Exosomal Wnt-induced dedifferentiation of colorectal cancer cells contributes to chemotherapy resistance

• Published in: Oncogene Vol. 38; no. 11; pp. 1951 - 1965
• Main Authors: Hu, Y.-B., Yan, C., Mu, L., Mi, Y.–L., Zhao, H., Hu, H., Li, X.-L., Tao, D.-D., Wu, Y.-Q., Gong, J.-P., Qin, J.-C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-03-2019; Nature Publishing Group
• Subjects: 13/1; 13/109; 13/31; 14/19; 14/28; 14/34; 38/22; 38/39; 38/90; 631/67/1059/2326; 631/67/327; 631/67/71; 631/80; 64/60; Animals; Antineoplastic Agents - pharmacology; Apoptosis; Cancer cells; Cancer treatment; Care and treatment; Cell Biology; Cell Dedifferentiation - drug effects; Cell Dedifferentiation - genetics; Cell differentiation; Cell Proliferation - drug effects; Cells, Cultured; Cellular signal transduction; Chemoresistance; Chemotherapy; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Drug resistance; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Exosomes; Exosomes - drug effects; Exosomes - metabolism; Exosomes - pathology; Female; Fibroblasts; Fibroblasts - pathology; Fibroblasts - physiology; Fluorouracil - pharmacology; Health aspects; HT29 Cells; Human Genetics; Humans; Internal Medicine; Medicine; Medicine & Public Health; Mice; Mice, Inbred NOD; Mice, SCID; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - pathology; Neoplastic Stem Cells - physiology; Oncology; Oxaliplatin - pharmacology; Paracrine Communication - drug effects; Pyrazines - pharmacology; Pyridines - pharmacology; Recurrence (Disease); Stem cells; Tumors; Wnt protein; Wnt Signaling Pathway - drug effects; Wnt Signaling Pathway - physiology; Xenograft Model Antitumor Assays
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/s41388-018-0557-9

Cancer stem cells (CSCs) are inherently resistant to chemotherapy, and CSCs in chemotherapy-failed recurrent tumors are enriched; however, the cellular origin of chemotherapy-induced CSC enrichment remains unclear. Communication with stromal fibroblasts may induce cancer cell dedifferentiation into CSCs through secreted factors. We recently demonstrated that fibroblast-derived exosomes promote chemoresistance in colorectal cancer (CRC). Here, we report that fibroblasts confer CRC chemoresistance via exosome-induced reprogramming (dedifferentiation) of bulk CRC cells to phenotypic and functional CSCs. At the molecular level, we provided evidence that the major reprogramming regulators in fibroblast-exosomes are Wnts. Exosomal Wnts were found to increase Wnt activity and drug resistance in differentiated CRC cells, and inhibiting Wnt release diminished this effect in vitro and in vivo. Together, our results indicate that exosomal Wnts derived from fibroblasts could induce the dedifferentiation of cancer cells to promote chemoresistance in CRC, and suggest that interfering with exosomal Wnt signaling may help to improve chemosensitivity and the therapeutic window.