Ancient hot and cold genes and chemotherapy resistance emergence

Amy Wu, Qiucen Zhang, Guillaume Lambert, Zayar Khin, Robert A. Gatenby, Hyunsung John Kim, Nader Pourmand, Kimberly Bussey, Paul Davies, James C. Sturm, Robert H. Austin

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

We use a microfabricated ecology with a doxorubicin gradient and population fragmentation to produce a strong Darwinian selective pressure that drives forward the rapid emergence of doxorubicin resistance in multiple myeloma (MM) cancer cells. RNA sequencing of the resistant cells was used to examine (i) emergence of genes with high de novo substitution densities (i.e., hot genes) and (ii) genes never substituted (i.e., cold genes). The set of cold genes, which were 21% of the genes sequenced, were further winnowed down by examining excess expression levels. Both the most highly substituted genes and the most highly expressed never-substituted genes were biased in age toward the most ancient of genes. This would support the model that cancer represents a revision back to ancient forms of life adapted to high fitness under extreme stress, and suggests that these ancient genes may be targets for cancer therapy.

Original languageEnglish (US)
Pages (from-to)10467-10472
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume112
Issue number33
DOIs
StatePublished - Aug 18 2015

Keywords

  • Ancient genes
  • Cancer
  • Cold
  • Emergence
  • Hot

ASJC Scopus subject areas

  • General

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    Wu, A., Zhang, Q., Lambert, G., Khin, Z., Gatenby, R. A., Kim, H. J., Pourmand, N., Bussey, K., Davies, P., Sturm, J. C., & Austin, R. H. (2015). Ancient hot and cold genes and chemotherapy resistance emergence. Proceedings of the National Academy of Sciences of the United States of America, 112(33), 10467-10472. https://doi.org/10.1073/pnas.1512396112