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Ecm-cell adhesion-dependent control of cancer progression genes

University of British Columbia

Interactions with the extracellular matrix (ECM) are critical for tumor cell survival and dissemination. Cell-ECM interactions are mediated primarily by integrins, cell surface receptors that nucleate the formation of adhesomes. Adhesome complexes contain signaling proteins as well as proteins that link integrins to the cytoskeleton, thereby transducing extracellular forces into the cell. Both altered ECM composition and altered adhesome signaling can contribute to cancer progression. In this thesis I tested the hypothesis that ECM-integrin interactions drive cancer progression and that this depends on the adhesome proteins FAK and talin, and on mechanobiological tension. In chapter 3, I show that in B16F1 melanoma cells, the expression of three cancer signature genes, Cyr61, MUC18 and TRPM1, is strongly regulated by cell-ECM adhesion, independently of cytoskeletal tension. In chapter 4, I used global transcriptome profiling to compare gene expression changes caused by increased ECM ligand density versus cytoskeletal tension. These two perturbations regulated genes that belong to distinct pathways. Increasing ECM ligand density upregulated genes that are associated with adhesion, migration and ECM remodelling pathways, as well as the Hippo pathway, whereas applying mechanical stretch to the cells upregulated genes associated with metabolic pathways and the HIF-1 pathway. In chapter 5, I show that the regulation of the cancer signature genes is dependent on the adhesome proteins talin and FAK. Consistent with a role for talin in adhesome signaling, loss of talin had the same effect on MUC18 and TRPM1 mRNA levels as forcing B16F1 cells into suspension. Knocking down FAK however, regulated Cyr61 and MUC18 differently than knocking down talin. In chapter 6, I show that the two isoforms of talin, talin 1 and talin 2, differentially regulate expression of the three cancer signature genes and have different effects on B16F1 spreading, migration and in vivo tumor growth. Together, my findings illustrate the complexity of how changes in ECM-cell interactions, and subsequent adhesome signaling, influence processes that are critical for cancer progression.

Text

2018-07-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/58541

Microbiology and Immunology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/