Genetic variation drives cancer cell adaptation to ECM stiffness

• 成果类型: Article
• 署名作者: Wang, Ting - Ching; Sawhney, Suchitaa; Morgan, Daylin; Bennett, Richard L.; Rashmi, Richa; Estecio, Marcos R.; Brock, Amy; Singh, Irtisha; Baer, Charles F.; Licht, Jonathan D.; Lele, Tanmay P.
• 署名单位: Texas A&M University System; Texas A&M University College Station; Texas A&M University System; Texas A&M University College Station; University of Texas System; University of Texas Austin; State University System of Florida; University of Florida; Texas A&M University System; Texas A&M University College Station; University of Texas System; UTMD Anderson Cancer Center; State University System of Florida; University of Florida; Texas A&M University System
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-11341
• DOI: 10.1073/pnas.2403062121
• 发表日期: 2024-09-24
• 关键词: matrix stiffness; mechanical memory; EVOLUTION; Heterogeneity; metastasis; expression; phenotype; tension

摘要

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.