Matrix stiffness promotes colorectal cancer progression via Golgi-dependent cholesterol synthesis.
5 affiliations
- 1Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, PR China.
- 2Department of Gastroenterology, The Fourth Affiliated Hospital of Soochow University, Suzhou Dushu Lake Hospital, Medical Center of Soochow University, Suzhou, PR China.
- 3Department of Gastroenterology and Hepatology, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, PR China.
- 4Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, PR China. [email protected].
- 5Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, State Key Laboratory of Digestive Health, National Clinical Research Center for Digestive Diseases, Beijing Key Laboratory for Precancerous Lesion of Digestive Diseases, Beijing, PR China. [email protected].
Abstract
Extracellular matrix (ECM) stiffening and metabolic reprogramming are hallmarks of colorectal cancer (CRC) progression; however, the mechanistic link between biomechanical cues and cholesterol metabolism remains poorly defined. Here, we delineate a mechano-metabolic pathway in which matrix stiffness activates the mechanosensitive Ca²⁺ channel Piezo1 to drive structural reorganization of the Golgi apparatus, promoting its close apposition with the endoplasmic reticulum (ER). This organelle remodeling facilitates the proteolytic activation and nuclear translocation of SREBP2, thereby transcriptionally upregulating HMGCR, the rate-limiting enzyme for cholesterol synthesis, and elevating intracellular cholesterol. HMGCR upregulation is functionally essential for stiffness-induced epithelial-mesenchymal transition (EMT) and CRC progression. Mechanistically, HMGCR-mediated cholesterol accumulation promotes phosphorylation of β-catenin at Ser552, which disrupts β-catenin/E-cadherin complexes at adherens junctions, leading to β-catenin nuclear accumulation and EMT execution. Therapeutically, combined pharmacological inhibition of matrix crosslinking and cholesterol synthesis synergistically suppresses tumor growth and invasion while restoring epithelial architecture in vivo. Collectively, these findings reveal that Piezo1-dependent Golgi-ER reorganization triggers SREBP2-driven cholesterol synthesis, ultimately fueling β-catenin-mediated junctional disassembly and metastasis, and highlight the therapeutic promise of co-targeting tumor mechanics and metabolism.
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BibTeX
@article{yin2026matrix,
title = {{Matrix stiffness promotes colorectal cancer progression via Golgi-dependent cholesterol synthesis.}},
author = {Min-Yue Yin and Xue Li and Jun-Qi Zhang and Bo-Shen Lin and Chang-Hao Zhang and Yu-Hang Liu and Shu-Tian Zhang and Si-An Xie},
journal = {Cell death \& disease},
year = {2026},
month = jul,
doi = {10.1038/s41419-026-09101-5},
url = {https://europepmc.org/article/MED/42897141},
note = {CC BY},
}
RIS
TY - JOUR
TI - Matrix stiffness promotes colorectal cancer progression via Golgi-dependent cholesterol synthesis.
AU - Min-Yue Yin
AU - Xue Li
AU - Jun-Qi Zhang
AU - Bo-Shen Lin
AU - Chang-Hao Zhang
AU - Yu-Hang Liu
AU - Shu-Tian Zhang
AU - Si-An Xie
PY - 2026
DA - 2026/07/01
JO - Cell death & disease
DO - 10.1038/s41419-026-09101-5
UR - https://europepmc.org/article/MED/42897141
AB - Extracellular matrix (ECM) stiffening and metabolic reprogramming are hallmarks of colorectal cancer (CRC) progression; however, the mechanistic link between biomechanical cues and cholesterol metabolism remains poorly defined. Here, we delineate a mechano-metabolic pathway in which matrix stiffness activates the mechanosensitive Ca²⁺ channel Piezo1 to drive structural reorganization of the Golgi apparatus, promoting its close apposition with the endoplasmic reticulum (ER). This organelle remodeling facilitates the proteolytic activation and nuclear translocation of SREBP2, thereby transcriptionally upregulating HMGCR, the rate-limiting enzyme for cholesterol synthesis, and elevating intracellular cholesterol. HMGCR upregulation is functionally essential for stiffness-induced epithelial-mesenchymal transition (EMT) and CRC progression. Mechanistically, HMGCR-mediated cholesterol accumulation promotes phosphorylation of β-catenin at Ser552, which disrupts β-catenin/E-cadherin complexes at adherens junctions, leading to β-catenin nuclear accumulation and EMT execution. Therapeutically, combined pharmacological inhibition of matrix crosslinking and cholesterol synthesis synergistically suppresses tumor growth and invasion while restoring epithelial architecture in vivo. Collectively, these findings reveal that Piezo1-dependent Golgi-ER reorganization triggers SREBP2-driven cholesterol synthesis, ultimately fueling β-catenin-mediated junctional disassembly and metastasis, and highlight the therapeutic promise of co-targeting tumor mechanics and metabolism.
SN - 2041-4889
ER -