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Cancer invasion: reciprocity between the extracellular matrix and intrinsic ERK signaling

Award Number: R01CA255790
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/16/2022
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Cancer invasion: reciprocity between the extracellular matrix and intrinsic ERK signaling - Cancer cell invasion is the major cause of lung cancer morbidity. Invasion remain untargeted, in part due to an incomplete understanding of the molecular underpinnings of the cellular process. The long-term goal is to identify the mechanisms that drive lung adenocarcinoma invasion. The overall objective here is to elucidate the Tenascin-C and ERK signaling mechanisms that drive LUAD invasion. The central hypothesis is that ERK and Tenascin-C work together to induce LUAD invasion. This is based on our preliminary data. We show that Tenascin-C is expressed early after tumor initiation by activating upstream mutations in the ERK pathway. We also show that Tenascin-C and ERK are both expressed at the invasive edge of tumors, and that Tenascin-C induces ERK activity and ERK-dependent tumor cell invasion in vitro. The central hypothesis will be tested by pursuing three specific aims: 1) Determine the cell source and stimulus for Tenascin-C production in early LUAD, 2) Determine the mechanism by which Tenascin-C signals to LUAD tumor cells, and 3) Identify mechanisms of ERK-mediated LUAD invasion. Under the first aim, we will test if fibroblasts produce Tenascin-C in response to increased strain. In aim 2, we will determine if Tenascin-C signals to induce tumor cell invasion by activating tumor cell integrins and ERK. In aim 3, we will test if LOK/Ezrin are critical ERK effectors that drive the mesenchymal-mode invasion observed in LUAD. This will determine the mechanisms by which the lung cancer extracellular matrix interacts with oncogenic RAS/ERK signaling to drive invasion. The research proposed in this application is innovative, because it tests a new model of Tenascin-C induction, develops a computation model of tumor growth within the lung and under stretch, uses organotypic cultures, and tests a new, druggable ERK effector in the invasion process. The proposed research is significant because it is expected to advance our understanding of lung cancer with new knowledge of how mechanochemical signaling between the stroma and cancer confers cancer invasion. Ultimately, such knowledge has the potential to provide strong scientific justification for the development of new therapies to target invasion and reduce lung cancer morbidity and mortality.


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 = $461,852 )
2026	2026	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	5	5/7/2026	NON-COMPETING CONTINUATION	$461,852
														Subtotal = $461,852

Issue Date FY: 2025 ( Subtotal = $461,852 )
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	4	4/10/2025	NON-COMPETING CONTINUATION	$415,668
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	001	4	5/23/2025	NON-COMPETING CONTINUATION	$46,184
														Subtotal = $461,852

Issue Date FY: 2024 ( Subtotal = $470,018 )
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	3	4/15/2024	NON-COMPETING CONTINUATION	$438,759
2024	2024	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	001	3	5/1/2024	SUPPLEMENT FOR EXPANSION	$31,259
														Subtotal = $470,018

Issue Date FY: 2023 ( Subtotal = $536,325 )
2023	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	2	5/16/2023	NON-COMPETING CONTINUATION	$503,421
2023	2023	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	001	2	5/25/2023	SUPPLEMENT FOR EXPANSION	$32,904
														Subtotal = $536,325

Issue Date FY: 2022 ( Subtotal = $398,408 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Biology Research	000	1	5/16/2022	NEW	$398,408
														Subtotal = $398,408

Grand Total All Awards = $2,328,455

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Cancer invasion: reciprocity between the extracellular matrix and intrinsic ERK signaling

Award Number: R01CA255790

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/16/2022

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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