TY - JOUR
T1 - Mechanosensitive calcium channels and integrins coordinate the reprogramming of colorectal cancer cells into a fetal-like state
AU - van der Net, Mirjam C.
AU - Vliem, Marjolein J.
AU - Kemp, Lars J. S.
AU - Perez-Gonzalez, Carlos
AU - Haddad, Tariq S.
AU - Strating, Esther A.
AU - Krotenberg-Garcia, Ana
AU - Houtekamer, Ronja M.
AU - Pannekoek, Willem-Jan
AU - van den Anker, Karen B.
AU - Zwakenberg, Susan
AU - Monster, Jooske L.
AU - van der Horst, Suzanne E. M.
AU - Snippert, Hugo J. G.
AU - Khalil, Antoine A.
AU - van Rheenen, Jacco
AU - Suijkerbuijk, Saskia J. E.
AU - Kranenburg, Onno
AU - Simmer, Femke
AU - Nagtegaal, Iris D.
AU - Vignjevic, Danijela Matic
AU - Gloerich, Martijn
N1 - Publisher Copyright:
© 2025 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license. http://creativecommons.org/licenses/by/4.0/
PY - 2025/10/28
Y1 - 2025/10/28
N2 - 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.
AB - 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.
KW - Activation
KW - Colonization
KW - Expression
KW - Identification
KW - Ion-channel
KW - Lgr5(+) stem-cells
KW - Metastases
KW - Plasticity
KW - Regeneration
KW - Yap/taz
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=d7dz6a2i7wiom976oc9ff2iqvdhv8k5x&SrcAuth=WosAPI&KeyUT=WOS:001577726900001&DestLinkType=FullRecord&DestApp=WOS_CPL
U2 - 10.1016/j.celrep.2025.116308
DO - 10.1016/j.celrep.2025.116308
M3 - Article
C2 - 40986425
SN - 2211-1247
VL - 44
SP - 1
EP - 23
JO - Cell Reports
JF - Cell Reports
IS - 10
M1 - 116308
ER -
