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The Role of Lung Resident Mesenchymal Stem Cells in Post-Chemotherapy Lung Metastases of Breast Cancer

Award Number: R37CA237307
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/04/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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The Role of Lung Resident Mesenchymal Stem Cells in Post-Chemotherapy Lung Metastases of Breast Cancer - PROJECT SUMMARY/ABSTRACT Although chemotherapy has significantly improved the survival of breast cancer patients, treatment failure still remains a major clinical issue worldwide. Current knowledge about treatment failure is mostly derived from research on intrinsic and acquired chemoresistance in epithelial tumor cells. However, recent studies have implicated a critical role for host cells (i.e., the tissue microenvironment) in building a protective “niche” for tumor cells enabling their escape from chemotherapeutic treatments. Notably, the host regenerative response upon chemotherapy “injury”, which is regarded as a host intrinsic mechanism to repair damaged tissues, may be exploited by tumor cells for their local recurrence or distant metastases. The proposed study will build on our extensive experience in the study of tumor-stroma interactions in breast cancer metastasis, and will investigate the poorly explored question of how chemotherapy-induced changes in the lung stroma foster the early relapse of tumor cells in the lung. Based on our previous findings that tissue resident mesenchymal stem cells (MSCs) acquire a significantly higher potential to promote local tumor growth upon cancer therapies, we hypothesize that systemic chemotherapy treatment stimulates regenerative responses in lung resident MSCs, which are, in turn, utilized by drug-resistant disseminated tumor cells (DTCs) for their metastatic relapse in the lung. By designing different chemotherapy treatment scenarios in animal models mimicking clinical situations in human breast cancer patients, we will in Aim 1 determine how chemotherapeutic drugs cisplatin and doxorubicin modulate the lung resident MSCs using our newly established endogenous MSC modeling platform in mice. Subsequently, we will in Aim 2 delineate the molecular mechanisms underlying drug-activated lung resident MSCs to support metastatic tumor growth in the lung, with a focus on the TLR4 signaling pathway and the key wound healing cytokine osteopontin (OPN). Finally, we will in Aim 3 define the translational potential of stroma targeting approaches using both patient-derived xenograft models and breast cancer patient specimen analyses. We will specifically focus on the therapeutic efficacy of combining chemotherapy with TLR4 or OPN blockage in treatment of patient-derived human basal-like xenograft breast tumors. Further, by analyzing clinical plasma samples from human breast cancer patients, we expect to develop plasma OPN as a biomarker to predict early metastatic relapse of breast cancer patients after chemotherapy. Overall, our proposed study will energize an underdeveloped field of research that investigates the impact of cancer therapeutics on the pre-metastatic microenvironment. Findings from the proposed study will facilitate the development of clinically applicable strategies to improve treatment efficacy and prevent metastatic relapse of breast cancer by interfering with the tissue metastatic microenvironment.


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 = $404,888 )
2025	2025	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Treatment Research	003	6	7/21/2025	EXTENSION WITH OR WITHOUT FUNDS	$40,489
2025	2025	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Treatment Research	000	6	2/12/2025	EXTENSION WITH OR WITHOUT FUNDS	$364,399
2025	2025	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Treatment Research	002	6	6/11/2025	EXTENSION WITH OR WITHOUT FUNDS	$39,970
2025	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Treatment Research	001	5	6/11/2025	NON-COMPETING CONTINUATION	-$39,970
														Subtotal = $404,888

Issue Date FY: 2024 ( Subtotal = $384,644 )
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Treatment Research	000	5	1/5/2024	NON-COMPETING CONTINUATION	$364,399
2024	2024	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Treatment Research	001	5	4/17/2024	NON-COMPETING CONTINUATION	$20,245
														Subtotal = $384,644

Issue Date FY: 2023 ( Subtotal = $381,098 )
2023	2023	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Treatment Research	001	4	4/19/2023	NON-COMPETING CONTINUATION	$381,098
2023	2022	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Treatment Research	000	3	3/3/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $381,098

Issue Date FY: 2022 ( Subtotal = $424,373 )
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Treatment Research	001	3	6/21/2022	NON-COMPETING CONTINUATION	$38,430
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Treatment Research	000	3	1/28/2022	NON-COMPETING CONTINUATION	$345,870
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Treatment Research	002	3	8/12/2022	SUPPLEMENT FOR EXPANSION	$40,073
														Subtotal = $424,373

Issue Date FY: 2021 ( Subtotal = $384,300 )
2021	2021	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Treatment Research	000	2	3/9/2021	NON-COMPETING CONTINUATION	$384,300
														Subtotal = $384,300

Issue Date FY: 2020 ( Subtotal = $400,313 )
2020	2020	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Cancer Treatment Research	000	1	2/4/2020	NEW	$400,313
														Subtotal = $400,313

Grand Total All Awards = $2,379,616

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The Role of Lung Resident Mesenchymal Stem Cells in Post-Chemotherapy Lung Metastases of Breast Cancer

Award Number: R37CA237307

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/04/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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