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

Award Number: R01CA247234
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $315,104 )
2024	2024	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Biology Research	000	5	5/14/2024	NON-COMPETING CONTINUATION	$315,104
														Subtotal = $315,104

Issue Date FY: 2023 ( Subtotal = $325,054 )
2023	2023	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Biology Research	000	4	5/31/2023	NON-COMPETING CONTINUATION	$325,054
														Subtotal = $325,054

Issue Date FY: 2022 ( Subtotal = $325,054 )
2022	2022	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Biology Research	000	3	5/9/2022	NON-COMPETING CONTINUATION	$325,054
														Subtotal = $325,054

Issue Date FY: 2021 ( Subtotal = $331,688 )
2021	2021	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Biology Research	000	2	6/18/2021	NON-COMPETING CONTINUATION	$331,688
														Subtotal = $331,688

Issue Date FY: 2020 ( Subtotal = $331,688 )
2020	2020	UNIVERSITY OF OKLAHOMA	865 RESEARCH PKWY STE 530	OKLAHOMA CITY	OK	73104	OKLAHOMA	USA	Cancer Biology Research	000	1	5/27/2020	NEW	$331,688
														Subtotal = $331,688

Grand Total All Awards = $1,628,588

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

Award Number: R01CA247234

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 06/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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