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.

// <![CDATA[ $('.header-date').hide();$('#titleAuthors').hide();$('#abstractHeader').hide(); // ]]> Liang Liu1, 2, *, Cong Xu3, *, Jer-Tsong Hsieh4, Jianping Gong1, 2, Daxing Xie1, 2 1Tongji Cancer Research Institute, Tongji Hospital, Tongji Medical College in Huazhong University of Science and Technology, Wuhan, Hubei 430030, China 2Department of Gastrointestinal Surgery, Tongji Hospital, Tongji Medical College in Huazhong University of Science and Technology, Wuhan, Hubei 430030, China 3Department of Gastroenterology, Tongji Hospital, Tongji Medical College in Huazhong University of Science and Technology, Wuhan, Hubei 430030, China 4Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA *These authors contributed equally to this work Correspondence to: Daxing Xie, e-mail: dxxie@tjh.tjmu.edu.cn Jianping Gong, e-mail: jpgong@tjh.tjmu.edu.cn Jer-Tsong Hsieh, e-mail: jt.hsieh@utsouthwestern.edu Keywords: DAB2IP, AIP1, cancer, tumor suppressor Received: July 23, 2015 Accepted: November 15, 2015 Published: December 08, 2015

Metastasis is a critical factor for the high mortality of colorectal cancer (CRC), but its mechanism is not completely understood. Epithelial-mesenchymal transition (EMT) is thought to play a key role in metastasis and also increases the cancer stem cell (CSC) feature that facilitates metastatic colonization. In this study, we investigated the biological roles of DAB2IP regulating EMT and stem cell–like features in human CRC. We demonstrate that DAB2IP suppresses NF-κB-mediated EMT and CSC features in CRC cells. In DAB2IP knockout mice, we discovered the hyperplasia in colonic epithelium which aberrantly represents the mesenchymal feature and NF-κB pathway activation. In clinic CRC tissue, we also reveal that reduced DAB2IP can enrich the CD133⁺ subpopulation. DAB2IP expression was inversely correlated with tumor differentiation and metastasis and patients with lower DAB2IP expression had shorter overall survival time. Taken together, our study demonstrates that DAB2IP inhibits NF-κB-inducing EMT and CSC to suppress the CRC progression and also suggests that DAB2IP is a beneficial prediction factor for CRC patient prognosis.