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Spatiotemporal mechanisms of eIF5A1/2-mediated metastasis in triple-negative breast cancer

Award Number: SC1GM121182
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/13/2017
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Spatiotemporal mechanisms of eIF5A1/2-mediated metastasis in triple-negative breast cancer - PROJECT SUMMARY Metastasis is the leading cause of mortality in patients with solid tumors. Since there are no clinically- approved targeted therapies for treating triple-negative breast cancer (TNBC), metastatic TNBC pre- sents a dire clinical situation for which intervention strategies are urgently needed. The long-term goal of this proposal is to elucidate novel tumor cell autonomous and non-autonomous mechanisms that drive TNBC progression and metastasis. The overall objective of this proposal is to define the molecu- lar/cellular basis by which post-translational hypusination and nucleocytoplasmic transport of eukaryotic initiation factor 5A (eIF5A1/2) governs pseudopodium-enriched atypical kinase one (PEAK1)-dependent invasion/dissemination and lipocalin two (LCN2)-mediated reprogramming of the premetastatic niche (PMN). Toward this end, evidence is presented that the eIF5A1/2 hypusination/activation pathway associates with poor TNBC prognosis and is required for TGFβ/PEAK1-driven metastasis and LCN2 expression in TNBC cells. Furthermore, the eIF5A1/2-LCN2 axis is identified as a novel mechanism through which primary tumor cells remodel the PMN to support TNBC cell expansion. Thus, the central hypothesis of this proposal is that hypusination and cytoplasmic localization of eIF5A1/2 in TNBC cells drives PEAK1-dependent TGFβ/fibronectin signaling crosstalk and LCN2-mediated anti-inflammatory reprogramming of the premetastatic niche to support metastasis. The approach is innovative because it represents a substantive departure from the status quo by elucidating targetable eIF5A1/2-dependent translational mechanisms of cell state plasticity at early and late stages in the metastatic cascade using the single-cell Cyclic ImmunoFluorescence (CycIF) platform, our novel in vivo/ex vivo tumor cell-free PMN reprogramming assay, the Multifunctional Approach to Pharmacological Screening (MAPS) platform and a suite of preclinical mouse models that faithfully recapitulate complementary aspects of human TNBC metastasis and progression. Furthermore, the proposed research is significant because it will define spatiotemporal mechanisms by which dysregulation of eIF5A1/2 expression, hypusination and subcellular localization drive TNBC pathogenesis and identify targeted treatment strategies for metastatic TNBC. Specific Aim 1 will determine cancer cell autonomous mechanisms of eIF5A1/2- mediated TNBC cell invasion and dissemination. Specific Aim 2 will identify eIF5A1/2-dependent mechanisms of premetastatic niche reprogramming that support TNBC cell seeding and expansion. The collective knowledge gained from these studies will elucidate targetable mechanisms that govern both early and late stages of TNBC metastasis and establish rationale for new therapeutic combina- tions to overcome TNBC progression and improve patient outcomes.


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: 2024 ( Subtotal = $448,850 )
2024	2024	THE UNIVERSITY CORPORATION	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	8	1/10/2024	NON-COMPETING CONTINUATION	$326,250
2024	2024	THE UNIVERSITY CORPORATION	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	002	8	6/18/2024	NON-COMPETING CONTINUATION	$36,250
2024	2024	THE UNIVERSITY CORPORATION	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	001	8	1/12/2024	SUPPLEMENT FOR EXPANSION	$86,350
														Subtotal = $448,850

Issue Date FY: 2023 ( Subtotal = $492,026 )
2023	2023	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	002	7	2/15/2023	NON-COMPETING CONTINUATION	$36,250
2023	2023	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	7	12/26/2022	NON-COMPETING CONTINUATION	$326,250
2023	2023	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	001	7	2/3/2023	SUPPLEMENT FOR EXPANSION	$129,526
														Subtotal = $492,026

Issue Date FY: 2022 ( Subtotal = $419,253 )
2022	2022	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	6	1/5/2022	NON-COMPETING CONTINUATION	$326,250
2022	2022	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	003	6	8/12/2022	SUPPLEMENT FOR EXPANSION	$43,175
2022	2022	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	001	6	1/6/2022	SUPPLEMENT FOR EXPANSION	$12,796
2022	2022	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	002	6	6/14/2022	NON-COMPETING CONTINUATION	$36,250
2022	2020	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	004	4	9/26/2022	NON-COMPETING CONTINUATION	$782
														Subtotal = $419,253

Issue Date FY: 2021 ( Subtotal = $375,296 )
2021	2021	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	002	5	7/23/2021	SUPPLEMENT FOR EXPANSION	$12,796
2021	2021	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	004	5	7/31/2021	COMPETING CONTINUATION	$19,014
2021	2021	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	001	5	2/26/2021	COMPETING CONTINUATION	$362,500
2021	2020	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	2/25/2021	NON-COMPETING CONTINUATION	$0
2021	2020	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	003	4	7/31/2021	NON-COMPETING CONTINUATION	-$19,014
														Subtotal = $375,296

Issue Date FY: 2020 ( Subtotal = $362,500 )
2020	2020	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	1/1/2020	NON-COMPETING CONTINUATION	$326,250
2020	2020	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	001	4	3/17/2020	NON-COMPETING CONTINUATION	$36,250
														Subtotal = $362,500

Issue Date FY: 2019 ( Subtotal = $362,500 )
2019	2019	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	12/21/2018	NON-COMPETING CONTINUATION	$362,500
														Subtotal = $362,500

Issue Date FY: 2018 ( Subtotal = $362,500 )
2018	2018	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	001	2	5/11/2018	NON-COMPETING CONTINUATION	$36,250
2018	2018	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	2	12/5/2017	NON-COMPETING CONTINUATION	$326,250
														Subtotal = $362,500

Issue Date FY: 2017 ( Subtotal = $362,500 )
2017	2017	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	1/13/2017	NEW	$362,500
														Subtotal = $362,500

Grand Total All Awards = $3,185,425

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Spatiotemporal mechanisms of eIF5A1/2-mediated metastasis in triple-negative breast cancer

Award Number: SC1GM121182

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/13/2017

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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