Mechanosensitive calcium channels and integrins coordinate the reprogramming of colorectal cancer cells into a fetal-like state

  • Cell Rep. 2025 Sep 22;44(10):116308. doi: 10.1016/j.celrep.2025.116308.
Mirjam C van der Net  1 ,  Marjolein J Vliem  1 ,  Lars J S Kemp  1 ,  Carlos Perez-Gonzalez  2 ,  Tariq S Haddad  3 ,  Esther A Strating  4 ,  Ana Krotenberg-Garcia  5 ,  Ronja M Houtekamer  1 ,  Willem-Jan Pannekoek  1 ,  Karen B van den Anker  1 ,  Susan Zwakenberg  1 ,  Jooske L Monster  1 ,  Suzanne E M van der Horst  6 ,  Hugo J G Snippert  6 ,  Antoine A Khalil  1 ,  Jacco van Rheenen  7 ,  Saskia J E Suijkerbuijk  5 ,  Onno Kranenburg  4 ,  Femke Simmer  3 ,  Iris D Nagtegaal  3 ,  Danijela Matic Vignjevic  2 ,  Martijn Gloerich  8
Affiliations
  • 1. Center for Molecular Medicine, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands.
  • 2. Institut Curie, PSL Research University, CNRS UMR, Paris, France.
  • 3. Department of Pathology, Radboud University Medical Centre, Nijmegen, the Netherlands.
  • 4. Laboratory Translational Oncology, Division of Imaging and Cancer, University Medical Center Utrecht, Utrecht, the Netherlands.
  • 5. Division of Developmental Biology, Institute of Biodynamics and Biocomplexity, Department of Biology, Faculty of Science, Utrecht University, Utrecht, the Netherlands.
  • 6. Center for Molecular Medicine, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands; Oncode Institute, Amsterdam 1066, the Netherlands.
  • 7. Oncode Institute, Amsterdam 1066, the Netherlands; Division of Molecular Pathology, The Netherlands Cancer Institute, CX Amsterdam, Amsterdam, the Netherlands.
  • 8. Center for Molecular Medicine, University Medical Center Utrecht and Utrecht University, Utrecht, the Netherlands. Electronic address: [email protected].
PMID: 40986425 DOI: 10.1016/j.celrep.2025.116308
Abstract

Colorectal Cancer (CRC) cells exhibit high plasticity and transition between different cellular states during the development of metastasis. Lgr5-expressing Cancer Stem Cells fuel the growth of the primary tumor and metastasis, yet disseminated tumor cells arriving at the metastatic site and seeding liver metastases are devoid of Lgr5 expression. Using CRC Organoid models, we demonstrate that mechanical interactions with Collagen I, a main constituent of the interstitial matrix, instruct the reprogramming of CRC cells. Collagen I-induced pulling forces are sensed by integrins and mechanosensitive calcium channels, which together direct the transition of CRC cells into a cellular state with transcriptional similarities to fetal intestinal cells. CRC cells infiltrating the interstitial stroma show upregulation of this fetal-like transcriptional program, which correlates with the ability of Lgr5-negative cells to initiate metastasis formation. Our findings indicate that mechanical interactions with Collagen I regulate cell fate transitions associated with the metastatic cascade of CRC.

Keywords
CP: Cancer; CP: Cell biology; Lgr5; TRPV4; YAP1; cancer stem cell; colorectal cancer; fetal-like state; integrins; mechanosensitive calcium channels; mechanotransduction.
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