The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism.
The extracellular matrix supports breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism.
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DOI：
10.1371/journal.pbio.3002406
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发表时间：
2024-01
期刊：
影响因子：
9.8
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中科院分区：
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乳腺肿瘤嵌入在富含胶原蛋白I的细胞外基质（ECM）网络中，由于血流受限和肿瘤生长加快，营养物质缺乏。癌细胞需要代谢适应来忍受这些条件。在这里，我们证明了ECM的存在支持浸润性乳腺癌细胞的生长，但不是非转化的乳腺上皮细胞，在氨基酸饥饿下，通过一种机制，需要巨胞饮依赖性ECM摄取。重要的是，我们发现这种行为是在癌症进展过程中获得的。ECM内化，随后是溶酶体降解，导致了几种氨基酸的细胞内水平的上调，最明显的是酪氨酸和苯丙氨酸。这导致饥饿条件下ECM上的酪氨酸催化剂升高，导致富马酸盐水平升高，可能进入三羧酸（TCA）循环。有趣的是，这种途径是ECM依赖性细胞生长和氨基酸饥饿下的侵入性细胞迁移所必需的，因为对羟基苯丙酮酸羟化酶样蛋白（HPDL）（途径的第三种酶）的敲低，在2D和3D系统中对抗ECM上的细胞生长和运动性，而不影响塑料上的细胞增殖。最后，高HPDL表达与乳腺癌患者的预后不良相关。总的来说，我们的研究结果强调，肿瘤微环境（TME）中的ECM代表了一种替代营养来源，通过调节苯丙氨酸和酪氨酸代谢来支持癌细胞生长。乳腺肿瘤嵌入在富含胶原的细胞外基质（ECM）网络中，由于血流受限和肿瘤生长加快，营养物质缺乏。这项研究表明，侵袭性乳腺癌细胞使用巨胞饮依赖性摄取和溶酶体降解ECM来促进其生长。
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. Breast tumors are embedded in a collagen-rich extracellular matrix (ECM) network, where nutrients are scarce due to limited blood flow and elevated tumor growth. This study shows that invasive breast cancer cells use macropinocytosis-dependent uptake and lysosomal degradation of ECM to promote their growth.
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DOI：
10.1083/jcb.201508080
发表时间：
2016-02-01
期刊：
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影响因子：
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