Stromal softness confines pancreatic cancer growth through lysosomal-cathepsin mediated YAP1 degradation
The progression and malignancy of many tumors are associated with increased tissue stiffness. Conversely, the oncogenically transformed cells can be confined in soft stroma. Yet, the underlying mechanisms by which soft matrix confines tumorigenesis and metastasis remain elusive. Here, we show that pancreatic cancer cells are suppressed in the soft extracellular matrix, which is associated with YAP1 degradation through autophagic-lysosomal pathway rather than Hippo signal mediated proteasome pathway. In the soft stroma, PTEN is upregulated and activated, which consequently promotes lysosomal biogenesis, leading to the activation of cysteine-cathepsins for YAP1 degradation. In vitro, purified cathepsin L can directly digest YAP1 under acidic conditions. Lysosomal stress, either caused by chloroquine or overexpression of cystatin A/B, results in YAP1 accumulation and malignant transformation. Likewise, liver fibrosis induced stiffness can promote malignant potential in mice. Clinical data show that down-regulation of lysosomal biogenesis is associated with pancreatic fibrosis and stiffness, YAP1 accumulation, and poor prognosis in PDAC patients. Together, our findings suggest that soft stroma triggers lysosomal flux-mediated YAP1 degradation and induces cancer cell dormancy.
Authors
- Yun Gao (ORCID: https://orcid.org/0000-0003-3530-7259)
- Xiaofeng Zheng (ORCID: https://orcid.org/0000-0003-2850-7308)
- Feng Ren (ORCID: https://orcid.org/0000-0002-0152-408X)
- Yiran Ou
- Stephen J. Pandol (ORCID: https://orcid.org/0000-0003-0818-6017)
- Sujun Zheng (ORCID: https://orcid.org/0000-0002-6367-5764)
- Mouad Edderkaoui (ORCID: https://orcid.org/0000-0002-2549-8242)
- Yuan‐Ping Han (ORCID: https://orcid.org/0000-0001-6282-7319)
- Huan Yang (ORCID: https://orcid.org/0000-0003-1808-4735)
- Ying Tong (ORCID: https://orcid.org/0000-0002-8460-0585)
- Richard Hu (ORCID: https://orcid.org/0000-0002-5298-3737)
- Tianci Zhang (ORCID: https://orcid.org/0000-0001-9692-1469)
- Xiaoyan Sun (ORCID: https://orcid.org/0000-0002-4317-6888)
- Jiaye Liu (ORCID: https://orcid.org/0000-0003-4434-3120)
- Qiang Wang (ORCID: https://orcid.org/0000-0002-1219-7889)
- Jingjing Chen (ORCID: https://orcid.org/0009-0001-8913-8780)
Institutions
- Cedars-Sinai Medical Center (US)
- Capital Medical University (CN)
- Sichuan University (CN)
- West China Hospital of Sichuan University (CN)
- Olive View-UCLA Medical Center (US)
- Beijing YouAn Hospital (CN)
- State Key Laboratory of Biotherapy
Publication Details
- Journal
- Cellular and Molecular Life Sciences
- Published
- 2024-10-26
- DOI
- https://doi.org/10.1007/s00018-024-05466-y
- Citations
- 10
- Primary Topic
- Hippo pathway signaling and YAP/TAZ
- Type
- article
- Field-Weighted Citation Impact
- 3.26
Funders
- National Natural Science Foundation of China
- Sichuan Province Science and Technology Support Program
- Chengdu Science and Technology Program