1. Tumor Biomechanics Alters Metastatic Dissemination of Triple Negative Breast Cancer via Rewiring Fatty Acid Metabolism.
- Author
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Filipe EC, Velayuthar S, Philp A, Nobis M, Latham SL, Parker AL, Murphy KJ, Wyllie K, Major GS, Contreras O, Mok ETY, Enriquez RF, McGowan S, Feher K, Quek LE, Hancock SE, Yam M, Tran E, Setargew YFI, Skhinas JN, Chitty JL, Phimmachanh M, Han JZR, Cadell AL, Papanicolaou M, Mahmodi H, Kiedik B, Junankar S, Ross SE, Lam N, Coulson R, Yang J, Zaratzian A, Da Silva AM, Tayao M, Chin IL, Cazet A, Kansara M, Segara D, Parker A, Hoy AJ, Harvey RP, Bogdanovic O, Timpson P, Croucher DR, Lim E, Swarbrick A, Holst J, Turner N, Choi YS, Kabakova IV, Philp A, and Cox TR
- Subjects
- Humans, Female, Mice, Cell Line, Tumor, Animals, Biomechanical Phenomena, Disease Models, Animal, Neoplasm Metastasis, Triple Negative Breast Neoplasms metabolism, Triple Negative Breast Neoplasms pathology, Fatty Acids metabolism, Tumor Microenvironment
- Abstract
In recent decades, the role of tumor biomechanics on cancer cell behavior at the primary site has been increasingly appreciated. However, the effect of primary tumor biomechanics on the latter stages of the metastatic cascade, such as metastatic seeding of secondary sites and outgrowth remains underappreciated. This work sought to address this in the context of triple negative breast cancer (TNBC), a cancer type known to aggressively disseminate at all stages of disease progression. Using mechanically tuneable model systems, mimicking the range of stiffness's typically found within breast tumors, it is found that, contrary to expectations, cancer cells exposed to softer microenvironments are more able to colonize secondary tissues. It is shown that heightened cell survival is driven by enhanced metabolism of fatty acids within TNBC cells exposed to softer microenvironments. It is demonstrated that uncoupling cellular mechanosensing through integrin β1 blocking antibody effectively causes stiff primed TNBC cells to behave like their soft counterparts, both in vitro and in vivo. This work is the first to show that softer tumor microenvironments may be contributing to changes in disease outcome by imprinting on TNBC cells a greater metabolic flexibility and conferring discrete cell survival advantages., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)
- Published
- 2024
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