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Tumor-derived extracellular vesicles in the pre-metastatic niche.

Award Number: R01CA207983
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Tumor-derived extracellular vesicles in the pre-metastatic niche. - Metastasis is the leading cause of death in cancer patients, and its early detection and prevention are currently difficult. Thus, a better understanding of the earliest stages of metastasis, is an important and presently unmet challenge. The objective of this application is to gain a better understanding of the mechanisms leading to the formation of the pre-metastatic niche (PMN), an early step in the metastatic process, with the goal of finding targets for intervention. The focus of this highly collaborative grant is on the role of tumor-derived extracellular vesicles (TEV) in melanoma (MEL) and neuroblastoma (NB). Recently published1 and preliminary data revealed that TEV are primarily, but not exclusively, captured by macrophages (MF) in metastasis-tropic organs prior to their colonization by tumor cells, and that they trigger an inflammatory reaction in MF that includes the production of interleukin (IL)-18 and IL-1β and activation of the inflammasome. We also found that TEV-capturing cells in the PMN are heterogenous, including MF and non-MF cells, with the contribution of non-MF cells, including myeloid derived suppressive cells (MDSC), increasing as the PMN evolves toward a metastatic niche (MN). Using newly murine models of orthotopic metastasis to track endogenously released TEV and their capture in the PMN developed in our laboratory, state of the art single cell analysis methods, and a unique collection of patient samples, we will test the hypothesis that TEV capture by resident MF in the PMN triggers via the inflammasome the release of inflammatory cytokines/chemokines, which signal for the recruitment of bone marrow -derived myeloid cells (BMDMC) and MDSC to the PMN, supporting the subsequent colonization of the PMN by metastatic tumor cells. In AIM 1, we will perform spatiotemporal analysis of the PMN formation and its evolution into MN, identifying at the single cell level subpopulations of TEV-capturing cells defined by their RNA and protein expression. We will use pharmacological and loss-of-function approaches targeting the activation of the inflammasome in the PMN to determine whether the development of the PMN is disrupted and metastatic colonization inhibited. In AIM 2, we will perform kinetics analysis of the colonization of the PMN by BMDMC. We will determine whether TEV-capturing MF send signal(s) that promote the differentiation of BMDMC into MDSC through the release of IL-1β and IL-18 or other cytokines. We will demonstrate the role of IL-18 and IL-1β on PMN formation and metastatic colonization using pharmacological inhibition of IL-18 or mice deficient in IL-1β or IL-18. In AIM 3, we will use a unique collection of retrospective and prospective liver tissues from children with NB to characterize by Imaging Mass Cytometry the PMN in human samples, comparing the results with those from murine models. We expect to identify mechanisms involved in the formation of the PMN and MN, providing a strong premise for development of intervention approaches that could prevent the initiation of metastasis. Considering the current absence of therapeutic agents preventing metastasis, the project, if successful, could have a significant impact for MEL, NB, and other cancers.


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 = $685,156 )
2025	2025	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Biology Research	000	7	8/21/2025	NON-COMPETING CONTINUATION	$685,156
														Subtotal = $685,156

Issue Date FY: 2024 ( Subtotal = $702,906 )
2024	2024	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Biology Research	001	6	9/10/2024	COMPETING CONTINUATION	$702,906
2024	2021	CHILDREN'S HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Biology Research	000	5	1/29/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $702,906

Issue Date FY: 2021 ( Subtotal = $433,850 )
2021	2021	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Biology Research	000	5	5/17/2021	NON-COMPETING CONTINUATION	$433,850
														Subtotal = $433,850

Issue Date FY: 2020 ( Subtotal = $441,121 )
2020	2020	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Biology Research	000	4	6/1/2020	NON-COMPETING CONTINUATION	$441,121
														Subtotal = $441,121

Issue Date FY: 2019 ( Subtotal = $434,730 )
2019	2019	CHILDRENS HOSPITAL LOS ANGELES	4650 SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Biology Research	000	3	5/23/2019	NON-COMPETING CONTINUATION	$434,730
														Subtotal = $434,730

Issue Date FY: 2018 ( Subtotal = $449,691 )
2018	2018	THE CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Biology Research	000	2	6/6/2018	NON-COMPETING CONTINUATION	$449,691
														Subtotal = $449,691

Issue Date FY: 2017 ( Subtotal = $423,016 )
2017	2017	THE CHILDRENS HOSPITAL LOS ANGELES	4650 W SUNSET BLVD	LOS ANGELES	CA	90027	LOS ANGELES	USA	Cancer Biology Research	000	1	7/21/2017	NEW	$423,016
														Subtotal = $423,016

Grand Total All Awards = $3,570,470

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Tumor-derived extracellular vesicles in the pre-metastatic niche.

Award Number: R01CA207983

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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