# Targeting aberrant enhancer landscapes in pancreatic cancer

> **NIH NIH R01** · COLD SPRING HARBOR LABORATORY · 2024 · $432,000

## Abstract

PROJECT SUMMARY
Lineage plasticity is a prominent feature of human pancreatic ductal adenocarcinoma (PDAC), which
accompanies several stages of this disease ranging from tumor initiation, chemotherapy resistance, and the
acquisition of metastatic traits. Our work in this area has relied heavily on the application of epigenomics and
high throughput genetic screening in clinically relevant PDAC models. An important attribute of our work is to
take deep-dives into causal molecular mechanisms, which naturally focuses on the lineage master regulator
proteins that implement aberrant cell fate transitions. Our work seeks to challenge the view that transcription
factors are undruggable by defining the molecular details of their cancer maintenance functions. Into the next
funding cycle of this grant, our focus will continue to be on the basal (also known as adenosquamous) cell state,
which is known to emerge aberrantly during PDAC progression. In our published work, we have defined
mechanisms by which Np63 and ZBED2, two transcription factors that are expressed in the normal basal
lineage but not in the normal human pancreas, drive basal identity in PDAC. The next funding cycle of this grant
will pursue key unanswered questions related to these factors in PDAC biology. The first Aim will focus on
MED12, a novel master regulator of basal identity in PDAC and transcriptional coactivator of Np63, which we
identified by way of an unbiased genetic screen. We will perform CRISPR base-editor tiling screens coupled with
molecular reporters to map MED12 mutations that disrupt Np63 function without altering other MED12
transcriptional functions. We will biochemically and epigenomically characterize these novel MED12 alleles to
gain an atomic level understanding of its involvement in sustaining basal identity in PDAC. The second aim builds
upon our prior work showing that a basal identity in PDAC reprograms the stroma via a unique secretory
phenotype driven by Np63. We will establish novel in vivo basal-like PDAC models with inducible Np63 and
MED12 knockdown to compare how each factor drives a secretory phenotype that reprograms the tumor stroma.
The third aim focuses on ZBED2, which was unstudied prior to our recent publication, but we have shown that
this factor can destabilize the classical-ductal identity in PDAC by antagonizing IRF1 function, which in turn leads
to repression of the GATA6 gene. Since much of our prior work on ZBED2 occurred in tissue culture systems,
the logical extension of this work will be to manipulate ZBED2, IRF1, and GATA6 in organoid models of PDAC
in vivo, a system that fosters the lineage plasticity potential seen in human PDAC. We seek to test the hypothesis
that acquisition of ZBED2 expression can ‘kickstart’ ductal-to-basal trans-differentiation by interfering with the
IRF1-GATA6 axis. Collectively, this research will reveal several fundamental biological characteristics of basal
identity in PDAC, which may have broader implic...

## Key facts

- **NIH application ID:** 10978483
- **Project number:** 2R01CA229699-06
- **Recipient organization:** COLD SPRING HARBOR LABORATORY
- **Principal Investigator:** CHRISTOPHER VAKOC
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $432,000
- **Award type:** 2
- **Project period:** 2019-07-02 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10978483

## Citation

> US National Institutes of Health, RePORTER application 10978483, Targeting aberrant enhancer landscapes in pancreatic cancer (2R01CA229699-06). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10978483. Licensed CC0.

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