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Mechanisms of pancreatic cancer initiation and progression from normal human pancreatic tissue

Award Number: R01CA237159
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Mechanisms of pancreatic cancer initiation and progression from normal human pancreatic tissue - Mechanisms of pancreatic cancer initiation and progression from normal human pancreatic tissue For the past thirty years, the survival rate for many cancers has improved, but survival for pancreatic ductal adenocarcinoma (PDAC) has not, due to lack of both early detection methods and effective treatments. Genetically modified mouse models have been widely used to study PDAC pathogenesis. However, mouse cancer models may overlook some profound differences between human and mouse cells. To understand the mechanisms of human PDAC tumorigenesis, we have established a novel system to isolate and genetically manipulate primary acinar cells and ductal cells from normal human pancreatic tissue. This unique system provides us with the opportunity to study the earliest changes in acinar or ductal cells during human PDAC initiation. Pancreatitis-induced acinar to ductal metaplasia (ADM) is considered to be the earliest change during PDAC development. Using our system, we recapitulated acinar to ductal metaplasia (ADM) in vitro at the single-cell level, and identified that the TGFβ signaling pathway induces ADM in human acinar cells, partially through SMAD4-mediated pathway. During ADM, cells gained new characteristic properties, including transient proliferative capacity. However, the underlying mechanisms facilitating these changes remain unclear. We will use our system to further investigate the ADM process. KRAS is the earliest and most frequently mutated oncogene in pancreatic cancer. However, the mechanism by which oncogenic KRAS initiates neoplasia is not well understood, and it is generally accepted that additional genetic/epigenetic alterations are required to cooperate with KRAS mutation to initiate PDAC development. We found that mutant KRAS can extend the proliferation of AD cells (acinar cells that have undergone ADM). We hypothesize that ADM-associated changes cooperate with oncogenic KRAS to initiate pancreatic cancer. Although the SMAD4 pathway is required for ADM, this gene is frequently mutated in the late-stage PDAC samples, suggesting that it may have distinct functions under different cellular contexts. Interestingly, mouse PDAC models with SMAD4 deletion developed intraductal papillary-mucinous neoplasm (IPMN) rather than pancreatic intraepithelial neoplasia (PanIN). Whether this result is due to differences between mice and humans or due to the different cell lineages from which the tumors developed remains to be discovered. The findings from the proposed investigations will reveal human-specific aspects of PDAC tumorigenesis. The outcomes of these studies will not only provide an opportunity to discover prognostic markers but also give us insight into PDAC tumorigenesis that may lead to development of new methods for cancer treatment.


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: 2025 ( Subtotal = $202,379 )
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	001	6	5/22/2025	NON-COMPETING CONTINUATION	$20,239
2025	2025	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	000	6	3/5/2025	NON-COMPETING CONTINUATION	$182,140
														Subtotal = $202,379

Issue Date FY: 2024 ( Subtotal = $336,835 )
2024	2024	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	001	5	4/16/2024	NON-COMPETING CONTINUATION	$17,729
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	000	5	1/23/2024	NON-COMPETING CONTINUATION	$319,106
														Subtotal = $336,835

Issue Date FY: 2023 ( Subtotal = $347,471 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	000	4	1/27/2023	NON-COMPETING CONTINUATION	$347,471
														Subtotal = $347,471

Issue Date FY: 2022 ( Subtotal = $152,184 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	001	3	4/28/2022	NON-COMPETING CONTINUATION	$15,220
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	000	3	2/22/2022	NON-COMPETING CONTINUATION	$136,964
														Subtotal = $152,184

Issue Date FY: 2021 ( Subtotal = $353,419 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	000	2	3/3/2021	NON-COMPETING CONTINUATION	$353,419
														Subtotal = $353,419

Issue Date FY: 2020 ( Subtotal = $352,275 )
2020	2020	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Cancer Cause and Prevention Research	000	1	2/21/2020	NEW	$352,275
														Subtotal = $352,275

Grand Total All Awards = $1,744,563

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Mechanisms of pancreatic cancer initiation and progression from normal human pancreatic tissue

Award Number: R01CA237159

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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