TY - JOUR
T1 - CD55 regulates self-renewal and cisplatin resistance in endometrioid tumors
AU - Saygin, Caner
AU - Wiechert, Andrew
AU - Rao, Vinay S.
AU - Alluri, Ravi
AU - Connor, Elizabeth
AU - Thiagarajan, Praveena S.
AU - Hale, James S.
AU - Li, Yan
AU - Chumakova, Anastasia
AU - Jarrar, Awad
AU - Parker, Yvonne
AU - Lindner, Daniel J.
AU - Nagaraj, Anil Belur
AU - Kim, J. Julie
AU - DiFeo, Analisa
AU - Abdul-Karim, Fadi W.
AU - Michener, Chad
AU - Rose, Peter G.
AU - DeBernardo, Robert
AU - Mahdi, Haider
AU - McCrae, Keith R.
AU - Lin, Feng
AU - Lathia, Justin D.
AU - Reizes, Ofer
N1 - Funding Information:
This work was funded by National Institutes of Health grant CA191263 to O. Reizes and J.D. Lathia. The work in the Reizes laboratory is also supported by the Cleveland Clinic Foundation, Clinical and Translational Science Collaborative of Cleveland (UL1TR000439), Case Comprehensive Cancer Center, Case Western Reserve University (P30 CA043703), the Cleveland Clinic VeloSano Bike Race, and the Laura J. Fogarty Endowed Chair for Uterine Cancer Research (O. Reizes). The Lathia laboratory also receives funding from National Institutes of Health grants NS089641, NS083629, and CA157948; a Distinguished Scientist Award from the Sontag Foundation, a Research Scholar Award from the American Cancer Society, Blast GBM, the Cleveland Clinic VeloSano Bike Race, and the Case Comprehensive Cancer Center, Case Western Reserve University. This work used the Leica SP8 confocal microscope that was purchased under National Institutes of Health SIG grant 1S10OD019972-01. The authors declare no competing financial interests.
Publisher Copyright:
© 2017 Saygin et al.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20170438
DO - 10.1084/jem.20170438
M3 - Article
C2 - 28838952
AN - SCOPUS:85028801431
SN - 0022-1007
VL - 214
SP - 2715
EP - 2732
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 9
ER -
