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Mitophagy-Mediated Cell Death in Mammary Tumorigenesis

Award Number: R01CA262439
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Mitophagy-Mediated Cell Death in Mammary Tumorigenesis - Project Summary Background: The metastasis of cancerous cells to distant and vital organs is responsible for in excess of 90% of cancer mortalities. Given this extraordinarily high mortality rate, there is a significant need for the development of novel therapeutic approaches that either eliminate metastatic cancer cells or eradicate incipient cancer cells prior to metastatic dissemination. An important barrier to tumor progression and metastasis is anoikis, a caspase- dependent cell death program induced by loss of integrin-mediated attachment to extracellular matrix (ECM). However, it has become clear that ECM-detachment can induce anoikis-independent mechanisms that can compromise cell viability. More specifically, we have discovered that detachment of non-cancerous epithelial cells from ECM triggers a significant elevation in the levels of reactive oxygen species (ROS) which compromises cell survival in an anoikis-independent fashion. The understanding of the cellular changes that contribute to the elevation of ROS during ECM-detachment remains rudimentary and the strategies utilized by cancer cells to combat ROS during ECM-detachment are insufficiently explored. Therefore, these points represent significant knowledge gaps that this grant proposal aims to address. Discernment of mechanistic information regarding the links between ECM-detachment, ROS, and cell survival could provide targets for the design of the therapeutic approaches aimed at specifically eliminating ECM-detached cancer cells; an outcome that may have significant impact for patients with metastatic disease. Objective/hypothesis: In aggregate, our preliminary studies have unveiled a novel cell death mechanism (with a tumor suppressive function) that compromises the viability of ECM-detached cells: the induction of mitophagy as consequence of RIPK1 signaling. As such, these data have motivated our central hypothesis that RIPK1- mediated mitophagy during ECM-detachment functions as a barrier to breast cancer progression. Specific Aim I: To elucidate the molecular mechanism by which ECM-detachment promotes RIPK1-dependent mitophagy and initiates cell death. Specific Aim II: To assess the capacity of RIPK1-mediated mitophagy to antagonize tumor formation in vivo and to evaluate antioxidant inhibition as a novel strategy to limit tumorigenesis in cancers that are deficient in RIPK1-mediated mitophagy Anticipated Outcomes: Following the completion of these studies, we will have accumulated significant mechanistic knowledge regarding the relationship between ECM-detachment, RIPK1 mitophagy, and cell death. Thus, the completion of these studies will unveil fundamental biological insights regarding cancer cell survival during ECM-detachment that may ultimately lead to the development of therapeutic approaches to limit the dissemination of breast cancer cells.


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 = $0 )
2025	2024	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Cancer Biology Research	000	4	6/6/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $469,109 )
2024	2024	UNIVERSITY OF NOTRE DAME DU LAC	836 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Cancer Biology Research	001	4	8/7/2024	NON-COMPETING CONTINUATION	$378,677
2024	2024	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Cancer Biology Research	002	4	9/12/2024	SUPPLEMENT FOR EXPANSION	$73,042
2024	2024	UNIVERSITY OF NOTRE DAME DU LAC	836 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Cancer Biology Research	000	3	7/10/2024	SUPPLEMENT FOR EXPANSION	$17,390
														Subtotal = $469,109

Issue Date FY: 2023 ( Subtotal = $390,635 )
2023	2023	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Cancer Biology Research	000	3	8/22/2023	NON-COMPETING CONTINUATION	$390,635
														Subtotal = $390,635

Issue Date FY: 2022 ( Subtotal = $390,635 )
2022	2022	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Cancer Biology Research	000	2	8/26/2022	NON-COMPETING CONTINUATION	$390,635
														Subtotal = $390,635

Issue Date FY: 2021 ( Subtotal = $398,607 )
2021	2021	UNIVERSITY OF NOTRE DAME DU LAC	940 GRACE HALL	NOTRE DAME	IN	46556	ST JOSEPH	USA	Cancer Biology Research	000	1	8/17/2021	NEW	$398,607
														Subtotal = $398,607

Grand Total All Awards = $1,648,986

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Mitophagy-Mediated Cell Death in Mammary Tumorigenesis

Award Number: R01CA262439

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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