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THE EFFECT OF TUMOR MICROENVIRONMENT ON METASTASIS

Award Number: R01CA255153
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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THE EFFECT OF TUMOR MICROENVIRONMENT ON METASTASIS - ABSTRACT Metastasis, the primary cause of breast cancer-related mortality, is a multistep process culminating with the formation of tumor foci within distant organs. However, only a subpopulation of cancer cells within the primary tumor microenvironment is capable of completing the entire metastatic cascade, which includes intravasation, survival in circulation, extravasation, and tumor growth at distant sites. Currently, there are no curative treatments for metastatic breast cancer. Understanding the factors that induce a pro-metastatic cancer cell phenotype and cancer cell dissemination mechanisms is key to developing life-saving therapies against this deadly disease. We identified a population of highly invasive, non-proliferating, non-apoptotic, chemo-resistant cancer cells capable of intravasation. These cells express high levels of MenaINV, a pro-metastatic isoform of the actin-regulatory protein Mena, and low levels of the anti-metastatic isoform, Mena11a. We found that MenaINV expression (published) and a stem cell program (preliminary results) are induced by Notch signaling in tumor cells by direct contact with tumor-associated macrophages. The emergence of MenaINV-High/Mena11aLow stem cells may be one of the crucial steps to metastasis because these cells are not only intravasation- competent but also have tumor-initiating capability. In primary breast tumors, cancer cells expressing MenaINV- High/Mena11aLow are able to enter blood vessels through Tumor Microenvironments of Metastasis (TMEM) doorways. These tightly controlled transient openings in capillary walls were first described by our group and are composed of macrophages, endothelial cells and Mena-expressing tumor cells in direct physical contact. Similar micro-anatomical structures are also observed in lung metastases, but the dissemination mechanism from this secondary site is currently unknown. Interestingly, we found that chemotherapy induces co- expression of MenaINV and stem cell transcription factor Sox9 in tumor cells through a macrophage-dependent mechanism. Importantly, we and others found that chemotherapy also increases the density of TMEM doorways. Thus, we hypothesize that tumor-associated macrophages induce a pro-metastatic cancer cell phenotype in primary tumors and metastatic foci, enabling them to disseminate via TMEM doorways, and that this process is potentiated by chemotherapy. We aim to delineate the involvement of NF-kB and Notch in co- induction of invasive (MenaINV-High) and stem phenotypes in both primary tumor and lung metastases in vivo, evaluate cancer cell dissemination mechanisms in lung metastases and evaluate the effect of chemotherapy on cancer cell re-dissemination from lung metastasis and co-activation of stem and MenaINV-High phenotype. Our findings will provide mechanistic insights into the effects of the tumor microenvironment on the induction of metastasis and cancer cell re-dissemination from metastatic foci. This will enable us to identify molecular targets for future therapies that could be combined with chemotherapy to improve outcomes for patients with metastatic disease which would be a major advance in the battle against 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 = $505,327 )
2025	2025	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	001	5	5/22/2025	NON-COMPETING CONTINUATION	$50,532
2025	2025	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	000	5	3/4/2025	NON-COMPETING CONTINUATION	$454,795
														Subtotal = $505,327

Issue Date FY: 2024 ( Subtotal = $480,062 )
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	000	4	2/21/2024	NON-COMPETING CONTINUATION	$454,795
2024	2024	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	001	4	4/16/2024	NON-COMPETING CONTINUATION	$25,267
														Subtotal = $480,062

Issue Date FY: 2023 ( Subtotal = $495,221 )
2023	2023	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	000	3	2/28/2023	NON-COMPETING CONTINUATION	$495,221
														Subtotal = $495,221

Issue Date FY: 2022 ( Subtotal = $495,221 )
2022	2022	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	000	2	6/23/2022	NON-COMPETING CONTINUATION	$495,221
														Subtotal = $495,221

Issue Date FY: 2021 ( Subtotal = $505,327 )
2021	2021	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Cancer Biology Research	000	1	2/18/2021	NEW	$505,327
														Subtotal = $505,327

Grand Total All Awards = $2,481,158

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THE EFFECT OF TUMOR MICROENVIRONMENT ON METASTASIS

Award Number: R01CA255153

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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