, H., Chang, K., Rollins, F., Kendall, J., Edwards, L., Singh, V. A., Stone, G. C., Schatz, M. C., Hicks, J., Hannon, G., Sordella, R. (January 2017) TGF-beta reduces DNA ds-break repair mechanisms to heighten genetic diversity and adaptability of CD44+/CD24- cancer cells. Elife, 6. ISSN 2050-084X (Electronic)2050-084X (Linking)

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URL: https://www.ncbi.nlm.nih.gov/pubmed/28092266
DOI: 10.7554/eLife.21615

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 due to 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 critical 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.

Item Type: Paper
Uncontrolled Keywords: cancer biology cell biology human
Subjects: diseases & disorders > cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > DNA repair
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > TGF-beta
CSHL Authors:
Communities: CSHL Cancer Center Program > Signal Transduction
CSHL labs > Chang lab
CSHL labs > Hannon lab
CSHL labs > Hicks lab
CSHL labs > Schatz lab
CSHL labs > Sordella lab
CSHL labs > Wigler lab
Watson School > Publications
Northwell Health
Depositing User: Matt Covey
Date: 16 January 2017
Date Deposited: 17 Jan 2017 20:48
Last Modified: 11 Jan 2019 19:58
Related URLs:
URI: http://repository.cshl.edu/id/eprint/34028

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