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Nuclear Dysfunction in Cancer: The Role of Mechanical Stresses Transmittedby the LINC Complex

Award Number: U01CA225566
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/06/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Nuclear Dysfunction in Cancer: The Role of Mechanical Stresses Transmittedby the LINC Complex - PROJECT ABSTRACT The nuclear lamina is physically connected through nuclear envelope proteins to the cytoskeleton by the LINC complex (linker of nucleoskeleton to cytoskeleton), which spans the nuclear envelope and allows the transmission of mechanical forces to the nucleus. LINC complex proteins are frequently mutated or dysregulated in cancer, and some of these mutations have been proposed to be cancer drivers. Yet, how alterations to the LINC complex might promote cancer development is not known. This application's overarching hypothesis is that cytoskeletal force transmission to the nucleus is altered in cancer due to driver mutations in LINC proteins contributing to loss of epithelial polarity, aberrant tissue structure, abnormal gene expression, transformation and invasive cancer cell migration. The following aims are proposed: Aim 1. Define alterations to LINC complex- transmitted mechanical stresses in cancer. How the LINC complex transmits mechanical forces to position the nucleus and integrates tension in normal breast epithelia will be determined. The molecular and physical mechanisms for nuclear positioning in invasive breast epithelial cancer 3-D migration will be determined. Aim 2. Determine how the LINC complex contributes to altering the epigenetic organization of the genome during progression to breast cancer. The extent to which LINC disruption affects spatial partitioning of genes in the nucleus and heterochromatin organization will be identified; these effects will be correlated with cell phenotype, gene expression and epigenomic profiles. The requirement for an intact LINC complex for transformation to malignancy will be examined. The cancer nucleus remains highly understudied, with much to learn known about the physical principles that govern nuclear positioning, dysmorphia and chromatin organization, and how altered nuclear stresses contribute to cancer cell dysfunction. The focus of both aims is on the impact of cytoskeletal stresses transmitted by the LINC complex on gene expression and cell function. This necessarily requires an integrated understanding of both molecular and physical mechanisms. Extensive expertise gained in other systems will be coupled with new approaches for measuring forces on the nucleus. These include a direct force probe to interrogate nuclear mechanical responses in spread, living cells and nuclear tension sensors for the study of nuclear forces in both cancer and normal cells. Physically-based computational models will be used to interpret the resulting data. A physical approach will be applied to characterize the cancer nucleus and generate unique, genome-wide data sets for gene expression after experimentally altering LINC complex connections to discover the role of the LINC complex in breast cancer pathogenesis.


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 = $0 )
2025	2024	TEXAS A&M ENGINEERING EXPERIMENT STATION	3124 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cancer Biology Research	000	5	4/7/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $569,658 )
2024	2024	TEXAS A&M ENGINEERING EXPERIMENT STATION	3124 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cancer Biology Research	000	5	2/28/2024	NON-COMPETING CONTINUATION	$538,596
2024	2024	TEXAS A&M ENGINEERING EXPERIMENT STATION	3124 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cancer Biology Research	001	5	4/17/2024	NON-COMPETING CONTINUATION	$31,062
														Subtotal = $569,658

Issue Date FY: 2023 ( Subtotal = $565,214 )
2023	2023	TEXAS A&M ENGINEERING EXPERIMENT STATION	3124 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cancer Biology Research	001	4	8/3/2023	NON-COMPETING CONTINUATION	$0
2023	2023	TEXAS A&M ENGINEERING EXPERIMENT STATION	3124 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cancer Biology Research	000	4	3/6/2023	NON-COMPETING CONTINUATION	$565,214
														Subtotal = $565,214

Issue Date FY: 2022 ( Subtotal = $618,208 )
2022	2022	TEXAS A&M ENGINEERING EXPERIMENT STATION	3124 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cancer Biology Research	002	3	9/13/2022	NON-COMPETING CONTINUATION	$0
2022	2022	TEXAS A&M ENGINEERING EXPERIMENT STATION	7607 EASTMARK DR	COLLEGE STATION	TX	77840	BRAZOS	USA	Cancer Biology Research	000	3	2/14/2022	NON-COMPETING CONTINUATION	$567,742
2022	2022	TEXAS A&M ENGINEERING EXPERIMENT STATION	3124 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cancer Biology Research	001	3	6/23/2022	NON-COMPETING CONTINUATION	$50,466
														Subtotal = $618,208

Issue Date FY: 2021 ( Subtotal = $674,324 )
2021	2021	TEXAS A&M ENGINEERING EXPERIMENT STATION	7607 EASTMARK DR	COLLEGE STATION	TX	77840	BRAZOS	USA	Cancer Biology Research	002	2	1/27/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2021	2021	TEXAS A&M ENGINEERING EXPERIMENT STATION	7607 EASTMARK DR	COLLEGE STATION	TX	77840	BRAZOS	USA	Cancer Biology Research	001	2	1/26/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$674,324
2021	2021	TEXAS A&M ENGINEERING EXPERIMENT STATION	7607 EASTMARK DR	COLLEGE STATION	TX	77840	BRAZOS	USA	Cancer Biology Research	005	2	7/26/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2021	2021	TEXAS A&M ENGINEERING EXPERIMENT STATION	7607 EASTMARK DR	COLLEGE STATION	TX	77840	BRAZOS	USA	Cancer Biology Research	004	2	4/27/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$630,894
2021	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Biology Research	000	1	1/26/2021	NEW	$0
2021	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Biology Research	003	1	4/27/2021	NEW	-$630,894
														Subtotal = $674,324

Issue Date FY: 2020 ( Subtotal = $681,368 )
2020	2020	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Cancer Biology Research	000	1	3/6/2020	NEW	$681,368
														Subtotal = $681,368

Grand Total All Awards = $3,108,772

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Nuclear Dysfunction in Cancer: The Role of Mechanical Stresses Transmittedby the LINC Complex

Award Number: U01CA225566

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 03/06/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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