Juin, A. | Search bioRxiv

bioRxiv2022

CYRI-B mediated macropinocytosis drives metastasis via lysophosphatidic acid receptor uptake

Pancreatic ductal adenocarcinoma carries a dismal prognosis, with high rates of metastasis and few treatment options. Hyperactivation of KRAS in almost all tumours drives RAC1 activation, conferring enhanced migratory and proliferative capacity as well as macropinocytosis. Macropinocytosis is well understood as a nutrient scavenging mechanism, but little is known about its functions in trafficking of signaling receptors. We find that CYRI-B is highly expressed in pancreatic tumours in a mouse model of KRAS and p53- driven pancreatic cancer. Deletion of CYRI-B accelerates tumourigenesis, leading to enhanced ERK and JNK-induced proliferation in precancerous lesions, indicating a role as a buffer of RAC1 hyperactivation in early stages. However, as disease progresses, loss of CYRI-B inhibits metastasis. CYRI-B depleted tumour cells show reduced chemotactic responses to lysophosphatidic acid, a major driver of tumour spread, due to impaired macropinocytic uptake of LPAR1 receptor. Overall, we implicate CYRI-B as a mediator of growth and signaling in pancreatic cancer, providing new insights into pathways controlling metastasis.

cancer biology↗

bioRxiv2022

Collagen-VI expression is negatively mechanosensitive in pancreatic cancer cells and supports the metastatic niche

Pancreatic cancer is a deadly disease with high rates of metastasis, though how tumor cells establish metastatic lesions is not fully understood. A key feature of primary pancreatic tumors is extensive fibrosis due to deposition of extracellular matrix. While pancreatic cancer cells are programmed by stimuli derived from a stiff ECM, metastasis requires loss of attachment as well as adaptation to a softer microenvironment upon reaching distant sites. Growing evidence suggests that stiff ECM influences pancreatic cancer cell behaviour. Here we argue that this influence is reversible and that pancreatic cancer cells can be reprogrammed upon sensing of soft substrates. Through use of engineered polyacrylamide hydrogels with tuneable mechanical properties, we show that Collagen-VI is specifically upregulated on soft substrates, due to a lack of integrin engagement and low YAP1 activity. Collagen-VI supports migration in vitro and metastasis formation in vivo. Metastatic nodules formed by pancreatic cancer cells lacking Col6a1 expression, were characterised by stromal cell-derived collagen-VI deposition, suggesting that collagen-VI, either cancer or stroma derived, is an essential component of the metastatic niche. Summary StatementCollagen-VI is expressed by pancreatic tumors and metastases in a mechanosensitive way to promote niche colonisation.

cancer biology↗