Sunday, July 6, 2025 7/6/2025

Mechanisms of gene expression regulation in pancreatic cancer

Award Number: K00CA284259
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/09/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2028

Group Awards By:

View Award Description

Mechanisms of gene expression regulation in pancreatic cancer - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $103,639 )
2024	2024	WHITEHEAD INSTITUTE FOR BIOMEDICAL RESEARCH	455 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Research Manpower	000	3	8/26/2024	EXTENSION WITH OR WITHOUT FUNDS	$103,639
														Subtotal = $103,639

Grand Total All Awards = $103,639

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Mechanisms of gene expression regulation in pancreatic cancer

Award Number: K00CA284259

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/09/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2028

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer