# Epigenetic Regulation of Hemidesmosome Signaling in Pancreatic Cancer

> **NIH NIH R03** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $166,096

## Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive human cancers, with less than 8% of
patients surviving beyond five years after diagnosis. A key impediment to the treatment of PDAC is a highly
desmoplastic tumor stroma. The abundance of non-neoplastic cells and extracellular matrix (ECM) in the stroma
have been implicated in promoting aggressive tumor growth and inhibiting effective drug delivery. The ECM has
long been thought to be primarily produced by stromal cells, including cancer associated fibroblasts (CAFs).
However, our characterization of xenograft tumor models, in vitro co-cultures of CAFs and PDAC cells, and laser
capture microdissected tumors has revealed that PDAC cells express a large proportion of the ECM.
Furthermore, these studies revealed a CAF-dependent reprogramming of PDAC cells that allows for the
expression of ECM components observed in tumors. We have previously demonstrated that the BET family of
chromatin adaptors play key roles in the growth of PDAC tumors by regulating pathways in both PDAC and
stromal cells. Building on this work, we have found the expression of the ECM in PDAC is broadly regulated by
BET proteins. Among these BET-dependent genes are components of the hemidesmosome, a multiprotein
complex that mediates signaling from the ECM to the cytoskeletal network of cells. This proposal will examine
the mechanisms by which BET proteins mediate the CAF-dependent expression of the ECM in PDAC cells and
define the biological role of Collagen XVII, a critical subunit of hemidesmosomes. In Specific Aim 1 of this
application, low passage PDAC cell lines and immortalized PDAC-derived CAF cultures will be utilized to
examine the transcriptional mechanisms by which CAFs mediate the BET-dependent expression of the ECM-
encoding genes in PDAC cells. In Specific Aim 2, we will employ tumor models that temporally regulate the
expression of Collagen XVII to define whether CAF-induced expression of Collagen XVII in PDAC cells contribute
to PDAC tumor growth. Downstream Collagen XVII signaling pathways will be analyzed in tumors to elucidate
the mechanisms by which this signaling contributes to tumor biology.

## Key facts

- **NIH application ID:** 10046923
- **Project number:** 1R03CA241971-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Andrew Liss
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $166,096
- **Award type:** 1
- **Project period:** 2020-08-10 → 2022-07-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10046923

## Citation

> US National Institutes of Health, RePORTER application 10046923, Epigenetic Regulation of Hemidesmosome Signaling in Pancreatic Cancer (1R03CA241971-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10046923. Licensed CC0.

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