Exosomal CD44 Cooperates with Integrin α6β4 to Support Organotropic Metastasis via Regulating Tumor Cell Motility and Target Host Cell Activation

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Rapid metastasis to vital organs such as the lung, liver, and brain is responsible for the vast majority of pancreatic cancer deaths. Liver metastasis of pancreatic cancer accounts for the high mortality rate in patients. Exosomes derived from pancreatic cancer cells tend to be enriched in proteins that are anchored to the cell membrane, supporting the reprogramming of the tumor microenvironment and the progression of distant metastatic lesions. For the first time, our study has demonstrated that cluster of differentiation 44 (CD44), a transmembrane glycoprotein delivered by exosomes, is involved in the metastatic process of pancreatic cancer. Moreover, CD44 was found to interact with integrin α6β4 to form a complex, thereby remodeling intracellular skeleton proteins, and to promote tumor cell motility through the activation of the Src and Ras signaling cascades. Notably, we also demonstrated that the CD44–α6β4 complex can be delivered to the target region via the paracrine effects of exosomes. The selective uptake of CD44-competent tumor exosomes by liver cells activated fibrotic pathways and generated a pre-metastatic niche by stimulating the cytokines, proinflammatory factors, and growth factors that ultimately support tumor metastasis. Our results suggest the potential application of exosomal CD44 as a biomarker for the clinical diagnosis of and therapy for pancreatic cancer.