ABSTRACT
Effective targeting of cancer stem cells (CSCs) requires neutralization of self-renewal and chemoresistance, however 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 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 via a bifurcating signaling axis and provide an opportunity to target both signaling pathways in endometrioid tumors.
SUMMARY CD55 is a membrane complement regulatory protein that attenuates complement-mediated cytotoxicity. Saygin et al. elucidate a new role for CD55 as a signaling hub for cancer stem cell self-renewal and cisplatin resistance pathways in endometrioid tumors and open a new line of research into chemotherapeutic-refractory cancers.
- GPI
- glycophosphatidylinositol
- LIME
- LCK interacting transmembrane adaptor
- PAG
- protein associated with glycosphingolipid-enriched microdomains
- CSC
- cancer stem cell
- DAF
- decay accelerating protein
- LCK
- Endometrioid Tumor, ET
- CSC
- cancer stem cell
- mCRP
- membrane-bound complement regulatory protein
- ROR2
- receptor tyrosine kinase like orphan receptor 2
- LCK
- lymphocyte-specific protein tyrosine kinase
- JNK
- c-Jun N-terminal kinase
Footnotes
Contact: Dr. Justin D. Lathia, Department of Cellular and Molecular Medicine, Lerner Research Institute, 9500 Euclid Ave., NC10, Cleveland, OH 44195, USA, lathiaj{at}ccf.org, Phone: 216-445-7475, Fax: 216-444-8359; Dr. Ofer Reizes, Department of Cellular and Molecular Medicine, Lerner Research Institute, 9500 Euclid Ave., NC10, Cleveland, OH 44195, USA, reizeso{at}ccf.org, Phone: 216-445-0880, Fax: 216-444-8359
Conflicts of interest: None to declare
