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.
Highlights
Uterine and ovarian cancers are the most common gynecological cancers in the US (Baldwin et al, 2012; Siegel et al, 2016)
Of the other two membrane complement regulatory proteins included in the screen, CD59 was expressed higher in cancer stem cell (CSC), whereas there was no appreciable difference in CD46 expression (Fig. S1 A).We further validated these results in several cisplatin-naive endometrioid tumor cell lines (A2780, TOV112D) and a patient-derived xenograft model (EEC-4), at the protein and RNA levels (Fig. 1, C and D; and Fig. S1, B–D)
Cisplatin resistance is a hallmark of endometrioid CSCs (Wiechert et al, 2016), and given the high expression of CD55 in CSCs and cisplatin-resistant parental cells, we investigated whether CD55 inhibition affects cisplatin resistance
Summary
Uterine and ovarian cancers are the most common gynecological cancers in the US (Baldwin et al, 2012; Siegel et al, 2016). These tumors are characterized by four main histological subtypes: endometrioid, serous, mucinous, and clear cell carcinoma (Karst and Drapkin, 2010; Kurman and Shih, 2016). In advanced-stage disease, both uterine and ovarian cancers are treated with cytoreductive surgery and platinum-based cytotoxic chemotherapy (Armstrong et al, 2006). Many patients achieve clinical remission with this standard approach, advanced-stage uterine and ovarian cancers are prone to recurrence (Hanker et al, 2012). Chemoresistance is generally defined as progression of disease within 6 mo of
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