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ECM Remodeling Bridges Mechanotransduction with Metabolic Rewiring in Breast Cancer Cells
CC BY 4.0 · Indian J Med Paediatr Oncol 2024; 45(S 01): S1-S16
DOI: DOI: 10.1055/s-0044-1788240
*Corresponding author: (e-mail: spatwardhan@actrec.gov.in).
Abstract
Background: Extracellular matrix (ECM) stiffness is a hallmark of breast cancer progression, which has significant impact on cancer cell behavior like migration, invasion, contractility. These energetically expensive processes necessitate the metabolic reprogramming of cancer cells. However, precise mechanism by which the dynamics of ECM cause the rewiring of metabolism remains unclear.
Materials and Methods: To mimic the stiffness of normal mammary stroma (0.5 kPa) and metastatic tumor stroma (5 kPa), we utilize 2.5-dimensional stiffness tunable functionalized ECM scaffolds. Metabolic assays were performed as per manufacturer’s instructions. Mitochondrial number and dynamics were studied using TEM and confocal microscopy. Protein expression was probed using western blotting.
Results: We show that breast cancer cells grown on stiff ECM exhibit enhanced proliferation, adhesion, and morphological changes associated with increased invasion. ECM stiffness triggers metabolic rewiring resulting in increased ATP production by modulating mitochondrial and glucose metabolism. This was corroborated by high levels of oxidative phosphorylation (OXPHOS) and glycolysis in response to a rigid matrix. Additionally, we showed that cells grown on stiff substrates display an increase in mitochondrial number due to enhanced mitochondrial fission and mitobiogenesis. Subsequently, we have observed notable alterations in the real-time glycolytic activity of breast cancer cells, both in presence and absence of stiffness-tuned exosomes.
Conclusion: Our research demonstrates how ECM remodeling contributes to the metabolic rewiring of breast cancer cells, which in turn helps to produce more ATP. This work also suggests a unique role for exosomes linking cancer cell bioenergetics and mechanotransduction.
Publication History
Article published online:
08 July 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India
*Corresponding author: (e-mail: spatwardhan@actrec.gov.in).
Abstract
Background: Extracellular matrix (ECM) stiffness is a hallmark of breast cancer progression, which has significant impact on cancer cell behavior like migration, invasion, contractility. These energetically expensive processes necessitate the metabolic reprogramming of cancer cells. However, precise mechanism by which the dynamics of ECM cause the rewiring of metabolism remains unclear.
Materials and Methods: To mimic the stiffness of normal mammary stroma (0.5 kPa) and metastatic tumor stroma (5 kPa), we utilize 2.5-dimensional stiffness tunable functionalized ECM scaffolds. Metabolic assays were performed as per manufacturer’s instructions. Mitochondrial number and dynamics were studied using TEM and confocal microscopy. Protein expression was probed using western blotting.
Results: We show that breast cancer cells grown on stiff ECM exhibit enhanced proliferation, adhesion, and morphological changes associated with increased invasion. ECM stiffness triggers metabolic rewiring resulting in increased ATP production by modulating mitochondrial and glucose metabolism. This was corroborated by high levels of oxidative phosphorylation (OXPHOS) and glycolysis in response to a rigid matrix. Additionally, we showed that cells grown on stiff substrates display an increase in mitochondrial number due to enhanced mitochondrial fission and mitobiogenesis. Subsequently, we have observed notable alterations in the real-time glycolytic activity of breast cancer cells, both in presence and absence of stiffness-tuned exosomes.
Conclusion: Our research demonstrates how ECM remodeling contributes to the metabolic rewiring of breast cancer cells, which in turn helps to produce more ATP. This work also suggests a unique role for exosomes linking cancer cell bioenergetics and mechanotransduction.
No conflict of interest has been declared by the author(s).
Publication History
Article published online:
08 July 2024
© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)
Thieme Medical and Scientific Publishers Pvt. Ltd.
A-12, 2nd Floor, Sector 2, Noida-201301 UP, India