# PPARD hyperactivation promotes pancreatic intraepithelial neoplasia progression into pancreatic ductal adenocarcinoma

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $666,423

## Abstract

Pancreatic ductal adenocarcinoma (PDA) incidence is rising. Pancreatic intraepithelial neoplasms (PanINs) are
PDA precursors that are common in asymptomatic adults, but only few progress to PDA. The critical regulators
of PanIN progression to PDA and metastases remain unknown. KRAS mutations occur in > 92% of human low-
grade PanINs. Pancreatic KrasG12D mutation (mKRAS) in mice (KC mice) induces PanINs that mimic human low-
grade PanINs but fail to progress to PDA. High fat diet (HFD) and pancreatic P53 mutations (e.g., KPC mice)
promote a pancreatic immunosuppressive tumor microenvironment (iTME) and PanIN progression to PDA and
metastases in KC mice. Dietary fatty acids are natural activating ligands of peroxisome proliferator-activated
receptor-delta/beta (PPARD). PPARD is upregulated in human PDA, but its role in PDA is understudied. We
have found 1) PPARD was upregulated in human and KC mice PanINs; 2) Pancreatic PPARD knockout (KO) in
KC mice suppressed HFD promotion of PanIN progression to PDA; 3) PPARD activation by a HFD diet or diet
containing GW501516, a synthetic PPARD ligand (GW diet), accelerated PanIN progression to PDA in KC mice,
and to a greater extent, in KC/Pd mice with PPARD overexpression in pancreatic mKRAS+ cells; 4) PPARD
induced pancreatic epithelial cells to produce chemokines and cytokines (e.g. CCL2, IL-6, GM-CSF) that
recruited immunosuppressive cells to form an iTME; 5) PPARD KO in KPC cells (KPC-PdKO) suppressed PDA
and metastases while pancreatic PPARD overexpression in KPC mice (KPC/Pd) fed HFD promoted metastases;
and 6) PPARD and platelet derived growth factor receptor beta (PDGFRb) expression levels were correlated in
human PDA. iTME activates PDGFRb in PDA cells to promote metastasis. We thus hypothesize that activation
of upregulated PPARD in mKRAS+ pancreatic epithelial cells induces and sustains an iTME to promote PDA
progression and metastasis. Aim 1 will determine 1) whether activation of upregulated PPARD in pancreatic
mKRAS+ cells by a GW diet is sufficient to maintain an iTME and promote PDA progression in KPC/Pd mice
and KC/PD-i-fElasCreERT mice (Subaim 1a), in KPC cells with and without PDGFRb KO orthotopically injected
into syngeneic immunocompetent mice (B6.129S) and immunodeficient NSG mice (Subaim 1b), and in human
PanIN–derived organoids (PanIN-DO) transduced with Tet-on inducible PPARD expression lentivirus and
orthotopically transplanted into NSG mice with (HuCD34-NSG) and without (NSG) humanized immune systems
(Subaim 1c); and 2) the chemokines and cytokines, as well as their cell origins, that PPARD employs to maintain
pancreatic iTME using CITE-seq (Subaim 1d). Aim 2 will determine the effects of pancreatic PPARD KO on the
pancreatic iTME and PDA progression in KC/PdKO-fElasCreERT mice fed a HFD and in syngeneic and NSG mice
orthotopically injected with KPC-PdKO cells and fed a GW diet (Subaim 2a), as well as in HuCD34-NSG and
NSG mice transplanted with human PDA-derived organoids without ...

## Key facts

- **NIH application ID:** 10823417
- **Project number:** 1R01CA273732-01A1
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Imad Shureiqi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $666,423
- **Award type:** 1
- **Project period:** 2024-02-15 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10823417

## Citation

> US National Institutes of Health, RePORTER application 10823417, PPARD hyperactivation promotes pancreatic intraepithelial neoplasia progression into pancreatic ductal adenocarcinoma (1R01CA273732-01A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10823417. Licensed CC0.

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