The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism.
Breast 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 cancer cells to endure these conditions. Here, we demonstrated that the presence of ECM supported...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2024-01-01
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| Series: | PLoS Biology |
| Online Access: | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3002406&type=printable |
| _version_ | 1797315919561621504 |
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| author | Mona Nazemi Bian Yanes Montserrat Llanses Martinez Heather J Walker Khoa Pham Mark O Collins Frederic Bard Elena Rainero |
| author_facet | Mona Nazemi Bian Yanes Montserrat Llanses Martinez Heather J Walker Khoa Pham Mark O Collins Frederic Bard Elena Rainero |
| author_sort | Mona Nazemi |
| collection | DOAJ |
| description | Breast 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 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 macropinocytosis-dependent ECM uptake. Importantly, we showed that this behaviour was acquired during carcinoma progression. ECM internalisation, followed by lysosomal degradation, contributed to the up-regulation of the intracellular levels of several amino acids, most notably tyrosine and phenylalanine. This resulted in elevated tyrosine catabolism on ECM under starvation, leading to increased fumarate levels, potentially feeding into the tricarboxylic acid (TCA) cycle. Interestingly, this pathway was required for ECM-dependent cell growth and invasive cell migration under amino acid starvation, as the knockdown of p-hydroxyphenylpyruvate hydroxylase-like protein (HPDL), the third enzyme of the pathway, opposed cell growth and motility on ECM in both 2D and 3D systems, without affecting cell proliferation on plastic. Finally, high HPDL expression correlated with poor prognosis in breast cancer patients. Collectively, our results highlight that the ECM in the tumour microenvironment (TME) represents an alternative source of nutrients to support cancer cell growth by regulating phenylalanine and tyrosine metabolism. |
| first_indexed | 2024-03-08T03:11:47Z |
| format | Article |
| id | doaj.art-73bd8338597b4be8864562ecae43c95e |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-03-08T03:11:47Z |
| publishDate | 2024-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-73bd8338597b4be8864562ecae43c95e2024-02-13T05:30:47ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852024-01-01221e300240610.1371/journal.pbio.3002406The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism.Mona NazemiBian YanesMontserrat Llanses MartinezHeather J WalkerKhoa PhamMark O CollinsFrederic BardElena RaineroBreast 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 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 macropinocytosis-dependent ECM uptake. Importantly, we showed that this behaviour was acquired during carcinoma progression. ECM internalisation, followed by lysosomal degradation, contributed to the up-regulation of the intracellular levels of several amino acids, most notably tyrosine and phenylalanine. This resulted in elevated tyrosine catabolism on ECM under starvation, leading to increased fumarate levels, potentially feeding into the tricarboxylic acid (TCA) cycle. Interestingly, this pathway was required for ECM-dependent cell growth and invasive cell migration under amino acid starvation, as the knockdown of p-hydroxyphenylpyruvate hydroxylase-like protein (HPDL), the third enzyme of the pathway, opposed cell growth and motility on ECM in both 2D and 3D systems, without affecting cell proliferation on plastic. Finally, high HPDL expression correlated with poor prognosis in breast cancer patients. Collectively, our results highlight that the ECM in the tumour microenvironment (TME) represents an alternative source of nutrients to support cancer cell growth by regulating phenylalanine and tyrosine metabolism.https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3002406&type=printable |
| spellingShingle | Mona Nazemi Bian Yanes Montserrat Llanses Martinez Heather J Walker Khoa Pham Mark O Collins Frederic Bard Elena Rainero The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism. PLoS Biology |
| title | The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism. |
| title_full | The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism. |
| title_fullStr | The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism. |
| title_full_unstemmed | The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism. |
| title_short | The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism. |
| title_sort | extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism |
| url | https://journals.plos.org/plosbiology/article/file?id=10.1371/journal.pbio.3002406&type=printable |
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