Targeting Cancer-Associated Fibroblast Transdifferentiation Pathway for Ovarian Cancer Therapy
Abstract
Of all gynecological malignancies, ovarian cancer remains the most fatal gynecological cancer. This is primarily due to the asymptomatic nature of the disease that often leads to late diagnosis. This is further compounded by the lack of an effective targeted therapy. Therefore, better understanding of the mechanisms underlying ovarian cancer genesis and progression is critically needed to develop more efficient diagnostic and therapeutic strategies. The overarching goal of this project is to improve the current understanding of the mechanisms underlying ovarian cancer genesis and progression so as to develop better diagnostic and therapeutic strategies. To this goal, we investigated whether any new therapeutic signaling targets can be identified in ovarian cancer that can improve treatment efficiency and increase the overall survival of the ovarian cancer patients. Recent studies have shown that cancer cells recruit and convert normal cells that reside in their vicinity into cancer cell-like malignant cells. Specifically, cancer cells induce the transformation of tumor resident endothelial cells, epithelial cells, mesenchymal or hematopoietic stem cells, smooth muscle-cells, and quiescent normal fibroblasts into pro-tumorigenic cancer-associated fibroblasts (CAFs). CAFs, thus formed, provide a nurturing environment for the accelerated growth of the cancer cells and play a pivotal role in tumor progression, metastasis, and therapy resistance. However, the precise mechanism by which cancer cells induce the functional differentiation of NFs into CAFs is poorly understood thus far. Our recent studies have identified that cancer cells synthesize and secrete a lipid growth factor known as lysosphosphatidic acid (LPA), which acts on the adjacent fibroblasts to convert them into malignant CAFs. LPA triggers this in a two-step process. First, it alters the metabolic process of the normal fibroblasts so that the normal cells start producing metabolic building blocks that can be used by the cancer cells for their growth. Second, it alters the genes expression pattern in the normal fibroblasts so that they are fully converted into fully transformed CAFs that facilitate cancer growth and metastasis. Our studies have also identified the critical intermediary components through which LPA converts normal fibroblasts into CAFs. One unique, but ominous, feature of this pathway identified by us is that the LPA-initiated signaling mechanism affects both the cancer cells and the normal cells in the cancer cell neighborhood to promote the accelerated growth of ovarian cancer. However, this can be leveraged to our advantage by identifying the therapeutic target in this pathway that can inhibit cancer growth by targeting both the cancer cells and CAFs. Therefore, we reason that a clear understanding of the mechanism by which LPA triggers the conversion of normal fibroblasts into CAFs could unravel new intermediaries involved in this process so that effective targeted therapeutic strategies could be developed. In this proposal, we provide extensive preliminary data that substantiate the proposed objectives of the application. Our preliminary studies using ovarian cancer cell lines, as well as patient-derived ovarian cancer cells, indicate the potential mechanism through which LPA induces the cancer-promoting function of CAFs. Based on these findings, we hypothesize that the LPA-induced paracrine signaling pathway plays a critical role in the transdifferentiation of fibroblasts into CAFs; that delineating the underlying signaling nexus will identify potential therapeutic signaling nodes involved in this process; and that FDA-approved, repurposed, and/or investigative drugs targeting the signaling components could accelerate the development of targeted therapy in ovarian cancer. This integrated hypothesis will be tested under three specific aims. Aim 1 will investigate the mechanism by which LPA induces the differentiatio
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210415
Entities
People
- Danny Dhanasekaran
Organizations
- United States Army
- University of Oklahoma Health Sciences Center