Matriptase drives dissemination of ovarian cancer spheroids by a PAR-2/PI3K/Akt/MMP9 signaling axis

Q: What role does matriptase play in epithelial ovarian cancer progression?

Elevated matriptase is associated with disrupted epithelial cell–cell contacts, leading to formation of spheroids that promote metastasis.

Q: How do ovarian cancer spheroids contribute to intraperitoneal spread?

Spheroids and single cells disseminate within the peritoneum, interact with mesothelium, alter vascular permeability, and support survival, adhesion, and lesion formation at secondary sites.

Q: Which signaling pathway links matriptase activation to spheroid-promoting behavior?

Matriptase activation of PAR-2 triggers PI3K/Akt and MMP9-dependent disruption of cell–cell adhesion via release of the soluble E-cadherin ectodomain.

Sep 24, 2026

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Transmembrane serine protease matriptase is identified as a key regulator of epithelial cell–cell interactions in epithelial ovarian cancers. Elevated matriptase, reflected by an increased matriptase-to-HAI-1 ratio, disrupts adhesive contacts and generates loose prometastatic spheroids with enhanced mesothelial adhesion and submesothelial invasion. Mechanistically, this phenotype depends on matriptase activation of PAR-2 signaling through PI3K/Akt and MMP9, promoting E-cadherin ectodomain release. Findings support targeting the PAR-2 axis as a therapeutic strategy for aggressive intraperitoneal metastasis.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages31

Reading Time1 h 18 min

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Introduction

Ovarian cancer dissemination and survival

Multicellular spheroids and phenotypic plasticity

ARTICLE Matriptase drives dissemination of ovarian cancer spheroids by a PAR-2/PI3K/Akt/MMP9 signaling axis Nisha R. Pawar1,2,3􀀁, Marguerite S. Buzza1,2,3,4􀀁, Nadire Duru1,2􀀁, Amando A. Strong1􀀁, and Toni M. Antalis1,2,3,4􀀁 The transmembrane serine protease matriptase is a key regulator of both barrier-disruptive and protective epithelial cell–cell interactions. Elevated matriptase is a consistent feature of epithelial ovarian cancers (OvCa), where multicellular spheroids shed from the primary tumor into the peritoneal cavity are critical drivers of metastasis. Dynamic cell-to-cell adhesive contacts are required for spheroid formation and maintenance. Here, we show that overactive matriptase, reflected in an increased ratio of matriptase to its inhibitor hepatocyte growth factor activator inhibitor 1 (HAI-1), disrupts cell–cell contacts to produce loose prometastatic spheroids that display increased mesothelial cell adhesion and submesothelial invasion. We show that these activities are dependent on the matriptase activation of a protease-activated receptor-2 (PAR-2) signaling pathway involving PI3K/Akt and MMP9-induced disruption of cell–cell adhesion by the release of the soluble E-cadherinectodomain. These data reveal a novel pathological connection between matriptase activation of PAR-2 and disruption of cell–cell adhesion, and support the clinical investigation of this signaling axis as a therapeutic strategy for aggressive metastatic OvCa. Introduction Ovarian cancer (OvCa) is the fifth leading cause of cancer deaths in women in the United States and the deadliest gynecological malignancy. Although the 5-yr survival rate for women diagnosed with localized disease is 93%, over ∼60% of OvCa patients present with peritoneal disseminated disease at the time of diagnosis, which dramatically reduces the relative 5-yr survival to <30%(ACS, 2022) . While recent studies have revealed much about OvCa tumor initiation and origin (Kim et al., 2018), a major obstacle to effective treatment lies in the lack of knowledge of the biological underpinnings that govern tumor dissemination and metastasis (Fares et al., 2020) . In contrast to other cancers that spread by hematogenous or lymphatic routes, OvCa predominantly metastasizes intraperitoneally due to the anatomic location of the primary tumor. During disease progression, OvCa cells may be shed as floating single cells or multicellular spheroid clusters from the primary tumor mass (Allen et al., 1987; Goyeneche et al., 2020) . The tumor cells disseminate within the peritoneum and interact with the mesothelium lining of the peritoneal cavity where they drive changes in vascular permeability and increase abnormal abdominal fluid accumulation (ascites). Ascites fluid provides a rich source of nutrients and a microenvironment for tumor cell survival and proliferation (Lengyel, 2010; van Baal et al., 2018) . Intraperitoneal fluid movement facilitates tumor distribution, spread, and subsequent adhesion of malignant tumor cells and spheroids to the mesothelium lining of the peritoneal cavity. Finally, malignant tumor cells anchor within the submesothelial matrix and proliferate to form lesions at secondary sites, commonly the omentum, diaphragm, and bowel serosa (Lengyel, 2010) . Malignant multicellular spheroid aggregates or clusters are an understudied aspect of OvCa propagation, metastasis, and recurrence (Al Habyan et al., 2018) . The molecular drivers of peritoneal dissemination and the invasive transitions of malignant spheroids remain poorly understood. OvCa spheroid clusters can be generated by three-dimensional (3D) culture from OvCa cell lines or patient tumors and retain and amplify many of the features and functionality of disseminated metastatic OvCa (Heredia-Soto et al., 2018) . Spheroids derived from patient ascites are found to be inherently heterogeneous in maintaining phenotypic plasticity. They can transition dynamically between epithelial, mesenchymal, an

FAQs

What role does matriptase play in epithelial ovarian cancer progression?

Elevated matriptase is associated with disrupted epithelial cell–cell contacts, leading to formation of spheroids that promote metastasis.

How do ovarian cancer spheroids contribute to intraperitoneal spread?

Spheroids and single cells disseminate within the peritoneum, interact with mesothelium, alter vascular permeability, and support survival, adhesion, and lesion formation at secondary sites.

Which signaling pathway links matriptase activation to spheroid-promoting behavior?

Matriptase activation of PAR-2 triggers PI3K/Akt and MMP9-dependent disruption of cell–cell adhesion via release of the soluble E-cadherin ectodomain.

Sep 24, 2026

Uploaded by Cart