# Dissecting mechanisms of tumor initiation via immunomodulation

> **NIH NIH SC1** · CLARK ATLANTA UNIVERSITY · 2022 · $269,500

## Abstract

Project Summary/Abstract
 Since the year 2000, pancreatic cancer diagnosis has been on the rise with future projections
considering it to be the 2nd leading cause of cancer death by 2030. Furthermore, the majority of patients die
within 1 year of diagnosis due to a lack of early detection and early intervention, both of which limit therapy
options. Pancreatic ductal adenocarcinoma (PDAC) is the major form of pancreatic cancer and a disorder of
oncogenic Kras. Turning off Kras mutants, including KrasG12D or KrasG12V is the key to curing PDAC. However,
there are no known inhibitors which directly target these two mutants. PDAC originates from acinar cells
through the acinar-to-ductal metaplasia (ADM) process. Upon acquisition of oncogenic Kras mutation, it
converts acinar cells to duct-like cells, which subsequently develop into cancer cells. Because 1) activating
Kras mutations are required for PDAC growth and maintenance; 2) ADM is the initial step of PDAC
development; 3) KrasG12D and KrasG12V in PDAC are undruggable; and 4) PDAC patients are diagnosed too
late, it is important to understand how KrasG12D regulates ADM and precancerous lesion formation. Acquiring
information pertaining to the ADM process and its regulation will provide groundwork for the identification of
biomarkers used for early detection, and drug targets for early intervention successfully reducing the death toll
of PDAC. We identified CCL9 as a new downstream target of KrasG12D in pancreas acini of ADM and
subsequent PanIN development. So far, little is known about CCL9 in physiological and pathological settings.
Gene amplification of CCL15, a human orthologue of CCL9, is present in human PDAC and is a predictor of
shorter survival. The goal of this proposal is to dissect the mechanisms and functions of KrasG12D/CCL9 axis on
PDAC initiation and tumor development. We will accomplish this goal with the following specific aims. 1. To
delineate the mechanisms of CCL9-induced PDAC initiation through ADM; 2. To evaluate the in vivo function
of CCL9 in KrasG12D-mediated PDAC initiation. Successful completion of these aims will reveal new functions of
CCL9 in PDAC initiation and growth, add new mechanistic insights into the early event of PDAC development,
and establish the essential groundwork for CCL15, the human orthologue of CCL9, as one of the biomarkers
for early detection and the new treatment strategies for early intervention in the clinic to fight PDAC death.

## Key facts

- **NIH application ID:** 10374169
- **Project number:** 5SC1GM140907-02
- **Recipient organization:** CLARK ATLANTA UNIVERSITY
- **Principal Investigator:** Geou-Yarh Liou
- **Activity code:** SC1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $269,500
- **Award type:** 5
- **Project period:** 2021-03-17 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10374169

## Citation

> US National Institutes of Health, RePORTER application 10374169, Dissecting mechanisms of tumor initiation via immunomodulation (5SC1GM140907-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10374169. Licensed CC0.

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