Calpain-6 controls the fate of sarcoma stem cells by promoting autophagy and preventing senescence.
Sarcomas are still unsolved therapeutic challenges. Cancer stem cells are believed to contribute to sarcoma development, but lack of specific markers prevents their characterization and targeting. Here, we show that calpain-6 expression is associated with cancer stem cell features. In mouse models of bone sarcoma, calpain-6-expressing cells have unique tumor-initiating and metastatic capacities. Calpain-6 levels are especially high in tumors that have been successfully propagated in mouse to establish patient-derived xenografts. We found that calpain-6 levels are increased by hypoxia in vitro and calpain-6 is detected within hypoxic areas in tumors. Furthermore, calpain-6 expression depends on the stem cell transcription network that involves Oct4, Nanog, and Sox2 and is activated by hypoxia. Calpain-6 knockdown blocks tumor development in mouse and induces depletion of the cancer stem cell population. Data from transcriptomic analyses reveal that calpain-6 expression in sarcomas inversely correlates with senescence markers. Calpain-6 knockdown suppresses hypoxia-dependent prevention of senescence entry and also promotion of autophagic flux. Together, our results demonstrate that calpain-6 identifies sarcoma cells with stem-like properties and is a mediator of hypoxia to prevent senescence, promote autophagy, and maintain the tumor-initiating cell population. These findings open what we believe is a novel therapeutic avenue for targeting sarcoma stem cells.
['Andrique|Caroline|C|', 'Morardet|Laetitia|L|', 'Linares|Laetitia K|LK|', 'Cissé|Madi Y|MY|', 'Merle|Candice|C|', 'Chibon|Frédéric|F|', 'Provot|Sylvain|S|', 'Haÿ|Eric|E|', 'Ea|Hang-Korng|HK|', 'Cohen-Solal|Martine|M|', 'Modrowski|Dominique|D|']
D000818:Animals D001343:Autophagy D015415:Biomarkers D002154:Calpain D063646:Carcinogenesis D045744:Cell Line, Tumor D016922:Cellular Senescence D004195:Disease Models, Animal D020869:Gene Expression Profiling D055785:Gene Knockdown Techniques D006801:Humans D000860:Hypoxia D008297:Male D051379:Mice D008807:Mice, Inbred BALB C D008869:Microtubule-Associated Proteins D000071317:Nanog Homeobox Protein D009369:Neoplasms D014411:Neoplastic Stem Cells D050814:Octamer Transcription Factor-3 D055748:SOXB1 Transcription Factors D012509:Sarcoma D023041:Xenograft Model Antitumor Assays
Autophagy Cellular senescence Oncogenes Oncology