Tumor-niche CO-evolution: mechanisms driving ovarian cancer metastasis and therapeutic resistance

The National Cancer Institute awarded The University of Texas Southwestern Medical Center $621,121 on July 10, 2026, under the Cancer Biology Research program (CFDA 93.396) to investigate tumor-niche co-evolution mechanisms driving ovarian cancer metastasis and therapeutic resistance.

The research integrates clonal barcoding, single-cell RNA sequencing, and in vivo CRISPR screens to trace the evolutionary trajectory of metastatic ovarian cancer cells and define niche adaptive changes that promote disease progression and chemotherapy resistance. Aim 1 will elucidate niche-specific adaptation across disease progression by mapping temporal evolution of metastatic ovarian cancer populations during chemotherapy and performing mechanistic studies of drivers and gene-gene interactions that promote dissemination and therapeutic resistance. Aim 2 will define niche adaptive mechanisms to identify targetable signaling nodes overcoming chemoresistance by examining the immune milieu and biophysical niche structure regulating metastasis and treatment response. The work requires syngeneic immunocompetent in vivo mouse models to complement other experimental approaches, given that ovarian cancer metastasis is driven by dynamic cross-talk between tumor cells and host stromal, immune, and biophysical niche interactions that cannot be recapitulated in vitro, ex vivo, or fixed human tissue alone.

The award period runs from July 10, 2026, through June 30, 2031, with place of performance in Dallas, Texas.

Abstract

Metastatic ovarian cancer (movca) is a formidable clinical challenge, characterized by insidious progression, extensive tumor heterogeneity, and poor patient survival. In this project, we will comprehensively investigate the dynamic interplay between movca cells and their tumor microenvironment (TME), with a focus on single cell level interaction between disseminated tumor and its ovarian metastatic niche. Our goal is to define mechanisms of movca progression and therapeutic resistance mechanism which will provide rationale to inform the development of more effective, rationally designed targeted therapies for ovarian cancer patients. Our study builds on a robust platform that integrates clonal barcoding, single-cell RNA sequencing, and in vivo crispr screens to trace the evolutionary trajectory of movca cells and the functional significance of niche adaptive changes. Our preliminary results reveal the contributions of clonal dynamics and critical gene/cellular programs in driving movca. Because ovarian cancer metastasis is driven by the dynamic cross-talk between tumor cells and its host stromal, immune, and biophysical niche interactions that cannot be recapitulated in vitro, EX vivo, or fixed human tissue alone, this work will require syngeneic immunocompetent in vivo mouse models to complement other experimental models. Aim 1 will elucidate niche-specific adaptation across disease progression. We will map the temporal evolution of movca populations during chemotherapy and perform mechanistic studies of drivers and gene-gene interactions that promote dissemination and therapeutic resistance. Aim 2 will define niche adaptive mechanisms to identify targetable signaling nodes overcoming chemoresistance. We will examine the immune milieu and biophysical niche structure regulating metastasis and treatment response and use focused scope in vivo crispr screens to dissect dysregulated ovca signaling driving chemoresistance and to test dual-targeting strategies. Our project will lead to new therapeutic targets and provide important rationale of innovative strategies to disrupt the complex interplay between movca cells and their metastatic niche microenvironment.