Collagen I promotes cancer cell survival via amino acid import and mTORC1/S6 activation
- 1School of Biosciences, University of Sheffield, Sheffield, United Kingdom
Abstract
Invasive breast and pancreatic cancer cells thrive within a collagen I-rich, poorly perfused extracellular matrix (ECM) network, necessitating robust metabolic adaptation to endure nutrient deficiency, such as glucose starvation. Here we demonstrate that collagen I is critical for the survival and growth of breast and pancreatic cancer cells. Mechanistically, collagen I promotes α2 β1 integrin-dependent S6 phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) and drives the membrane localisation of the LAT1−4F2hc amino acid transporter. This process ensures a sustained intracellular essential amino acid supply, further fuelling mTORC1 signalling and limiting autophagy. This collagen I-driven pathway is essential for cancer cell survival, as inhibiting the activity of α2 β1 integrin or the LAT1-4F2hc transporter significantly reduces cell growth and invasion in both 2D and 3D models. Finally, the clinical relevance of these transporters is underscored by the significant upregulation of LAT1-4F2hc expression in basal-like breast and pancreatic cancer patients, correlating with poor prognosis and drug resistance. Collectively, our findings highlight that targeting the LAT1−4F2hc transporter might represent a highly promising therapeutic strategy to limit cancer cell growth and invasion in highly fibrotic and nutrient-deprived tumours.
How do invasive breast and pancreatic cancer cells thrive in collagen-rich environments under nutrient stress? This study shows that collagen I promotes mTORC1 activation and drives the localisation of the LAT1-4F2hc amino acid transporter in the membrane, ensuring a sustained intracellular amino acid supply.
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BibTeX
@article{nazemi2026collagen,
title = {{Collagen I promotes cancer cell survival via amino acid import and mTORC1/S6 activation}},
author = {Mona Nazemi and Bian Yanes and Eric Vancauwenberghe and Ifeoluwa Oyelade and Heather Walker and Elena Rainero},
journal = {PLOS Biology},
year = {2026},
month = sep,
doi = {10.1371/journal.pbio.3003555},
url = {https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003555},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Collagen I promotes cancer cell survival via amino acid import and mTORC1/S6 activation
AU - Mona Nazemi
AU - Bian Yanes
AU - Eric Vancauwenberghe
AU - Ifeoluwa Oyelade
AU - Heather Walker
AU - Elena Rainero
PY - 2026
DA - 2026/09/18
JO - PLOS Biology
DO - 10.1371/journal.pbio.3003555
UR - https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3003555
AB - Invasive breast and pancreatic cancer cells thrive within a collagen I-rich, poorly perfused extracellular matrix (ECM) network, necessitating robust metabolic adaptation to endure nutrient deficiency, such as glucose starvation. Here we demonstrate that collagen I is critical for the survival and growth of breast and pancreatic cancer cells. Mechanistically, collagen I promotes α2 β1 integrin-dependent S6 phosphorylation by the mammalian target of rapamycin complex 1 (mTORC1) and drives the membrane localisation of the LAT1−4F2hc amino acid transporter. This process ensures a sustained intracellular essential amino acid supply, further fuelling mTORC1 signalling and limiting autophagy. This collagen I-driven pathway is essential for cancer cell survival, as inhibiting the activity of α2 β1 integrin or the LAT1-4F2hc transporter significantly reduces cell growth and invasion in both 2D and 3D models. Finally, the clinical relevance of these transporters is underscored by the significant upregulation of LAT1-4F2hc expression in basal-like breast and pancreatic cancer patients, correlating with poor prognosis and drug resistance. Collectively, our findings highlight that targeting the LAT1−4F2hc transporter might represent a highly promising therapeutic strategy to limit cancer cell growth and invasion in highly fibrotic and nutrient-deprived tumours. How do invasive breast and pancreatic cancer cells thrive in collagen-rich environments under nutrient stress? This study shows that collagen I promotes mTORC1 activation and drives the localisation of the LAT1-4F2hc amino acid transporter in the membrane, ensuring a sustained intracellular amino acid supply.
SN - 1545-7885
ER -