The majority of high-grade serous ovarian cancer patients present with widespread metastatic disease within the abdominal cavity. Despite the current standard of care, which includes aggressive surgery and chemotherapy, only 20% of these patients will be long-term survivors. These staggering statistics highlight an urgent need for efficacious therapeutic targets and strategies. Uniquely, OvCa selectively metastasizes to mesothelial cell-lined surfaces in the peritoneal and pleural cavity.
Mesothelial cells are pluripotent mesodermal-derived cells that facilitate wound healing. These undifferentiated cells uniquely transform into fibroblasts and smooth muscle cells, remodeling the microenvironment, in response to abdominal infection. Mesothelial cells were previously thought to play a passive role in cancer metastasis, but my results and those of others show that mesothelial cells are present in the tumor microenvironment and actively promote cancer metastasis, supporting the existence of cancer-associated mesothelial cells. In support of this theory, a subpopulation of cancer-associated fibroblasts, adjacent to tumor cells in high-grade serous ovarian cancer metastatic tumors, consistently express the mesothelial cells-specific markers. These findings suggest that mesothelial cells give rise to cancer-associated fibroblasts in the ovarian cancer tumor microenvironment.
Historically, mesothelial cells were viewed as the passive cover of abdominal surfaces, and were disregarded as potential functional constituents in the ovarian cancer tumor microenvironment. Although the mechanisms underlying the pro-metastatic role of mesothelial cells have not been elucidated, my central hypothesis is that mesothelial cells support ovarian cancer metastasis. To test this hypothesis, the tumor-promoting role of mesothelial cells will be evaluated by ablating the mesothelial cells during OvCa metastasis in vivo (Aim 1), the fate of mesothelial cells will be tracked during OvCa metastasis (Aim 2), and ovarian cancer-induced alterations in mesothelial cells leading to tumor promotion will be assessed (Aim 3). Understanding the role of mesothelial cells in the tumor microenvironment during ovarian cancer metastasis, ultimately may lead to the identification of potential strategies to target mesothelial cell-dependent pathways that promote ovarian cancer metastasis.
This grant was made possible by a generous donation from Ovarian Cancer Alliance of Greater Cincinnati made in memory of Debbie Walter.