Biology subjects

Llanses Martinez, M.

Publications and source records attributed to Llanses Martinez, M..

2 recordsLinked to original sources

bioRxiv2024

Internalisation of integrin-bound extracellular matrix modulates invasive carcinoma cell migration

The interaction between cancer cells and the extracellular matrix (ECM) plays a pivotal role in tumour progression. While the extracellular degradation of ECM proteins has been well characterised, ECM endocytosis and its impact on cancer cell progression, migration and metastasis is poorly understood. ECM internalisation is increased in invasive breast cancer cells, suggesting it may support invasiveness. Here we developed a high-content screening assay to study ECM uptake. We identified that mitogen-activated protein kinase (MAPK) family members, MAP3K1 and MAPK11 (p38{beta}), and the protein phosphatase 2 (PP2) subunit PPP2R1A were required for the internalisation of ECM-bound 2{beta}1 integrin. Furthermore, 2{beta}1 integrin was necessary for macropinocytosis of soluble dextran, identifying it as a novel and targetable regulator of macropinocytosis in cancer. Moreover, disruption of 2 integrin, MAP3K1, MAPK11 and PP2R1A-mediated ECM internalisation significantly impaired cancer cell migration and invasion in 2D and 3D culture systems. Finally, 2{beta}1 integrin and MAP3K1 expression were significantly upregulated in pancreatic tumours and correlated with poor prognosis in pancreatic cancer patients. Strikingly, MAP3K1, MAPK11, PPP2R1A and 2 integrin expression were higher in chemotherapy-resistant tumours in breast cancer patients. Our results identified the 2{beta}1 integrin/p38 signalling axis as a novel regulator of ECM endocytosis, which drives invasive migration and tumour progression.

cancer biology↗

bioRxiv2021

The extracellular matrix promotes breast cancer cell growth under amino acid starvation by promoting tyrosine catabolism

Breast and pancreatic 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, and pancreatic cancer 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 upregulation 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 cycle. Interestingly, this pathway was required for ECM-dependent cell growth under amino acid starvation, as the knockdown of p-hydroxyphenylpyruvate hydroxylase-like protein (HPDL), the third enzyme of the pathway, opposed cell growth on ECM in both 2D and 3D systems, without affecting cell proliferation on plastic. Finally, high HPDL expression correlated with poor prognosis in breast and pancreatic cancer patients. Collectively, our results highlight that the ECM in the tumour microenvironment represents an alternative source of nutrients to support cancer cell growth, by regulating phenylalanine and tyrosine metabolism.

cancer biology↗