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Regulation of Tumor Invasion and Metastasis by Matrix Stiffness

Award Number: R01CA174869
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2015
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Regulation of Tumor Invasion and Metastasis by Matrix Stiffness - Breast tumors are often identified by manual palpation due to their apparent “hardness” compared to normal tissue. The presence of a fibrotic focus in breast tumors is associated with a 10-50-fold increase in tissue stiffness and correlates with distant metastasis and poor outcome. Recent studies show that increasing matrix stiffness can induce a malignant phenotype in cultured human mammary organoids, suggesting that mechanical properties of extracellular matrix directly regulate tumor metastasis. However, how mechanical forces are translated into biochemical signals to promote tumor invasion and metastasis is largely unknown. Our preliminary studies found that rigid matrix stiffness activates a novel mechanotransduction pathway to induce Epithelial-Mesenchymal Transition (EMT) and promote tumor metastasis. We therefore hypothesize that mechanical forces activates the LYN kinase to allow the EMT-inducing transcription factor TWIST1 to promote tumor invasion and metastasis. To test this hypothesis, we plan to 1) To elucidate the molecular mechanism by which high tissue stiffness activates a novel mechanotransduction cascade to promote TWIST1 nuclear translocation and EMT; 2) To elucidate the novel molecular mechanism by which soft matrix stiffness prevents TWIST1 nuclear translocation and inhibit EMT; 3) To determine the involvement of the Twist1 mechanotransduction pathway in promoting metastasis in vivo and in predicting human breast cancer progression.


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: 2026 ( Subtotal = $363,773 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	001	10	4/16/2026	NON-COMPETING CONTINUATION	$36,378
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	10	1/22/2026	NON-COMPETING CONTINUATION	$327,395
														Subtotal = $363,773

Issue Date FY: 2025 ( Subtotal = $852,034 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	002	9	4/25/2025	NON-COMPETING CONTINUATION	$0
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	007	9	9/10/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	005	9	8/25/2025	NON-COMPETING CONTINUATION	$0
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	006	9	9/8/2025	SUPPLEMENT FOR EXPANSION	$51,011
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	003	9	5/28/2025	NON-COMPETING CONTINUATION	$36,378
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	9	1/27/2025	NON-COMPETING CONTINUATION	$327,395
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	008	9	9/15/2025	SUPPLEMENT FOR EXPANSION	$437,250
2025	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	001	8	4/24/2025	TERMINATION	$0
2025	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	004	8	7/11/2025	OTHER REVISION	$0
														Subtotal = $852,034

Issue Date FY: 2024 ( Subtotal = $428,752 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	8	1/4/2024	NON-COMPETING CONTINUATION	$327,395
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	003	8	4/18/2024	SUPPLEMENT FOR EXPANSION	$4,376
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	002	8	4/17/2024	NON-COMPETING CONTINUATION	$18,189
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	001	8	1/25/2024	SUPPLEMENT FOR EXPANSION	$78,792
														Subtotal = $428,752

Issue Date FY: 2023 ( Subtotal = $442,291 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	7	1/30/2023	NON-COMPETING CONTINUATION	$356,497
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	001	7	2/16/2023	SUPPLEMENT FOR EXPANSION	$85,794
														Subtotal = $442,291

Issue Date FY: 2022 ( Subtotal = $401,195 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	002	6	9/3/2022	SUPPLEMENT FOR EXPANSION	$37,422
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	001	6	1/27/2022	COMPETING CONTINUATION	$363,773
2022	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	5	12/1/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $401,195

Issue Date FY: 2019 ( Subtotal = $343,925 )
2019	2019	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	5	7/23/2019	NON-COMPETING CONTINUATION	$343,925
														Subtotal = $343,925

Issue Date FY: 2018 ( Subtotal = $354,563 )
2018	2018	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	4	7/12/2018	NON-COMPETING CONTINUATION	$354,563
														Subtotal = $354,563

Issue Date FY: 2017 ( Subtotal = $354,563 )
2017	2017	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR DEPT 621	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	3	7/12/2017	NON-COMPETING CONTINUATION	$354,563
														Subtotal = $354,563

Issue Date FY: 2016 ( Subtotal = $354,563 )
2016	2016	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	2	7/13/2016	NON-COMPETING CONTINUATION	$354,563
														Subtotal = $354,563

Issue Date FY: 2015 ( Subtotal = $354,563 )
2015	2015	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	1	4/6/2015	NEW	$354,563
														Subtotal = $354,563

Grand Total All Awards = $4,250,222

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Regulation of Tumor Invasion and Metastasis by Matrix Stiffness

Award Number: R01CA174869

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2015

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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