# Lineage Specifiers Governing Pancreatic Cancer Growth and Molecular Subtype

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $17,360

## Abstract

Project Summary
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy with a five-year survival of
less than 5%. Genomic analyses of human samples suggest that PDAC can fundamentally be classified into
at least two major subtypes based on cancer cell autonomous properties: Classical and Basal-like. These two
subtypes have discrete cellular identities, as reflected by the differential expression of several lineage
specifiers, i.e. transcription factors that regulate differentiation state. The Classical subtype expresses high
levels of lineage specifiers pivotal for foregut endodermal determination (including HNF4A). The Basal-like
subtype expresses high levels of transcription factors promoting alternative identities, such as the
mesodermal lineage specifiers SIX4 and SIX1. Moreover, the Basal-like subtype confers poor prognosis and
responds less well to first-line chemotherapy compared to the Classical subtype. These correlations raise the
possibility that these lineage specifiers are not merely markers of PDAC subtype, but might regulate the
malignant potential of this disease. Our long-term goal is to identify the molecular regulators of PDAC
subtype and thereby identify subtype-specific vulnerabilities that might be exploited therapeutically. A major
rationale for this proposal is that the field must achieve a mechanistic understanding of PDAC molecular
subtype specification in order to develop such therapeutic strategies. In this proposal, our immediate goal is to
test the central hypothesis that a network of lineage specifiers, including HNF4 and SIX1/4, regulates PDAC
molecular subtype and malignant potential. We will test this hypothesis in the following specific aims using an
integrative approach that employs genetically engineered mouse models, novel organoid culture systems, and
patient derived xenografts: (1) Determine the role of distinct HNF4 isoforms in PDAC growth, molecular
subtype and drug response. (2) Elucidate the function of SIX1 and SIX4 in the Basal-like subtype of PDAC.

## Key facts

- **NIH application ID:** 10504285
- **Project number:** 3R01CA237404-02S1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Eric Lee Snyder
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $17,360
- **Award type:** 3
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10504285

## Citation

> US National Institutes of Health, RePORTER application 10504285, Lineage Specifiers Governing Pancreatic Cancer Growth and Molecular Subtype (3R01CA237404-02S1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10504285. Licensed CC0.

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