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Investigating the role of SHP2-PLCG1 interaction in PDAC calcium signaling and metabolism

Award Number: F31CA281118
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Investigating the role of SHP2-PLCG1 interaction in PDAC calcium signaling and metabolism - ABSTRACT Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal disease and is expected to become the second leading cause of cancer-associated-death in the US by the year 2025. Of these cases, greater than 90% of patients harbor a mutation to KRAS. Unfortunately, direct targeting of the mutations specific to PDAC have failed to gain traction, but due to mutant KRAS’s ubiquity to the disease, alternative methods to reduce downstream MAPK signaling have been investigated. Recently, targeting of the upstream regulator of KRAS activity, SHP2 has been brought to the forefront of the field. SHP2 is essential for the development of PDAC in mouse models, despite mutant KRAS presence. However, while the role of SHP2 in PDAC has been largely attributed to its regulation of the MAPK pathway, evidence in many other tissue types argue that SHP2 should be contributing to tumor progression through other mechanisms – most notably, through regulation of intracellular calcium flux. Our preliminary data shows that SHP2 interacts upstream of calcium flux with the enzyme phospholipase-c- gamma-1 (PLCγ1). Recent literature has described the mechanism of this interaction as we have begun to define the outcomes of disrupting the pairing and downstream calcium flux, providing evidence that uncouples the canonically attributed role of SHP2 in PDAC from the MAPK pathway. Our probing of the metabolic functions of SHP2 inhibited PDAC cells leads us to hypothesize that SHP2 and PLCγ1 interact to sustain calcium signaling required for the activation of mitochondrial enzymes in the citric acid cycle. In this vein, we will take a two pronged approach to investigating SHP2’s role in metabolism: first, by using the Agilent Seahorse Fuel-Flex testing we can pinpoint the metabolic dependencies of SHP2 inhibited cells, and mechanisms of resistance to metabolic stress; second, we will capture the steady state metabolite profile of PDAC cells in response to differential SHP2, MEK, or PLCγ1 activity to take an untargeted approach to defining the metabolic implications of each protein’s function individually and collectively. Additionally, we believe that the outcomes of this interaction are not limited to changes in mitochondrial function. Therefore, we hypothesize that by comparing SHP2 inhibited and MEK inhibited PDAC cells’ global changes to their phospho-proteome, we will be able to delineate the MAPK- independent-functions of SHP2 as an oncogene in PDAC signaling. We expect the outcomes of this proposal to highlight the importance of SHP2 in tumor progression/cancer cell signaling outside of the MAPK pathway, while still appreciating its role in regulating KRAS activity. We believe that the conclusions of this study will yield a new network of protein interactions to be investigated as targets in PDAC, eventually leading to development of therapeutics for improved patient outcome.


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: 2026 ( Subtotal = -$21,327 )
2026	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Cancer Research Manpower	001	2	1/27/2026	NON-COMPETING CONTINUATION	-$7,215
2026	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Cancer Research Manpower	000	2	11/20/2025	NON-COMPETING CONTINUATION	-$14,112
														Subtotal = -$21,327

Issue Date FY: 2024 ( Subtotal = $36,764 )
2024	2024	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Cancer Research Manpower	000	2	5/29/2024	NON-COMPETING CONTINUATION	$36,764
														Subtotal = $36,764

Issue Date FY: 2023 ( Subtotal = $35,484 )
2023	2023	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Cancer Research Manpower	001	1	6/30/2023	NEW	$0
2023	2023	UNIVERSITY OF KANSAS MEDICAL CENTER RESEARCH INSTITUTE, INC.	3901 RAINBOW BLVD	KANSAS CITY	KS	66160	WYANDOTTE	USA	Cancer Research Manpower	000	1	6/30/2023	NEW	$35,484
														Subtotal = $35,484

Grand Total All Awards = $50,921

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Investigating the role of SHP2-PLCG1 interaction in PDAC calcium signaling and metabolism

Award Number: F31CA281118

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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