# Mechanisms of gene expression regulation in pancreatic cancer

> **NIH NIH F99** · MAYO CLINIC ROCHESTER · 2024 · $48,974

## Abstract

PROJECT SUMMARY
 Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second deadliest cancer within the
next 10 years. Investigations into novel mechanisms of PDAC transformation are urgently needed as no
effective PDAC treatment currently exists. Transcriptional regulation during transformation is multifaceted with
genetic mutations and epigenetic alterations playing vital interconnected roles. A key unelucidated facet of
gene regulation in the context of transformation is the molecular mechanism which mediates changes in
chromatin reorganization. ChIP-seq and ChIP-PCR studies in an inducible model of oncogenic KRAS, a key
initiating factor in PDAC, demonstrate a relocation of heterochromatin to the nuclear periphery. These lamina
associated domains (LADs) are enriched in H3K9me2 and positioned at the nuclear lamina. ChIP-seq and
RNA-seq identified loss of active enhancer regions incorporated into LADs and downregulation of LAD
associated genes, respectively. To investigate the mechanism regulating the assembly of LADs downstream of
oncogenic KRAS we performed several molecular and biochemical studies. We conducted a screening BioID
utilizing Lamin A, a core component of the nuclear lamina known to interact with LADs, as bait. Lamin A BioID
identified a novel myosin, Myosin 18a (MYO18a), enriched at the nuclear lamina under oncogenic KRAS
signaling. Immunocytochemistry revealed increased nuclear localization of MYO18a and enrichment at the
lamina upon KRAS activation. Biochemical analysis validated MYO18a-Lamin A interaction and confirmed
MYO18a interaction with chromatin. siRNA knockdown for MYO18a rescued expression of genes associated
with oncogenic KRAS-mediated LADs. These data lead us to our central hypothesis that MYO18a acts as a
downstream effector of KRAS to modulate chromatin positioning at the nuclear lamina to silence oncogenic
gene expression. To test this hypothesis, we will conduct ChIP-seq and RNA-seq experiments in parallel to
detect MYO18a associated LADs in in vitro models of PDAC. LAD assembly will then be investigated in the
presence/absence of MYO18a. We will also develop MYO18a genetic engineered mouse models to explore
the role of MYO18a and nuclear MYO18a in PDAC development and progression. Further study into this
mechanism can provide valuable insight into gene regulation in the transformation process and will identify
potentially druggable targets.

## Key facts

- **NIH application ID:** 10901909
- **Project number:** 5F99CA284259-02
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** David R Pease
- **Activity code:** F99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 5
- **Project period:** 2023-08-09 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10901909

## Citation

> US National Institutes of Health, RePORTER application 10901909, Mechanisms of gene expression regulation in pancreatic cancer (5F99CA284259-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10901909. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*