title: Chemotherapy induces adaptive drug resistance and metastatic potentials via phenotypic CXCR4-expressing cell state transition in ovarian cancer.
abstract: Ovarian cancer (OVC) patients who receive chemotherapy often acquire drug resistance within one year. This can lead to tumor reoccurrence and metastasis, the major causes of mortality. We report a transient increase of a small distinctive CXCR4High/CD24Low cancer stem cell population (CXCR4High) in A2780 and SKOV-3 OVC cell lines in response to cisplatin, doxorubicin, and paclitaxel, treatments. The withdrawal of the drug challenges reversed this cell-state transition. CXCR4High exhibits dormancy in drug resistance and mesenchymal-like invasion, migration, colonization, and tumor formation properties. The removal of this cell population from a doxorubicin-resistant A2780 lineage (A2780/ADR) recovered the sensitivity to drug treatments. A cytotoxic peptide (CXCR4-KLA) that can selectively target cell-surface CXCR4 receptor was further synthesized to investigate the therapeutic merits of targeting CXCR4High. This peptide was more potent than the conventional CXCR4 antagonists (AMD3100 and CTCE-9908) in eradicating the cancer stem cells. When used together with cytotoxic agents such as doxorubicin and cisplatin, the combined drug-peptide regimens exhibited a synergistic cell-killing effect on A2780, A2780/ADR, and SKOV-3. Our data suggested that chemotherapy could establish drug-resistant and tumor-initiating properties of OVC via reversible CXCR4 cell state transition. Therapeutic strategies designed to eradicate rather than antagonize CXCR4High might offer a far-reaching potential as supportive chemotherapy.
authors.affiliation: Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, New York, United States of America.
authors.forename: Hyun Hee
authors.initials: HH
authors.lastname: Lee
authors.affiliation: Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, New York, United States of America.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Bellat
authors.affiliation: Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, New York, United States of America.
authors.forename: Benedict
authors.identifier: http://orcid.org/0000-0001-7673-659X
authors.initials: B
authors.lastname: Law
mesh_terms: D045744:Cell Line, Tumor; D003603:Cytotoxins / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: C527276:CXCR4 protein, human; D003603:Cytotoxins; D009363:Neoplasm Proteins; D010455:Peptides; D019718:Receptors, CXCR4; D004317:Doxorubicin