# Mechanisms for Salivary Tumor Epithelial-Mesenchymal Transitions

> **NIH NIH R01** · BECKMAN RESEARCH INSTITUTE/CITY OF HOPE · 2020 · $425,002

## Abstract

Malignant salivary cancers are a major challenge to human health due to high recurrence rates, distant
metastases, and few treatment options. Little is known about the impact of epithelial mesenchymal transition
(EMT) on the molecular events of salivary tumorigenesis and therapeutic stratifications. Our recent published
studies demonstrate a unique mouse model that contains an oncogenic Ras transgene, for which expression is
conditionally induced exclusively in elastase 1 (Ela)-expressing ductal cells of the submandibular glands
(SMGs). The expression of oncogenic RAS rapidly transforms normal SMGs into tumors resembling human
sarcomatoid SDCs within 24 days in almost all mice. Preliminary Data suggests that activated transforming
growth factor beta (TGFβ) signaling and remodeling of extracellular matrix (ECM) components and integrin
signaling could serve a potential therapeutic target. Our overall hypothesis is that oncogenic RAS activation
in cooperation with TGFβ-mediated EMT contributes to aggressive and fast-growing sarcomatoid SDC,
thus targeting TGFβ signaling or inhibition of ECM downstream signaling represent a rationalized
strategy to treat SDCs. Our goal is to discover the intrinsic factors within tumor cells as well as extrinsic
signals in the tumor microenvironment that trigger EMT and identify an intervention point that may serve as a
druggable target for treating sarcomatoid SDC. To achieve this goal, we propose three Specific Aims: Aim 1.
To establish mechanisms through which oncogenic RAS drives mouse SMG ductal epithelial-sarcomatoid
transformation and validate findings in human tumors. Aim 2. To determine if TGFβ receptor activation is a key
contributor to oncogenic RAS-mediated EMT and thus if TGFβ inhibition represents a therapeutic strategy for
salivary sarcomatoid carcinoma. Aim 3. To evaluate the cooperative interaction of ECM components with
integrin and integrin-linked kinase (ILK) during sarcomatoid SDC development. In this application, we propose
to use our unique transgenic mouse model to address these key questions: Do these tumor cells contain a
small subpopulation of tumorigenic cells with the ability to re-populate and expand sarcomatoid tumors in vivo?
If so, can we characterize them and compare them to the remaining tumor cells without this capacity? How
does TGFβ-rich SMG microenvironmental niche or ECM remodeling propel oncogenic RAS-driven
sarcomatoid SDC? Characterizing the signaling pathways involved in TGFβ-mediated EMT activation and/or
tumor cell-ECM interactions will provide novel mechanistic insights into the biology of salivary cancer initiation
and expansion and allow us to identify potential therapeutic targets. This is relevant to our understanding of
salivary tumor biology. This project is significant, as it will uncover mechanisms that promote the acquisition of
EMT or sarcomatoid phenotypes that can be translated to human cancers. This project is innovative, because
it will provide novel insight...

## Key facts

- **NIH application ID:** 9976327
- **Project number:** 5R01DE026304-05
- **Recipient organization:** BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
- **Principal Investigator:** David K. Ann
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $425,002
- **Award type:** 5
- **Project period:** 2016-08-05 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9976327

## Citation

> US National Institutes of Health, RePORTER application 9976327, Mechanisms for Salivary Tumor Epithelial-Mesenchymal Transitions (5R01DE026304-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9976327. Licensed CC0.

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