RT Journal Article
SR Electronic
T1 Extracellular Matrix Levels Modulate Outgrowths Dynamics in Ovarian Cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.30.478322
DO 10.1101/2022.01.30.478322
A1 Sarah Alshehri
A1 Tonja Pavlovic
A1 Sadaf Farsinejad
A1 Panteha Behboodi
A1 Li Quan
A1 Daniel Centeno
A1 Douglas Kung
A1 Marta Rezler
A1 Woo Lee
A1 Piotr Jasiński
A1 Elżbieta Dziabaszewska
A1 Ewa Nowak-Markwitz
A1 Dilhan Kalyon
A1 Mikołaj P. Zaborowski
A1 Marcin Iwanicki
YR 2022
UL http://biorxiv.org/content/early/2022/02/14/2022.01.30.478322.abstract
AB Ovarian carcinoma (OC) form outgrowths that extend from the outer surface of an afflicted organ into the peritoneum. OC outgrowth formation is poorly understood because there is a limited availability of OC cell culture models to examine the behavior of cell assemblies that form outgrowths. Prompted by immuno-chemical evaluation of extracellular matrix (ECM) components, laminin γ1 and collagens, in human tissues representing untreated and chemotherapy-recovered OC, we developed laminin and collagen-rich ECM-reconstituted cell culture models amenable to studies of cell assemblies that can form outgrowths. We demonstrate that ECM promotes outgrowth formation in fallopian tube non-ciliated epithelial cells (FNE) expressing mutant p53R175H and various OC cell lines. Outgrowths were initiated by cell assemblies that had undergone outward translocation and, upon mechanical detachment, could intercalate into mesothelial cell monolayers. Electron microcopy, optical coherence tomography (OCT) and small-amplitude oscillatory shear experiments revealed that elevating ECM levels increased ECM fibrous network thickness and led to high shear elasticity of ECM environment. These physical characteristics were associated with suppression of outgrowths. Culture environment with low ECM content mimicked viscoelasticity and fibrous networks of ascites and supported cell proliferation, cell translocation and outgrowth formation. These results highlight the importance of ECM microenvironments in modulating OC growth and could provide additional explanation of why primary and recurrent ovarian tumors form outgrowths that protrude into the peritoneal cavity containing ascites as opposed to breaking through the basement membrane and invading collagen-dense tissues.Competing Interest StatementThe authors have declared no competing interest.