# Exploiting the epithelial-to-mesenchymal transition for the differentiation of cancer stem cells

> **NIH NIH R00** · DARTMOUTH COLLEGE · 2020 · $249,000

## Abstract

Project Summary
About 15-20% of breast cancer patients fall under the basal-like category, which represent a diverse subtype
that is characterized by tumors that are more aggressive conferring poor prognosis. Deaths from these
carcinomas result from metastatic spread of the disease to distant sites and from therapeutic resistance, which
results in the relapse of cancers into more aggressive forms that are difficult to contain. Both these properties
are attributed to their cellular heterogeneity that arises through various mechanisms including clonal evolution
and the presence of cancer stem cells (CSCs). The epithelial-to-mesenchymal transition (EMT) is one program
that we have shown to be responsible for the generation of cells that have CSC-like properties.
Our current proposal aims to induce differentiation of these CSCs through the induction of a mesenchymal-to-
epithelial transition (MET). To do this, we carried out a screen to identify compounds that are capable of
inducing the transcription of E-cadherin, a hallmark of the epithelial/non-CSC state, in cells that are more
mesenchymal/CSC-like. Through this screen we identified Forskolin, an activator of cAMP, to be able to induce
E-cadherin transcription and a reversion of the mesenchymal/CSCs to a more benign epithelial state. Through
this proposal we aim to uncover the mechanism by which cAMP-elevating agents are able to induce an MET
by complete characterization of the essential downstream components of signalling, namely Protein Kinase A
(PKA) and its downstream substrates. We also aim to understand the epigenetic reprogramming that occurs
following activation of PKA through the functions of the histone-modifying enzyme PHF2. Both these
components will address the mechanisms by which CSCs can be differentiated to a state that renders them
highly sensitive to treatment with chemotherapeutic agents such as doxorubicin.
Despite over two decades of research, our ability to specifically target CSCs is still lacking. Through the study
of Phosphodiesterases and G-Protein Coupled Receptors (GPCRs) that modulate cAMP levels, I aim to
develop ways to specifically induce differentiation of CSCs that can be translated for therapeutic utility.

## Key facts

- **NIH application ID:** 9843447
- **Project number:** 5R00CA201574-05
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Diwakar R Pattabiraman
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2018-01-10 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9843447

## Citation

> US National Institutes of Health, RePORTER application 9843447, Exploiting the epithelial-to-mesenchymal transition for the differentiation of cancer stem cells (5R00CA201574-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9843447. Licensed CC0.

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