# Analysis of the regulatory networks regulating district stem cell-like states in aggressive cancers

> **NIH NIH U54** · YALE UNIVERSITY · 2021 · $421,033

## Abstract

Project Summary/Abstract
The work proposed here is an extension of the work performed by the Yale Cancer Systems Biology Center
over the last 5 years. It is an extension of the work stemming from but not proposed in the initial application.
The project detailed in this application will focus on the use of multi-OMIC approaches to reconstruct the
regularity networks driving phenotypic plasticity in cancer cells, and more specifically cancer stem cells.
Although this was not initially anticipated, we discovered that glioblastoma cell line and possibly glioblastoma
patient samples harbor stem cell populations that differ in their properties, particularly with respond to
activation of signaling pathways and activation of Rho-family small GTPases, Rac1 (Rac) and RhoA. The multi-
OMIC (transcriptomic, proteomic and phosphorus-proteomic) analysis cells displaying greater invasive motility
behavior in the context of bio-mimetic and clinically relevant RACE assay used in the work of the Center,
appear to primarily activate RhoA, through a variety of mechanisms relying on activation of AKT-mTOR and
RelB NF-kappaB signaling. On the other hand, cell displaying lower motility under these conditions appear to
activate stress response pathways, particularly JNK and p38 and a distinct small GTPase, Rac, antagonistic to
RhoA. This picture will be supplemented over the course of the project with additional experimental and data
analysis work, extending the analysis to characterization of epigenetic signatures of each of the phenotypic
states. We will also explore whether the cell motility behavior may be altered in distinct micro-environments,
favoring Rac-dependent rather RhoA-dependent motility. Furthermore, we hypothesize that both phenotypic
states may promote invasive spread, but through distinct routes within the brain tissue, e.g., through peri-
vascular spaces vs. through fibrous environment of corpus callosum or other fibrous areas of the brain. We will
test this hypothesis in various engineered and tissue models of cellular micro-environments. We anticipate that
the analysis undertaken during this cost extension project will substantially improve our understanding of the
phenotypic plasticity in brain and other cancers and will pave the way to more intelligent treatments mitigating
cancer growth and invasive spread.

## Key facts

- **NIH application ID:** 10407391
- **Project number:** 3U54CA209992-05S1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Andre Levchenko
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $421,033
- **Award type:** 3
- **Project period:** 2021-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407391

## Citation

> US National Institutes of Health, RePORTER application 10407391, Analysis of the regulatory networks regulating district stem cell-like states in aggressive cancers (3U54CA209992-05S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10407391. Licensed CC0.

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