# Role of Zinc Dependent EMT-Transcription Factors (EMT-TF) in Pancreatic Cancer Metastasis

> **NIH NIH R01** · UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR · 2021 · $331,688

## Abstract

The overall objective of this proposal is to delineate the mechanism of ZIP4-activated ZEB1-dependent
metastasis in pancreatic cancer (PC). Investigating the functional impact and the underlying mechanism of
this pathway is critical to understand the biology and make inroads on the progression and metastasis of
PC.
PC has the highest mortality rate of any cancer, with a 5-year survival rate below 8%. Despite progress in
improved diagnostic methods and development of targeted therapies, overall survival has not improved
significantly over recent decades. It is imperative to understand the biology of PC, and identify novel
molecular markers and therapeutic targets in PC in order to develop more effective treatments and reduce
drug resistance for this devastating disease. In this proposal, we aim to characterize the molecular
mechanisms underlying the function of a key zinc transporter, ZIP4, and a zinc dependent EMT-like
transcription factor (EMT-TF) ZEB1 in PC metastasis. Our preliminary data demonstrate that ZIP4 promotes
PC growth and metastasis through the modulation of ZEB1. Further studies revealed that this newly
identified ZIP4-ZEB1 axis upregulates integrins, and in turn integrin-mediated cell adhesion, migration and
invasion. We will use these findings as a foundation to further our understanding of the mechanism(s)
underlying ZIP4 oncogenic function in PC. We hypothesize that ZIP4 promotes PC metastasis through a
distinct signaling pathway leading to the activation of an EMT-TF ZEB1, and this pathway represents a
novel therapeutic target for this dismal disease. Three independent but interrelated specific aims are
proposed to address this hypothesis. We will determine the impact of the ZIP4-regulated ZEB1 pathway in
PC cells. We will determine the impact of the ZIP4-regulated ZEB1 pathway in two independent mouse
models of PC (orthotopic xenograft and spontaneous models). We will also delineate the signaling pathway
downstream of ZIP4-activated ZEB1-dependent transcription of integrins in PC.
The ZIP4-activated ZEB1 upregulation represents a novel signaling pathway modulating the growth,
metastasis, and drug resistance of PC tumors. The proposed studies will help define the mechanism
regulating this oncogenic axis and understand the biology of the progression and metastasis of PC. Both
mechanistic and functional studies are proposed using state-of-the-art technologies and genetically
engineered mouse models. The results obtained from this study will be of high impact since they will
significantly advance our understanding on a key zinc transporter and a zinc dependent EMT-TF ZEB1 in
PC metastasis.

## Key facts

- **NIH application ID:** 10172876
- **Project number:** 5R01CA247234-02
- **Recipient organization:** UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
- **Principal Investigator:** MIN LI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $331,688
- **Award type:** 5
- **Project period:** 2020-06-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10172876

## Citation

> US National Institutes of Health, RePORTER application 10172876, Role of Zinc Dependent EMT-Transcription Factors (EMT-TF) in Pancreatic Cancer Metastasis (5R01CA247234-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10172876. Licensed CC0.

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