# Tracing and targeting the epigenetic heterogeneity in breast cancer metastasis

> **NIH NIH K99** · BAYLOR COLLEGE OF MEDICINE · 2022 · $128,995

## Abstract

Project Summary
Title: Tracing and targeting the epigenetic heterogeneity in breast cancer metastasis.
Metastasis is major cause of cancer-related death and is the most challenging to treat. Besides the well-studied
genomic mutations in cancer, our understanding of non-genomic alterations remains limited. The proposed
approach is to dissect the mechanisms of non-genomic intra-metastasis heterogeneity in breast cancer.
Recently, we demonstrated that osteoblasts (bone forming cells) promote a global alteration of chromatin
organization which associates with increased stemness, epithelial to mesenchymal transition, and
overexpression of multiple receptor tyrosine kinases included FGFR1 and PDGFRβ. Ultimately, estrogen
signaling was inhibited while endocrine resistance was increased. Mechanistically, we identified FGF2/PDBFβ/
EZH2 axis as a novel regulator of epigenetic reprogramming in breast cancer bone metastasis. However, several
outstanding questions remained unanswered: (i) what mechanisms drive phenotypic variations between
neighboring cells in bone metastasis, (ii) are epigenetic traits inheritable during metastasis progression, and (ii)
if yes, how do they influence therapeutic response? In this project, our goal is to understand the mechanisms of
intra-tumor heterogeneity in bone metastases and determine how epigenetic heterogeneity affects therapeutic
response beyond the genetic heterogeneity that has been extensively studied. We aim to trace and dissect the
epigenetic intra-tumor heterogeneity (eITH) using a cutting-edge barcoding strategy (K99 phase), identify
epigenetic modulators by integrating single cell multi-omics (K99-R00 phase), test new therapeutic approaches
and eventually expand our findings to other breast cancer metastasis sites (R00 phase) including lung, liver, and
brain. Baylor College of Medicine (BCM) is an internationally renowned institution for breast cancer research,
which gives me the opportunity to closely interact, exchange ideas, and share my findings with leading scientists,
clinicians and patient advocates. For my career transition, I assembled a team of senior scientists and experts
including my mentor, Professor Xiang H-F Zhang, who is well-established in breast cancer bone metastasis. My
co-mentor, Professor Jeffrey Rosen, is a distinguished scientist in mammary gland development and breast
cancer modeling. Because of the clinical relevance of the project, I also included Professor C. Kent Osborne,
founding director of the Dan L. Duncan Comprehensive Cancer Center (DLDCCC), Professor Matthew J. Ellis,
a world-renowned oncologist and director of the Breast Center, Dr. Bora Lim, an expert in aggressive subtypes
of breast cancer (e.g. inflammatory breast cancer), Professor Susan G. Hilsenbeck, a distinguished
biostatistician, and Dr. Zhandong Liu a computational biologist and statistician with expertise in single cell
analysis. Adding the expertise of my advisory team to the rich intellectual resource and cutt...

## Key facts

- **NIH application ID:** 10446911
- **Project number:** 1K99CA263033-01A1
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Igor Landry Bado
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $128,995
- **Award type:** 1
- **Project period:** 2022-04-01 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10446911

## Citation

> US National Institutes of Health, RePORTER application 10446911, Tracing and targeting the epigenetic heterogeneity in breast cancer metastasis (1K99CA263033-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10446911. Licensed CC0.

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