Targeting Cancer-Associated Fibroblast Transdifferentiation Pathway for Ovarian Cancer Therapy

Abstract

Ovarian cancer is a major cause of cancer-related mortality in women, with high recurrence rates and resistance to chemotherapy. Discovering new therapeutic targets is crucial, especially for recurrent, chemotherapy-resistant cases. Cancer cells interact with neighboring normal fibroblasts (NOFs), inducing their conversion into cancer-associated fibroblasts (CAFs) through paracrine signaling, but the underlying mechanism remains unclear. This study hypothesizes that lysophosphatidic acid (LPA) triggers metabolic reprogramming, essential for NOF to CAF transdifferentiation. The research aims to unveil the LPA-LPAR-HIF1 signaling nexus and identify potential therapeutic targets. The study's three specific aims encompass understanding LPA-induced metabolic programming and myofibroblast differentiation, delineating the role of LPA-induced HIF1 in fibroblast transcriptional reprogramming, and assessing the therapeutic potential of candidate genes and pseudohypoxia signaling nodes in ovarian cancer. In pursuit of these objectives, we conducted a comprehensive investigation of LPARs, G-subunits, and the long non-coding RNA XIST, leading to the identification of XIST's novel role in CAF differentiation and potential signaling targets that can disrupt CAF differentiation. Our results also shed light on the intricate interplay between LPA signaling and XIST-mediated gene expression, providing insights into the mechanism underlying HIF1 expression and CAF differentiation. Collectively, our progress during this period has uncovered new avenues for therapeutic interventions targeting the CAF differentiation pathway. This research holds promise for advancing ovarian cancer treatment by better understanding and potentially disrupting the mechanisms that contribute to chemotherapy resistance and recurrence.

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Document Details

Document Type
Technical Report
Publication Date
Jul 01, 2023
Accession Number
AD1214511

Entities

People

  • Danny N. Dhanasekaran

Organizations

  • University of Oklahoma

Tags

DTIC Thesaurus Topics

  • Cancer
  • Cell Line
  • Cells
  • Chemotherapy
  • Computational Biology
  • Computer Programming
  • Data Analysis
  • Diseases
  • Electronic Mail
  • Gene Expression
  • Identification
  • Medical Personnel
  • Neoplasms
  • Ovarian Cancer
  • Systems Biology
  • Technology Transfer
  • Therapy

Fields of Study

  • Biology

Readers

  • Oncology (Cancer Research).
  • Prostate Cancer Biology.
  • Theoretical Analysis.