# Defining pro-metastatic drivers in the pancreatic cancer tumor microenvironment

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2024 · $453,304

## Abstract

PROJECT ABSTRACT
Pancreatic adenocarcinoma (PDAC) is an almost uniformly fatal disease most often diagnosed after the
development of metastases. The tumor suppressor gene, TP53, is the most commonly altered gene in human
cancer and has been recognized as a genetic driver of PDAC in up to 75% of patients. While the functions of
TP53 mutations within cancer cells continue to be studied, knowledge of its non-cell autonomous roles in the
primary tumor microenvironment remain limited. The ultimate goal of our work is to exploit targets that arise in
PDAC tumor cells or in the tumor microenvironment (TME) as a consequence of p53 mutation for translation into
patient therapies. Recently, our laboratory discovered a cooperative signaling node between the top genetic
PDAC drivers, oncogenic KRAS and mutant p53, engaged through interactive binding between mutant p53 and
CREB1. This mutant p53/CREB1 complex subsequently activates multiple pro-metastatic transcriptional
networks within tumor cells. Our preliminary data indicate that mutant p53/CREB1 GOF also drives non-cell
autonomous functions through the activation of WNT/β-catenin signaling elements that direct cancer associated
fibroblasts (CAFs) to curate the primary TME into pro-metastatic landscapes. We hypothesize that targeted
disruption of the mutant p53/CREB1 complex is a viable opportunity to reverse cell- and non-cell autonomous
functions of mutant p53 for therapeutic translation in PDAC. Accordingly, the objective of this grant proposal is
to gain additional mechanistic insight into how p53 mutations in tumor cells drive pro-metastatic interactions with
cancer associated fibroblasts and to test if disruption of the mutant p53/CREB1 complex subverts vitals steps in
the metastatic cascade. Using genetically engineered mice and patient derived model systems, in aim 1 we will
confirm essential elements of the mutant p53/CREB1-WNT/β-catenin signaling axis that consort with cancer
associated fibroblasts to enhance migratory and invasive phenotypes. Moreover, we will test the efficacy of
combined targeted approaches to disrupt multiple levels of the mutant p53/CREB1-WNT11 signaling axis to
mitigate metastasis. In aim 2, we will clarify the role of the mutant p53/CREB1-WNT/β-catenin signaling axis in
the curation of the fibrotic TME as it relates to chemoresistance and metastasis while testing its reversibility using
genetic and pharmacologic strategies. In Aim 3, we will use human PDAC biospecimens and derived organoids
to correlate our findings from Aims 1 and 2. The proposed research is significant because p53 mutations are
present in 70 percent of PDAC patients and remain untargetable. As such, our approach to disrupt non-cell
autonomous mutant p53 gain of function could expose new therapeutic vulnerabilities or inform rational
combinatorial treatment strategies. The proposed research is innovative because we will study and modulate a
novel mutant p53/CREB1-WNT/β-catenin signaling axis to undermine...

## Key facts

- **NIH application ID:** 10980175
- **Project number:** 1R01CA269651-01A1
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Michael Paul Kim
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $453,304
- **Award type:** 1
- **Project period:** 2024-09-01 → 2029-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10980175

## Citation

> US National Institutes of Health, RePORTER application 10980175, Defining pro-metastatic drivers in the pancreatic cancer tumor microenvironment (1R01CA269651-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10980175. Licensed CC0.

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