Abstract
Ovarian cancer metastasizes into peritoneum through dissemination of transformed epithelia as multicellular spheroids. Harvested from the malignant ascites of patients, spheroids exhibit startling features of organization typical to homeostatic glandular tissues: lumen surrounded by smoothly contoured and adhered epithelia. Herein, we demonstrate that cells of specific ovarian cancer lines in suspension, aggregate into dysmorphic solid "moruloid" clusters that permit intercellular movement, cell penetration, and interspheroidal coalescence. Moruloid clusters subsequently mature into "blastuloid" spheroids with smooth contours, a temporally dynamic lumen and immotile cells. Blastuloid spheroids neither coalesce nor allow cell penetration. Ultrastructural examination reveals a basement membrane-like extracellular matrix coat on the surface of blastuloid, but not moruloid, spheroids. Quantitative proteomics reveals down-regulation in ECM protein Fibronectin-1 associated with the moruloid-blastuloid transition; immunocytochemistry also confirms the relocalization of basement membrane ECM proteins: collagen IV and laminin to the surface of blastuloid spheroids. Fibronectin depletion accelerates, and enzymatic basement membrane debridement impairs, lumen formation, respectively. The regulation by ECM dynamics of the morphogenesis of cancer spheroids potentially influences the progression of the disease.
Highlights
Survival of women afflicted with epithelial ovarian cancer (EOC) trails behind other gynecological malignancies, despite improvements in surgical-pharmacological approaches (Vaughan et al, 2011; Siegel et al, 2015)
Using spheroids from patients with high grade serous adenocarcinoma and ovarian cancer cell lines, we show that the changes in ECM are responsible for the conversion of an aggregated solid multicellular cancer cluster into one with a temporally dynamic cavitation, which has significant implications for its ability to negotiate through the confines of the peritoneal cavity
We extend these observations to demonstrate the importance of spatiotemporal expression of the basement membrane (BM)-constituting proteins in the metastatic niche of ovarian cancer patients as well as cell lines
Summary
Survival of women afflicted with epithelial ovarian cancer (EOC) trails behind other gynecological malignancies, despite improvements in surgical-pharmacological approaches (Vaughan et al, 2011; Siegel et al, 2015). A phase-contrast microscopic examination of spheroids from patients, or from aggregated epithelia of immortalized cancer lines cultured on low attachment substrata, shows features of morphogenetic organization: presence of a central lumen, radially arranged apposed epithelia and compacted spheroidal surfaces. Such traits are cognate to organized morphogenesis within the glandular epithelial organs (Nelson et al, 2006; Bhat & Bissell, 2014), which are built through principles that include, but are not limited to, cell–cell and matrix adhesion (Newman & Bhat, 2009; Benıtez et al, 2018). Loss of tissue architecture seen in tumorigenesis is characterized by the disappearance of such morphogenetic traits (such as matrix adhesion and polarity) (Hanahan & Weinberg, 2000; Bissell and Hines, 2011)
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