# Elucidating and targeting subtype-specific driver in pancreatic cancer

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $366,000

## Abstract

PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer death in the United States with
no effective therapy developed to date. With hope to guide the development of precision treatment, recent
large scale genetic profilings have established that PDAC is a heterogeneous disease comprised of many
distinct molecular subtypes, that correlate with histopathological characteristics and patient outcomes. Among
these tumor subtypes, squamous (also called quasi-mesenchymal or basal) subtype exhibit the worst
prognosis. However, the underlying mechanisms for the poor survival in this malignant subtype remains largely
unknown. Moreover, although oncogenic Kras mutation, the primary driver in PDAC, is universally present in
all tumor subtypes, the squamous tumor subtype exhibits diminished reliance on mutant Kras, suggesting
additional oncogenic driver dependency which may represent unique vulnerability in this subtype. The long-
term goal of my research effort is to systematically explore the molecular underpinnings of PDAC maintenance
and to identify context-dependent vulnerabilities as therapeutic targets. Our recent study has revealed
selective activation of YAP1 oncogene in squamous subtype tumors. We demonstrated that YAP1 and its
partner, TEAD transcription factor, are critical for the growth of squamous subtype tumors. Our current study
further identified a TEAD-specific metabolism pathway that is essential for a tumor stem cell-like population
that can survive independent of YAP1. Based on our finding, the central hypothesis is that the YAP1/TEAD
pathway is the major driver of squamous PDAC subtype that can be therapeutically targeted. To address our
hypothesis, we will utilize our novel PDAC mouse models and patient-derived xenograft models to: 1) elucidate
the molecular events leading to the activation of YAP/TEAD pathway and tumor growth in squamous subtype
of PDAC; 2) determine the mechanisms of TEAD-mediated metabolism reprograming and survival in the stem
cell-like population; 3) evaluate the efficacy of combined therapeutic strategy of targeting of YAP and TEAD-
dependent metabolism pathway. This grant is significant because a deep understanding of the YAP/TEAD
pathway in squamous subtype of PDAC offers important mechanistic insights and strong rationale to target this
unique tumor subgroup. It is anticipated that the research is of high translational relevance because our
proposed studies will provide strong preclinical evidence for novel combinatory strategies to treat this most
lethal form of PDAC.

## Key facts

- **NIH application ID:** 10131770
- **Project number:** 5R01CA214793-03
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Haoqiang Ying
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $366,000
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131770

## Citation

> US National Institutes of Health, RePORTER application 10131770, Elucidating and targeting subtype-specific driver in pancreatic cancer (5R01CA214793-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10131770. Licensed CC0.

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