2. Academic Validation
  3. Exosomal Wnt-induced dedifferentiation of colorectal cancer cells contributes to chemotherapy resistance

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

  • Oncogene. 2019 Mar;38(11):1951-1965. doi: 10.1038/s41388-018-0557-9.
Y-B Hu 1 2,  C Yan 1 2,  L Mu 1 2,  Y-L Mi 1 2,  H Zhao 1 2,  H Hu 1 2,  X-L Li 2,  D-D Tao 2,  Y-Q Wu 1,  J-P Gong 3 4,  J-C Qin 5 6
Affiliations

Affiliations

  • 1 Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 2 Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
  • 3 Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. jpgong@tjh.tjmu.edu.cn.
  • 4 Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. jpgong@tjh.tjmu.edu.cn.
  • 5 Department of Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. jcqin@tjh.tjmu.edu.cn.
  • 6 Molecular Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. jcqin@tjh.tjmu.edu.cn.
PMID: 30390075 DOI: 10.1038/s41388-018-0557-9
Abstract

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.

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