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.

中文翻译：

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外泌体 Wnt 诱导的结直肠癌细胞去分化有助于化疗耐药。

癌症干细胞（CSC）天生对化疗有抵抗力，化疗失败的复发性肿瘤中CSC会富集；然而，化疗引起的 CSC 富集的细胞起源仍不清楚。与基质成纤维细胞的通讯可能通过分泌因子诱导癌细胞去分化为 CSC。我们最近证明，成纤维细胞衍生的外泌体可促进结直肠癌（CRC）的化疗耐药性。在此，我们报道成纤维细胞通过外泌体诱导的大块 CRC 细胞重编程（去分化）向表型和功能性 CSC 赋予 CRC 化疗耐药性。在分子水平上，我们提供的证据表明成纤维细胞外泌体中的主要重编程调节因子是Wnt。研究发现，外泌体 Wnt 可以增加分化的 CRC 细胞中的 Wnt 活性和耐药性，而抑制 Wnt 释放可以减弱体外和体内的这种作用。总之，我们的结果表明，源自成纤维细胞的外泌体 Wnt 可以诱导癌细胞去分化，从而促进 CRC 的化疗耐药性，并表明干扰外泌体 Wnt 信号传导可能有助于改善化疗敏感性和治疗窗。