# Investigating the impact of chromosomal instability on prostate cancer aggressiveness

> **NIH NIH R01** · MAYO CLINIC ROCHESTER · 2024 · $485,354

## Abstract

PROJECT SUMMARY
Prostate cancer (PC) is a leading cause of male cancer-related deaths. Once disseminated PC is incurable as it
gradually progresses to all therapeutic options. The mechanisms underlying aggressive features and lethality of
metastatic PC remain an unmet clinical need. We and others have reported that metastatic PC displays the
highest levels of chromosomal instability (CIN), and we have shown that transcriptional reprogramming allows
PC CIN-adaptation and survival in advanced disease. Yet, the molecular underpinnings of CIN impact on PC
remain poorly understood. Using genetic, proteomic, epigenomics and high-resolution microscopy, we found that
CIN is linked to transcriptional rewiring and bookmarking suggesting a role of CIN in cell reprogramming in lethal
PC. High CIN PC remains highly dependent on mitotic fidelity programs like the ones controlled by MASTL kinase
to restrain lethal catastrophic CIN levels. We find that MASTL regulates new late mitotic processes involved in
centrosome biology and cytokinesis in PC cells. However, the substrates and effectors by which MASTL regulate
these functions remain unknown. Finally, our in vivo data strongly suggest a relevant role of CIN impacting anti-
tumor immunity in PC. In this application we will use unique genetic models to identify the substrates and
cofactors by which MASTL kinase regulates new functions in high CIN PC (Aim 1). We will investigate the
molecules and mechanisms underlying CIN-induced transcriptional reprogramming and gene bookmarking in
PC (Aim 2) and will explore the tumor immune cell intrinsic and extrinsic mechanisms triggered by CIN in PC
that may enhance immunotherapy efficacy (Aim 3). Through these studies we will mechanistically uncover novel
aspects of CIN consequences for PC and may identify new potential treatment strategies for this lethal disease.

## Key facts

- **NIH application ID:** 10993877
- **Project number:** 1R01CA294563-01
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** Veronica Rodriguez-Bravo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $485,354
- **Award type:** 1
- **Project period:** 2024-07-08 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10993877

## Citation

> US National Institutes of Health, RePORTER application 10993877, Investigating the impact of chromosomal instability on prostate cancer aggressiveness (1R01CA294563-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10993877. Licensed CC0.

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