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The role of PP2A B56a in pancreatic tumorigenesis

Award Number: K22CA237620
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/19/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2024

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The role of PP2A B56a in pancreatic tumorigenesis - Project Summary The majority of pancreatic ductal adenocarcinoma (PDA) patients present with late-stage, metastatic disease that is often resistant to therapeutics, resulting in extremely low survival rates. Understanding the mechanisms that regulate the early initiation and progression of PDA is critically important to the development of new, more accurate pancreatic cancer models for the identification of biomarkers and novel therapeutic targets. Protein phosphatases are master regulators of cell signaling pathways, including the MAPK and PI3K pathways. Studies from our lab and others have demonstrated that PDA tumors have increased expression of PP2A inhibitors and a corresponding decrease in PP2A function, suggesting that the inhibition of PP2A is a common event in PDA progression. The active PP2A holoenzyme is composed of three proteins including a catalytic subunit, a scaffolding subunit, and a regulatory (B) subunit that provides target specificity. While PP2A is thought to function as a tumor suppressor, the individual contribution of specific B subunits to disease progression is still poorly understood. We have identified the PP2A B subunit, B56, as being an important regulator of KRAS driven pathways, including the stabilization of the oncoprotein c-MYC. Given that KRAS mutations occur in 90-95% of PDA patients, regulation of this pathway by B56 represents an important gap in knowledge. In our preliminary studies, loss of B56 in mice accelerated the formation of pancreatic precursor lesions and increased the expression of transcription factors involved in cell fate and metastasis. Therefore, I hypothesize that B56 plays a critical role in mediating pancreatic cell plasticity, and that suppression of B56 will increase the susceptibility of pancreatic cells to oncogenic mutation, driving PDA initiation and transformation. This hypothesis will be addressed through the following three Specific Aims: 1) Determine the impact of oncogenic KRAS on PP2A-B56 complex formation and function, 2) Examine whether loss of B56 accelerates the progression of premalignant lesions in vitro and in vivo, and 3) Determine if therapeutic activation of PP2A-B56 can suppress the transcriptional and epigenetic changes that occur during PDA initiation. These studies will take advantage of techniques such as single cell epigenetic analysis, mouse modeling of PDA, and analysis of PP2A composition in human PDA tumors using cyclic immunofluorescence in order to provide a deep molecular understanding of PDA development in relation to phosphatase function. Importantly, the transcriptional deregulation of factors involved in cellular plasticity during early tumor development has been shown to have a significant impact on late stage tumor heterogeneity, subtype, and therapeutic response. Therefore, results from these studies will provide a strong basis for the future interrogation of both early and late stage disease, expanding my independent scientific program and supporting my long-term goal of understanding the molecular basis of PDA.


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 = -$836 )
2024	2022	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE # 1100	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Research Manpower	000	3	6/21/2024	NON-COMPETING CONTINUATION	-$836
														Subtotal = -$836

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Research Manpower	000	3	9/19/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $174,844 )
2022	2022	PURDUE UNIVERSITY	2550 NORTHWESTERN AVE STE 1900	WEST LAFAYETTE	IN	47906	TIPPECANOE	USA	Cancer Research Manpower	000	3	7/29/2022	NON-COMPETING CONTINUATION	$174,844
														Subtotal = $174,844

Issue Date FY: 2021 ( Subtotal = $174,844 )
2021	2021	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Research Manpower	000	2	7/19/2021	NON-COMPETING CONTINUATION	$174,844
														Subtotal = $174,844

Issue Date FY: 2020 ( Subtotal = $174,844 )
2020	2020	PURDUE UNIVERSITY	155 S GRANT ST	WEST LAFAYETTE	IN	47907	TIPPECANOE	USA	Cancer Research Manpower	000	1	8/19/2020	NEW	$174,844
														Subtotal = $174,844

Grand Total All Awards = $523,696

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The role of PP2A B56a in pancreatic tumorigenesis

Award Number: K22CA237620

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/19/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2024

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