Matrix Gla Protein drives stemness and tumor initiation in ovarian cancer

Abstract

Ovarian cancer (OC) displays the highest mortality among gynecological tumors, mainly due to early peritoneal dissemination, the high frequency of tumor relapse following primary debulking, and the development of chemoresistance. All these events are thought to be initiated and sustained by a subpopulation of neoplastic cells, termed ovarian cancer stem cells (OCSC), that are endowed with self-renewing and tumor-initiating properties. This implies that interfering with OCSC function should offer novel therapeutic perspectives to defeat OC progression. To this aim, a better understanding of the molecular and functional makeup of OCSC in clinically relevant model systems is essential. We have profiled the transcriptome of OCSC vs. their bulk cell counterpart from a panel of patient-derived OC cell cultures. This revealed that Matrix Gla Protein (MGP), classically known as a calcification-preventing factor in cartilage and blood vessels, is markedly enriched in OCSC. Functional assays showed that MGP confers several stemness-associated traits to OC cells, including a transcriptional reprogramming. Patient-derived organotypic cultures pointed to the peritoneal microenvironment as a major inducer of MGP expression in OC cells. Furthermore, MGP was found to be necessary and sufficient for tumor initiation in OC mouse models, by shortening tumor latency and increasing dramatically the frequency of tumor-initiating cells. Mechanistically, MGP-driven OC stemness was mediated by the stimulation of Hedgehog signaling, in particular through the induction of the Hedgehog effector GLI1, thus highlighting a novel MGP/Hedgehog pathway axis in OCSC. Finally, MGP expression was found to correlate with poor prognosis in OC patients, and was increased in tumor tissue after chemotherapy, supporting the clinical relevance of our findings. Thus, MGP is a novel driver in OCSC pathophysiology, with a major role in stemness and in tumor initiation.

An individualized stemness‐related signature to predict prognosis and immunotherapy responses for gastric cancer using single‐cell and bulk tissue transcriptomes

“…For example, gene MGP , a member of the osteocalcin/matrix Gla protein family, has been reported to drive stemness and tumor initiation in ovarian cancer. 62 Except for MGP , NDN , 63 SERP2 , 64 FSTL1 , 65 and CDH5 66 were also closely related to tumor stemness.…”

“…Among 72 genes, consisting of 47‐GPS, 19 genes were differentially upregulated in high‐risk group, and most of them were associated with tumor stemness, and tumor initiation and metastasis (Table S4). For example, gene MGP , a member of the osteocalcin/matrix Gla protein family, has been reported to drive stemness and tumor initiation in ovarian cancer 62 . Except for MGP , NDN , 63 SERP2 , 64 FSTL1 , 65 and CDH5 66 were also closely related to tumor stemness.…”

The Usefulness of Vitamin K-Dependent Proteins in the Diagnosis of Colorectal Carcinoma

“…It was demonstrated that the inactive form of MGP can be considered a marker for the assessment of vascular calcification [50]. Additionally, MGP is involved in a variety of cancers trough the overexpression of the MGP gene in breast cancer cells, in primary renal, testicular, and prostate carcinomas, in ovarian and digestive neoplasia, and in glioblastoma [2,3,33,38,[49][50][51][52][53].…”

ULK2 suppresses ovarian cancer cell migration and invasion by elevating IGFBP3

“…Ovarian cancer is the primary contributor to mortality among gynecological malignancies worldwide ( Chen et al, 2021 ), largely due to extensive dissemination to serosal surfaces and concurrent peritoneal metastasis ( Smolle, Taucher & Haybaeck, 2014 ; Nieddu et al, 2023 ; Zhang et al, 2022 ). However, the precise mechanisms underlying the metastatic progression of ovarian cancer remain poorly understood, highlighting a critical need to comprehend the molecular pathways implicated in disease development.…”