CD55 regulates self-renewal and cisplatin resistance in endometrioid tumors

Caner Saygin, Andrew Wiechert, Vinay S. Rao, Ravi Alluri, Elizabeth Connor, Praveena S. Thiagarajan, James S. Hale, Yan Li, Anastasia Chumakova, Awad Jarrar, Yvonne Parker, Daniel J. Lindner, Anil Belur Nagaraj, J. Julie Kim, Analisa DiFeo, Fadi W. Abdul-Karim, Chad Michener, Peter G. Rose, Robert DeBernardo, Haider MahdiKeith R. McCrae, Feng Lin, Justin D. Lathia*, Ofer Reizes

*Corresponding author for this work

Research output: Contribution to journalArticle

18 Scopus citations

Abstract

Effective targeting of cancer stem cells (CSCs) requires neutralization of self-renewal and chemoresistance, but these phenotypes are often regulated by distinct molecular mechanisms. Here we report the ability to target both of these phenotypes via CD55, an intrinsic cell surface complement inhibitor, which was identified in a comparative analysis between CSCs and non- CSCs in endometrioid cancer models. In this context, CD55 functions in a complement-independent manner and required lipid raft localization for CSC maintenance and cisplatin resistance. CD55 regulated self-renewal and core pluripotency genes via ROR2/JNK signaling and in parallel cisplatin resistance via lymphocyte-specific protein tyrosine kinase (LCK) signaling, which induced DNA repair genes. Targeting LCK signaling via saracatinib, an inhibitor currently undergoing clinical evaluation, sensitized chemoresistant cells to cisplatin. Collectively, our findings identify CD55 as a unique signaling node that drives self-renewal and therapeutic resistance through a bifurcating signaling axis and provides an opportunity to target both signaling pathways in endometrioid tumors.

Original languageEnglish (US)
Pages (from-to)2715-2732
Number of pages18
JournalJournal of Experimental Medicine
Volume214
Issue number9
DOIs
StatePublished - Jan 1 2017

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Saygin, C., Wiechert, A., Rao, V. S., Alluri, R., Connor, E., Thiagarajan, P. S., Hale, J. S., Li, Y., Chumakova, A., Jarrar, A., Parker, Y., Lindner, D. J., Nagaraj, A. B., Kim, J. J., DiFeo, A., Abdul-Karim, F. W., Michener, C., Rose, P. G., DeBernardo, R., ... Reizes, O. (2017). CD55 regulates self-renewal and cisplatin resistance in endometrioid tumors. Journal of Experimental Medicine, 214(9), 2715-2732. https://doi.org/10.1084/jem.20170438