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Origins and functions of pancreatic cancer-associated fibroblasts

Award Number: R01CA250917
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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Origins and functions of pancreatic cancer-associated fibroblasts - PROJECT SUMMARY/ABSTRACT The mechanisms underlying evolution of tumor-associated stroma remain poorly understood. In solid tumors featuring a prominent stromal reaction, an improved understanding of the functions and origins of abundant stromal cell types may facilitate the development of new and effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is the quintessence of a fibro-inflammatory malignancy, with 50-90% of tumor volume occupied by a dense, desmoplastic stroma. Cancer-associated fibroblasts (CAFs) are the key cell type which drives the stromal reaction in PDAC, and recent reports suggest that stromal CAFs represent a heterogeneous population of cells from diverse origins, potentially including cell types which support and others which suppress tumor growth. Pancreatic stellate cells (PSCs) are lipid-storing cells in healthy pancreas which can transdifferentiate to an activated CAF phenotype. PSCs have been suggested as the predominant source of fibroblasts in the PDAC tumor microenvironment. However, proper lineage tracing studies have never been performed, such that the relative contribution and specific functions of PSCs in the tumor microenvironment are unknown. Here we will take advantage of a novel mouse model we have developed to track PSC differentiation and function during pancreatic tumor progression in vivo. We hypothesize that PSC-derived fibroblasts in the PDAC microenvironment are a pro-inflammatory and tumor-supportive subset of PDAC CAFs, and thus represent a viable therapeutic target. Our preliminary data support the notion that PSCs contribute to only a subset of the CAF population in the tumor microenvironment, and the functions of these distinct populations are entirely unknown. Our data to date also highlight a potential role for genetic alterations in the epithelial compartment in orchestration of stromal fibroblast evolution. PDAC stromal heterogeneity and functional significance will be interrogated with the following specific aims. Aim 1: Determine the role of PSC- derived CAFs in pancreatic tumorigenesis. A novel mouse model will be used to ablate PSC-derived CAFs for the first time and analyze the impact on tumor growth, survival, and organization of the tumor microenvironment. Aim 2: Assess the consequence of tumor genotype in pancreatic cancer stromal evolution. Motivated by preliminary data, we will use our reporter mouse model and patient samples to analyze the interaction between p53 status in tumor cells and stromal CAF evolutionary routes, with important potential implications for tumor phenotype and therapy responses. Aim 3: Define the role of PSC-derived CAFs in therapy response and resistance. As PSC-derived CAFs express a transcriptional program associated with resistance to chemotherapy and immunotherapy, we will determine the effect of these CAFs on treatment response in vivo. These findings will shed light on mechanisms and consequences of stromal evolution during pancreatic tumorigenesis, and potentially identify distinct CAF populations of relevance in additional solid tumors.


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 = $375,586 )
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	001	6	5/28/2025	NON-COMPETING CONTINUATION	$37,559
2025	2025	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	6	3/12/2025	NON-COMPETING CONTINUATION	$338,027
														Subtotal = $375,586

Issue Date FY: 2024 ( Subtotal = $356,807 )
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	000	5	3/14/2024	NON-COMPETING CONTINUATION	$338,027
2024	2024	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVENUE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	001	5	4/18/2024	NON-COMPETING CONTINUATION	$18,780
2024	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	003	3	8/26/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$60,849
2024	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	002	2	8/26/2024	NON-COMPETING CONTINUATION	-$60,849
														Subtotal = $356,807

Issue Date FY: 2023 ( Subtotal = $424,741 )
2023	2023	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	003	4	3/8/2023	NON-COMPETING CONTINUATION	$379,585
2023	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	2	12/21/2022	NON-COMPETING CONTINUATION	-$254,766
2023	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	002	3	1/19/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$45,156
2023	2022	SLOAN-KETTERING INSTITUTE FOR CANCER RESEARCH	1275 YORK AVE	NEW YORK	NY	10065	NEW YORK	USA	Cancer Biology Research	001	3	12/21/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$254,766
														Subtotal = $424,741

Issue Date FY: 2022 ( Subtotal = $339,988 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	2	4/19/2022	NON-COMPETING CONTINUATION	$339,988
														Subtotal = $339,988

Issue Date FY: 2021 ( Subtotal = $355,498 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cancer Biology Research	000	1	3/26/2021	NEW	$355,498
														Subtotal = $355,498

Grand Total All Awards = $1,852,620

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Origins and functions of pancreatic cancer-associated fibroblasts

Award Number: R01CA250917

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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