Nazemi, M., Yanes, B., Martinez, M.L. et al. (3 more authors) (Submitted: 2021) The extracellular matrix promotes breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism. bioRxiv. (Submitted)
Abstract
Breast cancer tumours are embedded in a collagen I rich extracellular matrix (ECM) network where nutrients are scarce due to limited blood flow and elevated tumour growth. Metabolic adaptation is required for breast cancer cells to endure these conditions. Here, we demonstrated that the presence of ECM supported the growth of invasive breast cancer cells, but not non-transformed mammary epithelial cells, under amino acid starvation, through a mechanism that required ECM uptake. Importantly, we showed that this behaviour was acquired during carcinoma progression. ECM internalisation, followed by lysosomal degradation, contributed to the upregulation of the intracellular levels of several amino acids, including tyrosine and phenylalanine. Finally, we showed that cells on ECM had elevated tyrosine catabolism, leading to elevated fumarate levels, potentially feeding into the tricarboxylic acid cycle. Interestingly, this pathway was required for ECM-dependent cell growth under amino acid starvation, as the knockdown of HPDL, the third enzyme of the pathway, opposed cell growth on ECM without affecting cell proliferation on plastic. Collectively, our results highlight that the ECM surrounding breast cancer tumours represents an alternative source of nutrients to support cancer cell growth, by regulating phenylalanine and tyrosine metabolism.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021 The Author(s). For reuse permissions, please contact the Author(s). |
Dates: |
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Institution: | The University of Sheffield |
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > School of Biosciences (Sheffield) > Department of Biomedical Science (Sheffield) |
Depositing User: | Symplectic Sheffield |
Date Deposited: | 11 Aug 2021 13:28 |
Last Modified: | 11 Aug 2021 13:28 |
Status: | Submitted |
Publisher: | Cold Spring Harbor Laboratory |
Identification Number: | 10.1101/2021.06.09.447520 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:176992 |