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Gut microbiome-mediated differences within the pre-malignant mammary tissue environment enhance early breast tumor metastasis

Award Number: R01CA262634
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Gut microbiome-mediated differences within the pre-malignant mammary tissue environment enhance early breast tumor metastasis - A critical unmet medical need is to understand why some patients diagnosed with hormone receptor (HR+, estrogen- and progesterone-receptor positive; Her2 negative) breast cancer experience recurrences with distant metastatic disease whereas others do not, despite similar treatment. This is a significant issue considering that the majority of patients diagnosed with breast cancer and that experience metastatic relapse have HR+ tumors. Metastatic spread occurs early, often prior to the detection of the primary mass, and is facilitated by crosstalk between the tissue and developing tumor. This gives rise to the possibility that differences in the normal tissue environment exist which enhance the risk for metastatic disease. However, the mechanisms through which changes arise in the mammary tissue environment and their contributions to metastatic breast cancer remain largely undefined. We recently established gut commensal dysbiosis, defined as an inflammatory microbiome with low biodiversity, enhances metastasis of HR+ tumors. Establishing dysbiosis prior to tumor initiation significantly enhanced dissemination of tumor cells into the blood, distal lymph nodes, and lungs, with no impact upon primary tumor growth. Dysbiosis enhanced the accumulation of mast cells into the normal mammary tissue of non-tumor-bearing mice, whereas inhibition of mast cell degranulation significantly reduced metastatic dissemination. These results indicated an important role for tissue-associated mast cells in the promotion of breast tumor dissemination. Mechanistically, we demonstrate that blockade of CCL2 prior to tumor initiation is sufficient to reduce mast cell accumulation in the mammary tissue and to diminish dysbiosis-induced dissemination of HR+ tumor cells. The goal of this proposal is to define how gut commensal dysbiosis distally orchestrates cellular and molecular changes in normal mammary tissues of non-tumor-bearing mice that enhance susceptibility to HR+ tumor dissemination. Aim 1 will define how commensal dysbiosis distally changes the normal (non-tumor-bearing) mammary tissue immune environment to favor early HR+ tumor dissemination. We will integrate a variety of approaches to investigate the link between the gut microbiome, host metabolism, and metastatic breast cancer. Aim 2 will establish how mast cells promote early dissemination of HR+ tumors. The goal of this aim will be to define how mast cells are activated in mammary tissues of mice with dysbiosis and establish how mast cells initiate metastasis of HR+ tumors through interactions with tissue fibroblasts and macrophages. These mechanistic studies will have the potential to unveil novel therapeutic targets for the prevention of metastatic breast cancer, targets that could be identifiable prior to a tumor diagnosis. Considering the role of the gut commensal dysbiosis, modification of microbiome or targeting of commensal-associated metabolites emerges as a potential low cost therapeutic to prevent or reduce the incidence of metastatic breast cancer.


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 = $403,019 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	001	3	2/14/2025	NON-COMPETING CONTINUATION	$0
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	3	1/23/2025	NON-COMPETING CONTINUATION	$403,019
														Subtotal = $403,019

Issue Date FY: 2024 ( Subtotal = $425,409 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	2	1/23/2024	NON-COMPETING CONTINUATION	$403,019
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	001	2	4/16/2024	NON-COMPETING CONTINUATION	$22,390
														Subtotal = $425,409

Issue Date FY: 2023 ( Subtotal = $449,167 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Cancer Biology Research	000	1	2/17/2023	NEW	$449,167
														Subtotal = $449,167

Grand Total All Awards = $1,277,595

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Gut microbiome-mediated differences within the pre-malignant mammary tissue environment enhance early breast tumor metastasis

Award Number: R01CA262634

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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