NIH grant: Heritable clonal selection by ECM stiffness in cancer (1R01CA305395-01A1)

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NIH grant 1R01CA305395-01A1: Heritable clonal selection by ECM stiffness in cancer
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Tanmay P. Lele. Award: $453464.
Start: 2026-08-07T00:00:00.
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.

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