# Epi-genetic Programs in Cancer Progression

> **NIH NIH R35** · WHITEHEAD INSTITUTE FOR BIOMEDICAL RES · 2022 · $1,146,600

## Abstract

Project Summary/Abstract:
Much of current molecular oncology research is grounded on the paradigm that the behavior of cancer cells
and the tumors that they form is dictated by the mutant genomes that these cells have acquired en route to
entering into neoplastic/cancerous states. Implicit in this work is the notion that non-genetic mechanisms (that
are not directly influenced by DNA sequence) – notably changes organized by non-genetic (i.e., epigenetic)
regulatory circuits operating within a cancer cell – play a secondary role in dictating its behavior.
In fact, the majority of cancer cell traits may actually be governed by non-genetic regulatory programs that
operate in a relatively stable fashion to ensure that many of these traits are transmitted heritably from normal
cells-of-origin through multiple cancer cell generations during the course of multi-step tumor development. In
addition, activation within carcinoma cells of the cell-biologic program termed the epithelial-mesenchymal
transition (EMT) creates a second dimension of cancer cell behavior that is not dictated by the cells' DNA
sequences, acting by converting relatively benign carcinoma cells to malignant derivatives. These two non-
genetic regulatory mechanisms exert profound effects on the malignant progression of cancer cells and their
responsiveness to various forms of therapy. However, relatively little is known about how these non-
genetically determined traits of cancer cells are acquired and disrupted during tumor formation.
Super-enhancers (SEs) represent large aggregations of transcription factors (TFs) associated with a relatively
small number (several hundred) of gene promoters in both normal cells and cancer cells. These SEs are
responsible for orchestrating the differentiation programs of a variety of normal cell types that enables them to
become tissue-specialized cell types. The proposed research examines the disruptive effects of specific
oncogene-encoded proteins (and/or loss of tumor suppressor gene proteins) on the spectrum of SEs within
experimentally transformed human cells from a variety of normal cell lineages, with the goal of understanding
which SEs survive disruption and continue to influence the behavior of resulting tumorigenic cells (with respect
to their responsiveness to therapy and their malignant traits), and which are altered, resulting in the acquisition
of novel cancer cell traits. As a complement to these analyses will be an examination of the SEs associated
with the EMT programs activated in various types of transformed cells, these being activated either through the
induced expression of EMT-inducing TFs or the exposure of transformed cells to known EMT-inducing growth
factors and cytokines. By surveying SEs in normal cell types and their neoplastic derivatives, the proposed
work will generate an experimental platform that will enable many researchers to finally elucidate at the
molecular level why and how various distinct subtypes of human car...

## Key facts

- **NIH application ID:** 10467022
- **Project number:** 5R35CA220487-06
- **Recipient organization:** WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
- **Principal Investigator:** ROBERT A WEINBERG
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,146,600
- **Award type:** 5
- **Project period:** 2017-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467022

## Citation

> US National Institutes of Health, RePORTER application 10467022, Epi-genetic Programs in Cancer Progression (5R35CA220487-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10467022. Licensed CC0.

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