# TBEL Project 1

> **NIH NIH U54** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $370,013

## Abstract

PROJECT 1 - ABSTRACT
There are two distinct pathways to invasive neoplasia in the pancreas – the more common non-cystic
(pancreatic intraepithelial neoplasia or PanIN) and cystic (mostly, intraductal papillary mucinous
neoplasm or IPMN). Both PanIN and IPMNs occur at significantly higher rates in the population than invasive
cancer, reiterating that only a fraction of precursor lesions progress to pancreatic ductal adenocarcinoma
(PDAC), but determining which patient will progress is currently not possible. PanINs and IPMNs are both
characterized by the common occurrence of oncogenic KRAS mutations, while the latter also harbors
concomitant “hotspot” GNAS mutations in 2/3rd of cases. How these early epithelial alterations and their crosstalk
with the tumor microenvironment (TME) impacts progression to cancer remains understudied. The formation of
early pancreatic precursors is accompanied by the expansion of a heterogeneous fibroblast population. In
advanced disease, fibroblasts become cancer associated fibroblasts (CAFs). Little is known about precursor
lesion associated fibroblasts (PAFs), including prevalent differences between the two precursor subtypes. Our
preliminary data show that fibroblast reprogramming occurs in early pancreatic lesions, and leads to expression
of IL6, and IL33. While IL6 is secreted and known to regulate the immune microenvironment, IL33 is prevalently
nuclear in fibroblasts. Interestingly, IPMNs also have extremely elevated epithelial nuclear IL33. IL33 contains a
DNA binding domain and is known to regulate transcription. Based on these observations, we propose to study
the mechanisms of fibroblast reprogramming and comparing fibroblast gene expression in PanINs and IPMNs
(Aim 1). Further, we will study the role of fibroblast IL33 in lesion progression and establishment of the precursor
lesion microenvironment (PME) in PanIN and IPMN (Aim 2). Lastly, we will determine how epithelial IL33 in
IPMNs regulates the PME as well as progression to malignancy (Aim 3). We will integrate the mouse model and
in vitro studies with primary human tissue and organoids generated in the Wood laboratory (see Project 3).
Together, these studies will shed light on the composition and role of PAFs in different premalignant lesions of
the pancreas.

## Key facts

- **NIH application ID:** 10518937
- **Project number:** 1U54CA274371-01
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Marina Pasca Di Magliano
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $370,013
- **Award type:** 1
- **Project period:** 2022-09-21 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10518937

## Citation

> US National Institutes of Health, RePORTER application 10518937, TBEL Project 1 (1U54CA274371-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10518937. Licensed CC0.

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