# Elucidating time-dependent mechanisms of genetic and epigenetic reprogramming in single cancer cells

> **NIH NIH U54** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $345,604

## Abstract

PROJECT SUMMARY
A major mechanism by which tumors survive from both chemotoxic and targeted therapies is hypothesized to
be the result intra-tumoral heterogeneity. Tumor heterogeneity have been postulated to contribute to tumor
evolution and therapy evasion through different mechanisms: generation of resistant subclones, cooperation
between minor subclonal populations, minor subclones generating stromal signaling that favors tumor
progression, etc. The genetic and epigenetic diversity that underlies tumor heterogeneity is siystematially
missed by traditional genomic approaches. The overall goal of this project is to develop approaches to
characterize functional dependencies and specific transcriptional programs in distinct tumor subpopulations,
using single cell molecular profiling and analysis, with specific emphasis on clones and niches inducing relapse
or progression. The first aim (1) of this project is to develop and implement new methods to capture tumor
clonal representation and to integrate large-scale expression and mutational analysis in single cells. This will
be done by conducting deep exome and RNA sequencing together with single-cell profiling to identify point
mutations, indels, and gene fusions in tumor cells. The second aim of this project (2) is to identify
epigenetically distinct cell niches with identical mutational spectra that either escape treatment or can
regenerate the tumor. Clonally expanded tumor cells may be genetically identical with respect to the mutations
identified in (1) but represent distinct epigenetic states, characterized by distinct gene expression signatures.
The methods developed in (1) will be applied to residual tumor cells following therapy in PDX models to
elucidate the drivers of drug resistance in epigenetically distinct cells. Finally the third aim (3) is to identify the
molecular interactions that implement cell-cell communication processes, within a heterogenous tumor-
microenviroment milieu. This will be achieved by developing novel information theoretic methodologies for the
prioritization of specific ligands and receptors that mediate single cell communication and interaction. These
methodologies will be specifically applied to elucidate novel tumor checkpoint inhibitors and other mechanisms
that are relevant to immunotherapy applications.

## Key facts

- **NIH application ID:** 9976486
- **Project number:** 5U54CA209997-05
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Raul Rabadan
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $345,604
- **Award type:** 5
- **Project period:** — → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976486

## Citation

> US National Institutes of Health, RePORTER application 9976486, Elucidating time-dependent mechanisms of genetic and epigenetic reprogramming in single cancer cells (5U54CA209997-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9976486. Licensed CC0.

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