NIH grant: Tumor-Niche Co-evolution: Mechanisms Driving Ovarian Cancer Metastasis and Therapeutic Resistance (1R01CA309809-01A1)

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NIH grant 1R01CA309809-01A1: Tumor-Niche Co-evolution: Mechanisms Driving Ovarian Cancer Metastasis and Therapeutic Resistance
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Siyuan  Zhang. Award: $621121.
Start: 2026-07-10T00:00:00.
Project Summary
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.

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