2. Academic Validation
  3. Chaperone-mediated autophagy regulates the metastatic state of mesenchymal tumors

Chaperone-mediated autophagy regulates the metastatic state of mesenchymal tumors

  • EMBO Mol Med. 2025 Mar 7. doi: 10.1038/s44321-025-00210-w.
Xun Zhou # 1,  Eva Berenger # 1,  Yong Shi # 1,  Vera Shirokova 2,  Elena Kochetkova 1,  Tina Becirovic 1,  Boxi Zhang 1,  Vitaliy O Kaminskyy 1,  Yashar Esmaeilian 1,  Kayoko Hosaka 3,  Cecilia Lindskog 4,  Per Hydbring 5,  Simon Ekman 5 6,  Yihai Cao 3,  Maria Genander 2,  Marcin Iwanicki 7,  Erik Norberg 8,  Helin Vakifahmetoglu-Norberg 9
Affiliations

Affiliations

  • 1 Department of Physiology and Pharmacology, Karolinska Institutet, 171 65, Stockholm, Sweden.
  • 2 Department of Cell and Molecular Biology, Karolinska Institutet, 171 65, Stockholm, Sweden.
  • 3 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, 171 65, Stockholm, Sweden.
  • 4 Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden.
  • 5 Department of Oncology and Pathology, Karolinska Institutet, 171 64, Stockholm, Sweden.
  • 6 Thoracic Oncology Center, Theme Cancer, Karolinska University Hospital, 17176, Stockholm, Sweden.
  • 7 Department of Chemistry and Chemical Biology, Stevens Institute of Technology, Hoboken, NJ, USA.
  • 8 Department of Physiology and Pharmacology, Karolinska Institutet, 171 65, Stockholm, Sweden. Erik.norberg@ki.se.
  • 9 Department of Physiology and Pharmacology, Karolinska Institutet, 171 65, Stockholm, Sweden. Helin.norberg@ki.se.
  • # Contributed equally.
PMID: 40055574 DOI: 10.1038/s44321-025-00210-w
Abstract

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.

Keywords

Cancer; Chaperone-mediated Autophagy; EMT; Metastasis; TGFβ.

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