The mechanical microenvironment regulates ovarian cancer cell morphology, migration, and spheroid disaggregation

Abstract

There is growing appreciation of the importance of the mechanical properties of the tumor microenvironment on disease progression. However, the role of extracellular matrix (ECM) stiffness and cellular mechanotransduction in epithelial ovarian cancer (EOC) is largely unknown. Here, we investigated the effect of substrate rigidity on various aspects of SKOV3 human EOC cell morphology and migration. Young's modulus values of normal mouse peritoneum, a principal target tissue for EOC metastasis, were determined by atomic force microscopy (AFM) and hydrogels were fabricated to mimic these values. We find that cell spreading, focal adhesion formation, myosin light chain phosphorylation, and cellular traction forces all increase on stiffer matrices. Substrate rigidity also positively regulates random cell migration and, importantly, directional increases in matrix tension promote SKOV3 cell durotaxis. Matrix rigidity also promotes nuclear translocation of YAP1, an oncogenic transcription factor associated with aggressive metastatic EOC. Furthermore, disaggregation of multicellular EOC spheroids, a behavior associated with dissemination and metastasis, is enhanced by matrix stiffness through a mechanotransduction pathway involving ROCK, actomyosin contractility, and FAK. Finally, this pattern of mechanosensitivity is maintained in highly metastatic SKOV3ip.1 cells. These results establish that the mechanical properties of the tumor microenvironment may play a role in EOC metastasis.peer-reviewed)

Contribution of regulatory T cells to cancer: A review

“…Cancer cells are versatile cell types (Alamoud & Kukuruzinska, 2018) that their morphology and functional features are highly influenced from signals within the TME (McKenzie et al, 2018). Cancer cells and cellular components of the stroma of tumor coevolve in functioning to promote malignancy (McKenzie et al, 2018). In initial phases of tumorigenesis, cancer cell release growth factors for stimulating stroma production (Dauer et al, 2017), indicating intricate link between cancer cells with cells within the tumor stroma for shaping the behavior of both stroma cells and cancer cells.…”

The lipid kinase PI3Kα is required for the cohesion and survival of cancer cells disseminated in serous cavities

“…In this study, we developed a 3D culture method to better mimic the aggregate formation observed within the ascites fluid and responsible for short term peritoneal carcinomatosis. We used ovarian tumour cells SKOV-3 coming from ascites and realized tumourospheres in round-bottomed plates treated to prevent cell adhesion (47). After only a few hours, ovarian tumour cells form round or elliptical structures typically corresponding to those described in the literature (48), reproduced as well with 3D culture of patients (Fig.…”

Protein Kinase A activity is regulated by actomyosin contractility during cell migration and is required for durotaxis

“…Previously, we showed that efficient migration of SKOV-3 human ovarian cancer cells requires localized PKA activity within the leading edge (32). More recently, we demonstrated that SKOV-3 cell migration is also governed by the mechanical microenvironment; specifically, that cell contractility and migration positively correlate with ECM stiffness and that directional increases in ECM tension promote SKOV-3 cell durotaxis (27). In the present work, we explored the possibility that localized PKA activity in migrating cells might be regulated by mechanical signaling and cell-matrix tension.…”

“…In further consideration of what might regulate PKA activity during migration, we began to consider a cellular characteristic that is dependent on integrin-mediated adhesion, intrinsic to many cells across many modes of migration, and not typically associated with cell spreading -namely, actomyosin-dependent cellular contractility (1,13,17,50,51). Intracellular contractile forces regulate diverse aspects of signaling and cytoskeletal dynamics during cell migration (4,13,(20)(21)(22) and, importantly, these forces tend to be highest within the leading edge (23)(24)(25)(26)(27), placing them in the correct subcellular location to affect PKA activity.…”

“…The distribution of contractile forces within a migrating cell generates subcellular areas with varying degrees of intracellular tension, countered by both internal cytoskeletal scaffolds and by matrix adhesions (7,19). Intracellular contractile forces regulate myriad aspects of cell migration (4,13,(20)(21)(22) and, during the migration of many cell types, traction force tends to be highest within the leading edge, often within the lamella just behind actively protruding lamellipodia (23)(24)(25)(26)(27).…”