Chaperone-mediated autophagy regulates the metastatic state of mesenchymal tumors

Tumors often recapitulate programs to acquire invasive and dissemination abilities, during which pro-metastatic proteins are distinctively stabilized in cancer cells to drive further progression. Whether failed protein degradation affects the metastatic programs of cancer remains unknown. Here, we show that the human cancer cell-specific knockout (KO) of LAMP-2A, a limiting protein for chaperone-mediated autophagy (CMA), promotes the aggressiveness of mesenchymal tumors. Deficient CMA resulted in widespread tumor cell dissemination, invasion into the vasculature and cancer metastasis. In clinical samples, metastatic lesions showed suppressed LAMP-2A expression compared to primary tumors from the same cancer patients. Mechanistically, while stimulating TGFβ signaling dampens LAMP-2A levels, genetic suppression of CMA aggravated TGFβ signaling in cancer cells and tumors. Conversely, pharmacological inhibition of TGFβ signaling repressed the growth of LAMP-2A KO-driven tumors. Furthermore, we found that multiple EMT-driving proteins, such as TGFβR2, are degraded by CMA. Our study demonstrates that the tumor suppressive function of CMA involves negative regulation of TGFβ-driven EMT and uncovers a mechanistic link between CMA and a major feature of metastatic invasiveness.