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Heritable clonal selection by ECM stiffness in cancer

Award Number: R01CA305395
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/07/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2030

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Heritable clonal selection by ECM stiffness in cancer - Project Abstract Cancer metastasizes when tumor cells escape the primary site and colonize distant tissues. During this process, tumor cells encounter a wide range of mechanical environments: from soft tissues like brain (Young’s modulus of ~1 kPa) and lung (~5 kPa) to stiff tissues like bone (~1 GPa). Even within a single tumor, stiffness can vary from soft cores to stiffer, collagen-rich extracellular matrix (ECM) at the margins. The role of ECM stiffness in modulating tumor cell populations is of keen interest as varying ECM stiffness can profoundly affect cancer cell proliferation, migration, and drug resistance. Yet, prior research has largely overlooked the effects of heterogeneity, assuming that cancer cells in a population respond uniformly to ECM stiffness. This is a significant gap in our understanding of tumor progression: genetically distinct clones may exhibit diverse responses to ECM stiffness, enabling selection of ‘fittest’ clones over time that could define primary tumor behaviors such as proliferation and metastasis. Therefore, our objective is to determine how ECM stiffness governs tumor evolution by selecting for heritable, fitness-linked traits. We and others have shown that cancer cells proliferate poorly and spread poorly on soft ECMs compared to stiff ECMs. However, these findings were based on short-term cultures (a few days), failing to capture long-term evolutionary dynamics. In contrast, we cultured genetically heterogeneous tumor cells on soft ECMs for 3 months and found that proliferation rates recovered to those on stiff ECMs. These ‘soft-selected’ populations contained cells with enhanced spreading, unlike the poorly spread ancestral populations. In contrast, genetically homogeneous clonal populations showed no increase in growth or spreading, even after 3 months. Using DNA barcoding to track clonal lineages, we found that specific clones reproducibly increased in frequency across biological replicates. Taken together, these results strongly suggest that the increase in population growth rate was the result of selection for initially rare clones that inherently spread well on soft ECM and proliferated rapidly, rather than a plastic response. These findings motivate our central hypothesis: ECM stiffness imposes biophysical selection pressure that favors heritable traits which confer high cellular fitness. We propose a novel mechanobiological dimension to cancer evolution, complementing better-studied selective forces such as immune evasion and therapy resistance. We combine this conceptual novelty with technical innovations: (1) long-term lineage tracking using DNA barcodes, (2) nanoparticle- crosslinked hydrogels that tune ECM stiffness independently of biochemical cues, and (3) live-cell assays to measure trait transmission across generations. Our specific aims are:Aim 1: Determine whether cell spreading is heritable and linked to fitness. Aim 2: Define how 3D ECM environments influence clonal selection. Aim 3: Quantify stiffness-dependent fitness in patient-derived tumor cells. If successful, this work will shift the paradigm of tumor evolution by identifying ECM stiffness as a fundamental, previously unrecognized driver of clonal selection.


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 = $453,464 )
2026	2026	TEXAS A&M ENGINEERING EXPERIMENT STATION	3124 TAMU	COLLEGE STATION	TX	77843	BRAZOS	USA	Cancer Biology Research	000	1	8/7/2026	NEW	$453,464
														Subtotal = $453,464

Grand Total All Awards = $453,464

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Heritable clonal selection by ECM stiffness in cancer

Award Number: R01CA305395

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/07/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2030

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