# Identifying Molecular Drivers of Cellular Plasticity in Pancreatic Cancer

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $350,960

## Abstract

PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive disease that is projected to become the second
leading cause of cancer deaths in the Western world by 2030. Recently, studies utilizing transcriptional profiling
from resected PDA specimens have identified two molecularly distinct subtypes termed Classical and Basal.
These subtypes correlate with overall patient survival, with the Basal subtype predictive of higher rates of
metastasis, poor response to therapy and the worst outcomes. While this classification represents an important
breakthrough for identifying patients with the most aggressive variant of PDA, the underlying circuits that drive
key features of this variant are unknown. Without a clear understanding of this biology, our ability to effectively
treat patients with the deadliest form of PDA is compromised. Thus, a major goal in the field is to identify drivers
of the Classical and Basal subtypes of PDA in order to 1) effectively target Basal PDA or 2) promote conversion
to a less aggressive variant (Classical) that may respond more effectively to therapy.
 Towards this goal, we have discovered that the Hedgehog pathway transcription factor, GLI2, functions
in a non-canonical ligand independent manner as a critical regulator of the most aggressive Basal subtype of
PDA (Adams et al eLife, 2019; PMC6538376). The key findings in support of this model are, (1) GLI2 expression
is elevated in Basal PDA cell lines and patient tumors and predicts shorter survival in patients, (2) GLI2
suppression leads to loss of Basal identity and inhibits tumor growth while ectopic GLI2 expression in Classical
PDA cells causes a switch to the Basal state (3). Our findings underscore a previously unrecognized level of
plasticity in PDA cells and highlight an entirely new role for GLI2 in driving Basal identity in this disease. Building
on this work, we hypothesize that suppression of GLI2 represents a unique vulnerability in Basal PDA to
combat KRAS* resistance and tumor progression. Thus, we propose 2 specific aims that will 1) define the
non-canonical transcriptional circuits regulated by GLI2 in a cell-autonomous manner to mediate resistance to
KRAS* pathway suppression and 2) determine how GLI2-dependent secreted factors condition surrounding cells
to promote primary and metastatic tumor growth. These studies will determine the cellular circuits that control
Basal identity, define their role in the context of KRAS* resistance, tumor relapse and metastasis and lay the
groundwork for increasing the effectiveness of KRAS-targeted therapies that have entered the clinic.

## Key facts

- **NIH application ID:** 10840904
- **Project number:** 5R01CA240603-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Rushika Miriam Perera
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $350,960
- **Award type:** 5
- **Project period:** 2020-09-03 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10840904

## Citation

> US National Institutes of Health, RePORTER application 10840904, Identifying Molecular Drivers of Cellular Plasticity in Pancreatic Cancer (5R01CA240603-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10840904. Licensed CC0.

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