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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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 Northwell Health School of Biological Sciences > Publications CSHL Cancer Center Program > Cancer Genetics and Genomics Program CSHL Cancer Center Program > Cellular Communication in Cancer Program |
| Depositing User: | Matt Covey |
| Date: | 16 January 2017 |
| Date Deposited: | 17 Jan 2017 20:48 |
| Last Modified: | 07 Jul 2021 13:51 |
| PMCID: | PMC5345931 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/34028 |
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