title: SOX9-regulated cell plasticity in colorectal metastasis is attenuated by rapamycin.
abstract: The cancer stem cell (CSC) hypothesis proposes a hierarchical organization of tumors, in which stem-like cells sustain tumors and drive metastasis. The molecular mechanisms underlying the acquisition of CSCs and metastatic traits are not well understood. SOX9 is a transcription factor linked to stem cell maintenance and commonly overexpressed in solid cancers including colorectal cancer. In this study, we show that SOX9 levels are higher in metastatic (SW620) than in primary colorectal cancer cells (SW480) derived from the same patient. This elevated expression correlated with enhanced self-renewal activity. By gain and loss-of-function studies in SW480 and SW620 cells respectively, we reveal that SOX9 levels modulate tumorsphere formation and self-renewal ability in vitro and tumor initiation in vivo. Moreover, SOX9 regulates migration and invasion and triggers the transition between epithelial and mesenchymal states. These activities are partially dependent on SOX9 post-transcriptional modifications. Importantly, treatment with rapamycin inhibits self-renewal and tumor growth in a SOX9-dependent manner. These results identify a functional role for SOX9 in regulating colorectal cancer cell plasticity and metastasis, and provide a strong rationale for a rapamycin-based therapeutic strategy.
authors: Cellular Oncology group, Biodonostia Institute, San Sebastian, Spain.
authors: Estefania
authors: E
authors: Carrasco-Garcia
authors: Cellular Oncology group, Biodonostia Institute, San Sebastian, Spain.
authors: Lidia
authors: L
authors: Lopez
authors: Cellular Oncology group, Biodonostia Institute, San Sebastian, Spain.
authors: Paula
authors: P
authors: Aldaz
authors: Cellular Oncology group, Biodonostia Institute, San Sebastian, Spain.
authors: Sara
authors: S
authors: Arevalo
authors: Cellular Oncology group, Biodonostia Institute, San Sebastian, Spain.
authors: Juncal
authors: J
authors: Aldaregia
authors: Cellular Oncology group, Biodonostia Institute, San Sebastian, Spain.
authors: Larraitz
authors: L
authors: Egaña
authors: Department of Gastroenterology, Hospital Donostia and Instituto Biodonostia, University of the Basque Country, Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd), San Sebastian, Spain.
authors: Luis
authors: L
authors: Bujanda
authors: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
authors: Martin
authors: M
authors: Cheung
authors: Cellular Oncology group, Biodonostia Institute, San Sebastian, Spain.
authors: Nicolas
authors: N
authors: Sampron
authors: Cellular Oncology group, Biodonostia Institute, San Sebastian, Spain.|IKERBASQUE, Basque Foundation, Bilbao, Spain.
authors: Idoia
authors: I
authors: Garcia
authors: Cellular Oncology group, Biodonostia Institute, San Sebastian, Spain.|IKERBASQUE, Basque Foundation, Bilbao, Spain.
authors: Ander
authors: A
authors: Matheu
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D000066670:Cell Plasticity / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009361:Neoplasm Invasiveness / Q000235:genetics; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D055758:SOX9 Transcription Factor / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage
chemical_list: D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D020123:Sirolimus