# Type I Interferon Pathway in Pancreatic Adenocarcinoma

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $365,086

## Abstract

ABSTRACT
 Chronic pancreatitis provides proliferative advantage to oncogene-harboring pancreatic cells, shields
transformed cells from anti-tumor factors, and stimulates the metastatic process. Accordingly, pancreatic
inflammation emerges as an important factor in the development and progression of pancreatic ductal
adenocarcinoma (PDA), which is a lethal disease with low survival rate. A better understanding of the anti-
tumorigenic targets of pancreatic inflammation is critical for developing novel approaches to efficient therapies.
In proposed here studies, we focus on the importance of type I interferons (IFN1) cytokines that act through
IFNAR1 receptor to elicit a cell-autonomous tumor suppressive effects (e.g. cell senescence) in oncogene-
harboring cells. Our preliminary results suggest that this pathway is inactivated in response to pancreatic
inflammation-induced ubiquitination-dependent downregulation of IFNAR1 or through silencing of downstream
effectors such as IFN1-inducible metabolic enzyme cholesterol 25-hydroxylase (CH25H). Our new exciting
results include the observations that (i) IFNAR1 and CH25H are often lost in human PDA and mouse models of
PDA, (ii) re-expression of CH25H in human and mouse PDA cells inhibits their proliferation/survival, and (iii)
that genetic ablation of CH25H in mice stimulates PDA development. Based on these data we propose an
overarching hypothesis that inactivation of the IFN1-IFNAR1-CH25H pathway promotes PDA development and
progression. To test this hypothesis, we will characterize the IFN1-IFNAR1-CH25H pathway in human and
mouse PDA and determine the effects of inactivation of IFNAR1 in vitro and in vivo on growth of pancreatic
organoid cultures and development of PDA in mice. Conversely, cell-based and in vivo models deficient in
IFNAR1 ubiquitination and downregulation will help to assess the importance of IFNAR1 loss in PDA
development and progression. Furthermore, we propose to determine the tumor suppressive role of CH25H. We
will use the organoid/cell-based models to delineate the mechanisms underlying the loss of CH25H induction by
IFN1 in PDA cells and a novel conditional knockout model of CH25H to determine its importance in counteracting
PDA development. We will also conduct preclinical studies using Liver X Receptor agonists (that act downstream
of CH25H) against PDA in immunocompetent mice. Completion of these studies will determine the role of the
IFN1-IFNAR1-CH25H pathway in PDA pathogenesis and delineate the mechanisms of inactivation of this
pathway in PDA. We anticipate that future targeting of these mechanisms may be used for PDA treatment.

## Key facts

- **NIH application ID:** 10129920
- **Project number:** 5R01CA240814-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Serge Y Fuchs
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $365,086
- **Award type:** 5
- **Project period:** 2020-04-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10129920

## Citation

> US National Institutes of Health, RePORTER application 10129920, Type I Interferon Pathway in Pancreatic Adenocarcinoma (5R01CA240814-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10129920. Licensed CC0.

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