Chaperone-mediated Autophagy Deficiency Reprograms Cancer Metabolism Via TGFβ Signaling to drive Mesenchymal Tumor Growth

The role of chaperone-mediated autophagy (CMA) in cancer initiation and progression is not well understood due to the lack of a loss-of-function cancer models of LAMP2A, the key regulator of this process. Here, by generating an isoform-specific knockout of LAMP2A, we show that CMA deficiency promotes proliferation and tumor growth in human cancers of mesenchymal origin. Accordingly, we observed that LAMP2A diminishes in metastatic lesions compared to matched primary human tumors from the same patients. Loss of CMA enhanced TGFβ signaling in tumors, rewired the tumor metabolome to promote anabolic pathways and mitochondrial metabolism, meeting the metabolic requirements of rapid growth. Mechanistically, we show that TGFβR2 enhances the enzymatic activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), to promote the generation of nucleotides. Consequently, pharmacological inhibition of TGFβ-signaling in LAMP2A-KO cells suppresses G6PD activity, mitochondrial metabolism, and proliferation to WT levels. Conversely, pharmacological inhibition of mitochondrial metabolism suppressed LAMP2A-KO driven proliferation. Overall, our study provides a molecular mechanism on the CMA’s tumor-suppressive function by connecting two important oncogenic pathways, the TGFβ signaling and PPP metabolism, to the loss-of-function LAMP2A in mesenchymal cancer types. ### Competing Interest Statement The authors have declared no competing interest.