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  3. Genetic variation drives cancer cell adaptation to ECM stiffness

Genetic variation drives cancer cell adaptation to ECM stiffness

  • Proc Natl Acad Sci U S A. 2024 Sep 24;121(39):e2403062121. doi: 10.1073/pnas.2403062121.
Ting-Ching Wang 1,  Suchitaa Sawhney 2,  Daylin Morgan 3,  Richard L Bennett 4,  Richa Rashmi 5,  Marcos R Estecio 6,  Amy Brock 3,  Irtisha Singh 2 5,  Charles F Baer 7,  Jonathan D Licht 4,  Tanmay P Lele 1 2 8
Affiliations

Affiliations

  • 1 Artie McFerrin Department of Chemical Engineering, Texas A&M University, College Station, TX 77843.
  • 2 Department of Biomedical Engineering, Texas A&M University, College Station, TX 77843.
  • 3 Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX 78712.
  • 4 Division of Hematology and Oncology, University of Florida Health Cancer Center, Gainesville, FL 32610.
  • 5 Department of Cell Biology and Genetics, Texas A&M University, Bryan, TX 77807.
  • 6 Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
  • 7 Department of Biology, University of Florida, Gainesville, FL 32611.
  • 8 Department of Translational Medical Sciences, Texas A&M University, Houston, TX 77030.
PMID: 39302966 DOI: 10.1073/pnas.2403062121
Abstract

The progression of many solid tumors is accompanied by temporal and spatial changes in the stiffness of the extracellular matrix (ECM). Cancer cells adapt to soft and stiff ECM through mechanisms that are not fully understood. It is well known that there is significant genetic heterogeneity from cell to cell in tumors, but how ECM stiffness as a parameter might interact with that genetic variation is not known. Here, we employed experimental evolution to study the response of genetically variable and clonal populations of tumor cells to variable ECM stiffness. Proliferation rates of genetically variable populations cultured on soft ECM increased over a period of several weeks, whereas clonal populations did not evolve. Tracking of DNA barcoded cell lineages revealed that soft ECM consistently selected for the same few variants. These data provide evidence that ECM stiffness exerts natural selection on genetically variable tumor populations. Soft-selected cells were highly migratory, with enriched oncogenic signatures and unusual behaviors such as spreading and traction force generation on ECMs with stiffness as low as 1 kPa. Rho-regulated cell spreading was found to be the directly selected trait, with yes-associated protein 1 translocation to the nucleus mediating fitness on soft ECM. Overall, these data show that genetic variation can drive Cancer cell adaptation to ECM stiffness.

Keywords

ECM stiffness; cancer; mechanoadaptation; mechanobiology.

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