Annapurna Vadaparty

Downregulation of Decorin in ovarian cancer cells and colonization microenvironment drives progression

Epithelial ovarian cancer is a gynecological disease in which transformed cells, upon dissemination into the peritoneum colonize locales such as omenta and form metastatic foci. Colonization is an emergent outcome of the interactions between the invading cancer cells and extracellular matrix (ECM) of the peritoneal serosa. Although ECM is known to be remodeled in cancer, the dynamics in ovarian cancer of a major class of ECM-remodeling factors: the proteoglycans remain understudied. Here, we focus on Decorin, a proteoglycan with binding activity to the principal stromal ECM protein Collagen I and investigate its regulation of ovarian cancer colonization. We observe that Decorin is depleted in cancer deposits within omenta of cancer patients. The spreading of suspended spheroids of the ovarian cancer line SK-OV-3 on engineered Collagen I scaffolds is impaired when the latter is polymerized in the presence of Decorin. Decorin-supplemented Collagen I shows poorer fibrillar organization, which has been associated with slower kinetics of cancer cell migration. To our surprise, Decorin was also found to be depleted in primary tumor cells as well as in ovarian cancer cell lines compared with their controls. Overexpression of wild type Decorin, but not its glycosaminoglycan (GAG)-removed mutant in cancer cells decreased mean spheroid size, invasion through Collagen I matrix, and migration on fibronectin matrix scaffolds. Our results suggest that downregulation of an extracellular inhibitor of colonization occurs both in the seed and soil components of the metastatic toolkit; in addition, the GAG chains of Decorin may be crucial to its carcinomatosis-inhibiting functions.

Rheological transition driven by matrix makes cancer spheroids resilient under confinement

Cancer metastasis through confining peritoneal microenvironments is mediated by spheroids: clusters of disseminated cells. Ovarian cancer spheroids are frequently cavitated; such blastuloid morphologies possess an outer ECM coat. We investigated the effects of these spheroidal morphological traits on their mechanical integrity. Atomic force microscopy showed blastuloids were elastic compared with their prefiguring lumenless moruloid counterparts. Moruloids flowed through microfluidic setups mimicking peritoneal confinement, exhibited asymmetric cell flows during entry, were frequently disintegrated, and showed an incomplete and slow shape recovery upon exit. In contrast, blastuloids exhibited size-uncorrelated transit kinetics, rapid and efficient shape recovery upon exit, symmetric cell flows, and lesser disintegration. Blastuloid ECM debridement phenocopied moruloid traits including lumen loss and greater disintegration. Multiscale computer simulations predicted that higher intercellular adhesion and dynamical lumen make blastuloids resilient. Blastuloids showed higher E-cadherin expression, and their ECM removal decreased membrane E-cadherin localization. E-cadherin knockdown also decreased lumen formation and increased spheroid disintegration. Thus, the spheroidal ECM drives its transition from a labile viscoplastic to a resilient elastic phenotype, facilitating their survival within spatially constrained peritoneal flows.