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Role of extracellular matrix proteins and tumor stroma in DNA repair and cancer progression

Award Number: R01CA258372
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2021
PERIOD OF PERFORMANCE END DATE: 01/31/2026

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Role of extracellular matrix proteins and tumor stroma in DNA repair and cancer progression - PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is the fourth lethal cancer in the U.S. with a 5-year survival rate of only ~10%. The mainstay of therapy in PDA is chemotherapy, however, the majority of the tumors rapidly develop treatment resistance. Therefore, a critical need exists to understand what drives the emergence of drug resistance in PDA, and to develop better treatment strategies. One contributing factor to drug resistance in PDA is the tumor microenvironment, which is characterized by abundant stroma, rich in extracellular matrix (ECM) proteins, most frequently secreted by cancer-associated fibroblasts. The stroma and the secreted ECM proteins can induce resistance towards chemotherapies, which work by inflicting DNA damage. One way for the stroma to induce chemo-resistance would be by enhancing DNA repair. Our data show that the cancer- associated fibroblast-secreted ECM proteins stimulate DNA repair in PDA tumor cells, making them more resistant to treatments. The overall objective of this application is to investigate the mechanistic basis by which the tumor microenvironment, and particularly secreted stromal and ECM proteins, stimulate DNA repair. Our central hypothesis is that the candidate protein we have identified, called N-Myc-Downstream Regulated Gene 1 (NDRG1), conveys signals from the ECM contact to the DNA repair machinery, and our preliminary data support this hypothesis. To test this hypothesis further, we propose the following three specific aims: 1) to determine the detailed signaling events by which secreted ECM proteins lead to NDRG1 activation; 2) to determine the mechanism by which NDRG1 regulates DNA repair; and 3) to assess the efficacy of NDRG1- pathway inhibition in enhancing chemotherapy in patient-derived organoids and in vivo models of pancreatic cancer. The research proposed here is innovative, in our opinion, because the research on chemoresistance and DNA repair has not been studied in the context of adhesion signaling and stromal microenvironment, nor has the protein we propose to study here, NDRG1, been linked to DNA repair. Therefore, successful completion of this work would lead to a more complete mechanistic understanding on how tumor-stroma cross- talk and fibroblast-secreted matrix proteins regulate DNA repair, and how NDRG1 protein contributes to DNA repair and treatment resistance. These contributions are expected to be significant because they reveal novel DNA repair biology that is regulated by extracellular matrix environment in one of the most lethal, stroma rich and drug resistant cancers, and will allow us to test whether targeting this signaling pathway will enhance chemotherapy efficacy.


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 = $400,313 )
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	5	5/22/2025	NON-COMPETING CONTINUATION	$40,032
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	5	1/27/2025	NON-COMPETING CONTINUATION	$360,281
														Subtotal = $400,313

Issue Date FY: 2024 ( Subtotal = $380,298 )
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	4	12/20/2023	NON-COMPETING CONTINUATION	$360,281
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	4	4/17/2024	NON-COMPETING CONTINUATION	$20,017
														Subtotal = $380,298

Issue Date FY: 2023 ( Subtotal = $392,306 )
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	3	1/30/2023	NON-COMPETING CONTINUATION	$392,306
														Subtotal = $392,306

Issue Date FY: 2022 ( Subtotal = $392,306 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	001	2	4/25/2022	NON-COMPETING CONTINUATION	$32,025
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	2	1/13/2022	NON-COMPETING CONTINUATION	$360,281
														Subtotal = $392,306

Issue Date FY: 2021 ( Subtotal = $397,911 )
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Biology Research	000	1	1/20/2021	NEW	$397,911
														Subtotal = $397,911

Grand Total All Awards = $1,963,134

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Role of extracellular matrix proteins and tumor stroma in DNA repair and cancer progression

Award Number: R01CA258372

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2021

PERIOD OF PERFORMANCE END DATE: 01/31/2026

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