# Defining novel functions of ATF4 in early stages of pancreatic cancer tumorigenesis

> **NIH NIH F31** · UNIVERSITY OF CHICAGO · 2024 · $48,974

## Abstract

PROJECT SUMMARY/ABSTRACT
Pancreatic cancer is one of the deadliest cancers, and its mortality rate is only predicted to rise. The deadliness
of this disease arises, in part, from the latency of symptoms, which typically do not present until the disease is
at an advanced stage. Advanced stage pancreatic tumors are rarely resectable, with ineffective chemotherapies
as the only option for treatment. Considering this, a better understanding of pancreatic cancer initiation and
development could improve patient outcomes. Therefore, there is a critical need for research that could lead to
earlier detection, identification of biomarkers, and new therapeutic targets for pancreatic cancer. Using novel
experimental approaches, the proposed work aims to interrogate in mechanistic detail key regulatory
steps in the earliest stages of pancreatic ductal adenocarcinoma (PDAC), the deadliest form of
pancreatic cancer, addressing an unmet need in the field of pancreatic cancer biology.
 Transcription factor Atf4, a key regulator of the cellular response to various stresses, has not previously
been directly linked to PDAC development; however, my unpublished data shown here suggest that Atf4 plays
a critical role in two of the earliest steps in PDAC initiation, acinar to ductal metaplasia (ADM), and development
of pancreatic intra-epithelial neoplasia (PanINs). First, I observe Atf4 down-regulation in control acinar cells
induced to undergo ADM ex vivo. Additionally, ADM is accelerated and more extensive in vivo in pancreas from
mice with inducible and pancreas-specific deletion of Atf4. I also observe that deletion of Atf4 in cells undergoing
ADM results in significant upregulation of MMP7, a known regulator of ADM. Second, PanIN formation and
development of pancreatic ductal adenocarcinoma (PDAC) is blocked in mouse pancreas with inducible and
conditional Atf4 deletion. Initial data show that this may be due to induction of p53 target genes and cellular
senescence when Atf4 is lost. Lastly, Atf4 deficiency leads to accumulation of lipid in the pancreas of these mice,
a pathology known as fatty pancreas in humans. The results of these data have led to my central hypothesis
that Atf4 plays two distinct, critical roles in PDAC tumorigenesis, one in ADM, and the other in the
transition to precancerous PanIN lesions. To test this central hypothesis, I will use three novel mouse models,
first, an inducible pancreatic acinar cell specific deletion of Atf4 and two others where this strain is crossed to
two different widely used PDAC mouse models. To connect these mouse studies to human disease, I will also
make use of human PDAC patient data and samples. For this project, I propose two aims: 1. Define the role of
Atf4 in acinar to ductal metaplasia, and 2. Determine the role of Atf4 in PanIN development. This work will link
novel functions of Atf4 to PDAC tumorigenesis and potentially validate targeting the Atf4 pathway for therapeutic
purpose in PDAC.

## Key facts

- **NIH application ID:** 10997147
- **Project number:** 1F31CA287966-01A1
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Leah Marie Ziolkowski
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $48,974
- **Award type:** 1
- **Project period:** 2024-09-30 → 2026-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10997147

## Citation

> US National Institutes of Health, RePORTER application 10997147, Defining novel functions of ATF4 in early stages of pancreatic cancer tumorigenesis (1F31CA287966-01A1). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10997147. Licensed CC0.

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