(190y) Increased Resistance Enhances Cell Motility

Cell motility plays crucial role in development, immunity and cancer. Besides chemotaxis, durotaxis, and haptotaxis recently barotaxis – the migration of cells in response to physical pressure – has been identified as a parameter influencing cell migration for immune cells. However, the molecular mechanism responsible for resistance sensation by cells during migration is still elusive. Additionally, during invasion and intravasation, cancer cells migrate through regions of higher hydraulic resistance than that of normal blood. This made us hypothesize that motile cells (metastatic cancer cells and fibroblasts) might demonstrate distinct migration characteristics when subjected to increased resistance. In this research we have combined state-of-the-art bioengineering tools (microfluidics and soft lithography) and live cell imaging (FRET, FLIM, confocal) techniques to understand the response of cancerous (MDA-MB-231, human osteosarcoma) and normal cell types (human dermal fibroblasts) to increased resistance. Our results demonstrate that under high resistance the motility of cancer cells and normal dermal fibroblasts increased in both confined polydimethylsiloxane channels and 2D substrates. In line with the increased confined migration speed under increased resistance, MDA-MB-231 cells relied more on protrusive phenotypes compared to the predominantly bleb-based phenotype under normal resistance. These results suggest a common adaptability of cells towards increased motility when confronted with physiologically relevant resistance. We also investigated the molecular mechanisms underlying this phenomenon by studying the role of ion channels, actin nucleators, focal adhesions and actomyosin contractility using shRNA and CRISPR/CAS9 based gene editing, immunofluorescence and FRET/FLIM imaging of small GTPases. Collectively, our data suggest that resistance regulates both the modes and efficiency of cell migration. Furthermore, increasing resistance to physiologically relevant levels might induce plasticity in cancer cells, and these studies may enhance our understanding of the mechanisms underlying migration and plasticity, enabling better design of drugs specifically targeting the adaptability of these cells.