# Defining epigenetic signaling to reshape pancreatic tumor microenvironment

> **NIH NIH R37** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2022 · $462,567

## Abstract

PROJECT SUMMARY/ABSTRACT
The 5-year survival of pancreatic cancer patients remains at 10% primarily due to the tumor resistance to
standard chemo and immunotherapies. The profound immunosuppressive tumor microenvironment contributes
to treatment resistance. Notably, 82% of the neoadjuvant-treated pancreatic cancers carry loss of function
mutations for KMT2D, a histone modification enzyme. Epigenetics is known to impact cancer cell behavior.
However, how tumor cell-intrinsic epigenetic alterations modulate the pancreatic tumor microenvironment
remains elusive. The long-term goal is to develop new treatments to convert pancreatic cancer to an
immunologically hot tumor and improve the efficacy of immunotherapy and patient survival. The overall
objectives in this application are to 1) determine the impact of KMT2D signaling on the tumor
microenvironment and 2) characterize the mechanisms by which KMT2D regulates activin A expression. The
central hypothesis is that upregulation of activin A upon KMT2D loss in pancreatic cancer reprograms cancer-
associated fibroblasts and immune cells to promote a pro-tumoral immunosuppressive microenvironment. The
rationale for this project is that the knowledge of the mechanisms by which KMT2D regulates the tumor
microenvironment will pave the way for future preclinical and clinical development of new strategies to treat
pancreatic cancer. The central hypothesis will be tested by pursuing three specific aims: 1) Elucidate the
impact of KMT2D signaling on the immune composition in the tumor microenvironment; 2) Define the
regulation of heterogeneous cancer-associated fibroblasts by KMT2D signaling; and 3) Determine the
molecular mechanisms of activin A regulation by KMT2D in pancreatic cancer. Under the first and second
aims, we will use our established pancreatic cancer genetic mouse models with pancreas-specific inactivation
of KMT2D to determine the impact of KMT2D signaling on the differentiation and activation of cancer-
associated fibroblasts, macrophages, and T cells, and ligand-receptor interactions in the tumor
microenvironment and the underlying mechanisms. Single-cell RNA sequencing technology, mass cytometry,
and multiplex fluorescent immunohistochemistry will be used. For the third aim, we will characterize the
interactions between KMT2D and co-factors and the mechanisms of KMT2D-mediated regulation of activin A
transcription and enhancer activity using ChIP-seq, BruUV-seq, and functional luciferase reporter assays. The
research proposed in this application is innovative because it focuses on a novel concept that epigenetic
signaling from tumor cells remodels the tumor microenvironment and contributes to cancer progression and
uses state-of-the-art animal models and approaches. The proposed research is significant because it will shed
light on the mechanism of transcriptional regulation by KMT2D in pancreatic cancer and the effect of KMT2D
signaling on pancreatic tumor microenvironment, which will set th...

## Key facts

- **NIH application ID:** 10514158
- **Project number:** 1R37CA262209-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jiaqi Shi
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $462,567
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10514158

## Citation

> US National Institutes of Health, RePORTER application 10514158, Defining epigenetic signaling to reshape pancreatic tumor microenvironment (1R37CA262209-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10514158. Licensed CC0.

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