# The Pancreatic Cancer Microenvironment

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $364,845

## Abstract

Abstract
 The tumor microenvironment (TME) is recognized as a key factor in multiple stages of disease progression,
particularly local resistance, immune-escape, and distant metastasis, thereby substantially impacting the future
development of frontline interventions in clinical oncology. The receptor for advanced glycation end products
(RAGE) is a pattern recognition receptor predominantly involved in the recognition of endogenous molecules
released in the context of sterile inflammation and infection. We recently demonstrated that RAGE plays a unique
oncogenetic role in pancreatic ductal adenocarcinoma (PDAC). We demonstrated that: 1) RAGE was highly
expressed in mouse and human PDAC; 2) Global ablation of RAGE in mice prevented pancreatic cancer growth
in a genetically-modified spontaneous mouse model (Pdx1-Cre;K-RasG12D/+;RAGE-/-) and a xenograft mouse
model; 3) RAGE was essential for oncogenic K-Ras-mediated hypoxic signaling in PDAC development; and 4)
The mechanism by which this occurs in part involves inflammatory response-associated metabolic changes, cell
death-promoting limitations in autophagy, and a reduction in the accumulation of myeloid-derived suppressor
cells and regulatory T cells. These exciting findings raise several important questions regarding RAGE's novel
role in PDAC. We hypothesize that RAGE expression in multiple components of the TME is critical for PDAC
development and therapy resistance. We will pursue the following aims. Aim 1: identify RAGE as a critical
receptor of nuclear danger signal in the TME; Aim 2: define the cell-specific role of RAGE in the TME; and Aim
3: investigate antitumor efficacy of the combination of the RAGE inhibitor with chemoimmunotherapy in different
tumor models in mice. The completion of these exciting studies will provide new insights into our understanding
of the TME and guide future development of RAGE-based novel therapeutic strategies for PDAC patients.

## Key facts

- **NIH application ID:** 9697389
- **Project number:** 5R01CA211070-04
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Rui Kang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $364,845
- **Award type:** 5
- **Project period:** 2017-06-08 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9697389

## Citation

> US National Institutes of Health, RePORTER application 9697389, The Pancreatic Cancer Microenvironment (5R01CA211070-04). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9697389. Licensed CC0.

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