Hsp47 promotes cancer metastasis by enhancing collagen-dependent cancer cell-platelet interaction
Menée in vitro et à l'aide de xénogreffes sur un modèle murin, cette étude met en évidence un mécanisme par lequel HSP47, une protéine chaperon facilitant la sécrétion et le dépôt de collagène, favorise le développement de métastases en augmentant l'interaction entre les plaquettes sanguines et les cellules cancéreuses
Cancer cell–platelet interaction is crucial for cancer metastasis; however, how this interaction is regulated remains largely unknown. We have identified Hsp47 as an EMT inducer and showed that Hsp47 and its dependent collagen secretion enhanced cancer cell–platelet interaction. Importantly, Hsp47-induced cancer cell–platelet interaction enhanced cancer cell clustering, which is crucial for cancer cell colonization at distant sites. We also found that Hsp47 gene amplification and expression were associated with breast cancer metastasis. These results reveal a link between the Hsp47/collagen axis and platelet recruitment, and provide additional insight into how mesenchymal phenotypes in cancer cells contribute to breast cancer metastasis.Increased expression of extracellular matrix (ECM) proteins in circulating tumor cells (CTCs) suggests potential function of cancer cell-produced ECM in initiation of cancer cell colonization. Here, we showed that collagen and heat shock protein 47 (Hsp47), a chaperone facilitating collagen secretion and deposition, were highly expressed during the epithelial-mesenchymal transition (EMT) and in CTCs. Hsp47 expression induced mesenchymal phenotypes in mammary epithelial cells (MECs), enhanced platelet recruitment, and promoted lung retention and colonization of cancer cells. Platelet depletion in vivo abolished Hsp47-induced cancer cell retention in the lung, suggesting that Hsp47 promotes cancer cell colonization by enhancing cancer cell–platelet interaction. Using rescue experiments and functional blocking antibodies, we identified type I collagen as the key mediator of Hsp47-induced cancer cell–platelet interaction. We also found that Hsp47-dependent collagen deposition and platelet recruitment facilitated cancer cell clustering and extravasation in vitro. By analyzing DNA/RNA sequencing data generated from human breast cancer tissues, we showed that gene amplification and increased expression of Hsp47 were associated with cancer metastasis. These results suggest that targeting the Hsp47/collagen axis is a promising strategy to block cancer cell–platelet interaction and cancer colonization in secondary organs.