Hemidesmosomes (HDs) are adhesive structures that ensure stable anchorage of cells to the basement membrane. They are formed by α6β4-integrin heterodimers and linked to intermediate filaments via plectin. It has been reported that one of the most common events during the pathogenesis of prostate cancer (PCa) is the loss of HD organization. While the expression levels of β4-integrins are strongly reduced, the expression levels of α6-integrins and plectin are maintained or even elevated, and seem to promote tumorigenic properties of PCa cells, such as proliferation, invasion, metastasis, apoptosis- and drug-resistance. In this review, we discuss the potential mechanisms of how HD components might contribute to various cellular signaling pathways to promote prostate carcinogenesis. Moreover, we summarize the current knowledge on the involvement of α6β4-integrins and plectin in PCa initiation and progression.
Background: Modeling the pathophysiology of prostate cancer (PCa) remains a challenge and primary tissue-derived organoid cultures have emerged as promising models representing good tissue mimicry. Methods: We have established 36 PCa patient-derived organoid cultures that self-renew and can be maintained long-term. Using CRISPR-mediated genomic editing, selected PCa organoids were also genetically engineered to modulate their tumorigenic and self-renewal properties. We show that PCa organoids can also be readily utilized in drug sensitivity tests. In vivo, orthotopic xenograft studies were performed to recapitulate the original tumor phenotype. Finally, we performed scRNA and bulk RNA sequencing to show the multi-cellular involvement in PCa organoid self-renewal and tumorigenesis. Results: The morphological properties of cancer organoids were found to correlate with the disease grading. Importantly, detailed analyses of selected organoid lines indicated that they maintain the heterogeneity, gene expression profile, and histological architecture of their primary tumor-of-origin and recapitulate these features in vivo as xenografts. Finally, we show that α6-integrin expression is a requisite for the growth and long-term propagation of human PCa organoids while α2-integrin expression is dispensable. High expression levels of both α6- and α2-integrins have been documented in putative prostate epithelial stem cells which likely play an important role in PCa tumorigenesis. Our single-cell analysis identified a distinct cell population with a stem cell profile and high expression of α6- and α2-integrins. Discussion: Our data suggest that α6-integrin expression promotes PCa stem cell self-renewal and demonstrates the versatile biomedical utilities of PCa-derived organoid models.
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