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Mechanotransduction from the tumor microenvironment to the nuclear envelope protein emerin enables nuclear softening during cancer metastasis

Award Number: R15CA309616
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/23/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Mechanotransduction from the tumor microenvironment to the nuclear envelope protein emerin enables nuclear softening during cancer metastasis - This project will investigate the mechanism by which mechanical signaling through the inner nuclear envelope protein emerin modulates breast cancer metastasis. Triple-negative breast cancer (TNBC) remains one of the most lethal and therapeutically challenging subtypes of breast cancer due to its high propensity for metastasis and high rates of treatment resistance. To counter this resistance, it is incumbent on us to examine other, potentially overlooked mechanisms contributing to TNBC’s ability to invade tissues and metastasize. Our laboratory has identified a previously unrecognized mechanism by which TNBC cells acquire metastatic potential through alterations in nuclear mechanics. For a tumor to metastasize, cancer cells must traverse the nearby vessels, squeezing through small gaps in the endothelium. The major physical barrier to cells moving through these narrow gaps is the size and stiffness of the nucleus. These nuclear properties are governed by emerin, whose protein levels correlate with overall survival in patients, suggesting that emerin plays a central role in progression of malignant tissues. We showed that decreased expression of emerin, a key regulator of nuclear stiffness, is associated with more aggressive TNBC phenotypes. Reduced emerin levels facilitate nuclear deformability, enabling cancer cells to migrate through dense extracellular matrix (ECM) and disseminate. Restoring emerin stiffens the nucleus, thereby limiting invasion and metastasis in preclinical models. We hypothesize that reduced emerin expression or function acts as a key driver of breast cancer metastatic transformation by compromising the structural integrity of the nucleus. Previous work revealed that cancer nuclear stiffness is impacted by the tumor microenvironment (TME), as increased ECM stiffness causes decreased nuclear stiffness, both of which correlate with increased metastasis. Importantly, we demonstrated that increased ECM stiffness downregulates emerin protein levels, suggesting that emerin plays a key role in responding to changes in the ECM by altering nuclear structure. How it does this is unclear. The linker of nucleoskeleton and cytoskeleton (LINC) complex is the major conduit for transducing mechanical signals (i.e., changes in ECM stiffness) from the cell surface to the nucleus. Prior research revealed that changes in substrate stiffness caused LINC-dependent changes in the nucleoskeleton and in the expression of pro-migratory proteins, both of which are known to be affected by emerin. However, it remains to be determined 1) how ECM stiffness is transduced by the LINC complex to the nucleus and how it affects emerin levels, 2) how emerin’s interactions with the LINC complex affect specific emerin functions, and 3) if LINC-mediated pro-metastatic signaling is dependent on emerin. This work will identify targetable regulators of emerin and define how the TME promotes tumor progression via LINC mechanotransduction. Both of these discoveries are clinically valuable, as they may lead to new therapeutic targets and a new set of at-risk criteria that may transform TNBC treatment.


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 = $564,078 )
2026	2026	ROWAN UNIVERSITY	201 MULLICA HILL RD	GLASSBORO	NJ	08028	GLOUCESTER	USA	Cancer Biology Research	000	1	9/23/2026	NEW	$564,078
														Subtotal = $564,078

Grand Total All Awards = $564,078

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Mechanotransduction from the tumor microenvironment to the nuclear envelope protein emerin enables nuclear softening during cancer metastasis

Award Number: R15CA309616

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/23/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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