# Mechanisms of Epigenetic Plasticity in PDAC

> **NIH NIH R01** · GEORGETOWN UNIVERSITY · 2023 · $483,032

## Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most deadly human cancers and in ~95%
of cases driven by oncogenic mutations of Kras. Unfortunately, attempts to directly inhibit
oncogenic Kras or Ras effector pathways have been largely ineffective in treating PDAC due to
the development of resistance. Yap (Yes-associated-protein), an oncogenic transcription
regulator, not only is required for PDAC progression but also confers resistance to extinction of
oncogenic Kras signaling and other therapeutic agents in advanced PDAC tumors. Using a next-
generation inducible genetic engineered mouse model, we discovered that even though PDAC
tumors rely on Yap to maintain the transcriptional output necessary for tumor growth and survival,
a subpopulation of tumor cells with stem/progenitor-like characteristics undergo epigenetic
reprogramming eventually overcoming their Yap addiction in late stage PDAC. In this grant we
propose a multi-faceted effort to elucidate the molecular/cellular drivers of adaptive
reprogramming in Yap-ablated, advanced PDAC tumors, and explore novel therapeutic strategies
to overcome resistance to Yap blockade. Furthermore, we will use an inducible genetic lineage-
tracing model to track how the cancer “stem/progenitor” niches contribute to PDAC invasion,
metastasis and resistance to Yap ablation. Together, these experiments will not only provide
critical insights into the mechanisms underlying PDAC plasticity, but also inform potential new
strategies to overcome therapeutic resistance in PDAC.

## Key facts

- **NIH application ID:** 10634498
- **Project number:** 5R01CA252223-03
- **Recipient organization:** GEORGETOWN UNIVERSITY
- **Principal Investigator:** Alessandro Gardini
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $483,032
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10634498

## Citation

> US National Institutes of Health, RePORTER application 10634498, Mechanisms of Epigenetic Plasticity in PDAC (5R01CA252223-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10634498. Licensed CC0.

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