Journal
SCIENCE ADVANCES
Volume 7, Issue 28, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/sciadv.abh3457
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Funding
- National Institutes of Health [R01-CA183804, R01-CA254193, R01-GM134542]
- Alberta Cancer Foundation [26491]
- Spanish Ministry of Science, Education and Universities [RTI2018-099718-B-100]
- institutional Maria de Maeztu Programme for Units of Excellence in RD
- FEDER funds
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The study reveals a molecular mechanism by which cells avoid high shear during intravasation by activating TRPM7 channel to promote extracellular calcium influx, which then activates different pathways to coordinate the reversal of migration direction and avoid shear stress. Cells with higher TRPM7 activity levels intravasate less efficiently and establish less invasive metastatic lesions. This study provides a mechanistic interpretation for the role of shear stress and its sensor, TRPM7, in tumor cell intravasation.
Tumor cell intravasation preferentially occurs in regions of low fluid shear because high shear is detrimental to tumor cells. Here, we describe a molecular mechanism by which cells avoid high shear during intravasation. The transition from migration to intravasation was modeled using a microfluidic device where cells migrating inside longitudinal tissue-like microchannels encounter an orthogonal channel in which fluid flow induces physiological shear stresses. This approach was complemented with intravital microscopy, patch-clamp, and signal transduction imaging techniques. Fluid shear-induced activation of the transient receptor potential melastatin 7 (TRPM7) channel promotes extracellular calcium influx, which then activates RhoA/myosin-II and calmodulin/IQGAP1/ Cdc42 pathways to coordinate reversal of migration direction, thereby avoiding shear stress. Cells displaying higher shear sensitivity due to higher TRPM7 activity levels intravasate less efficiently and establish less invasive metastatic lesions. This study provides a mechanistic interpretation for the role of shear stress and its sensor, TRPM7, in tumor cell intravasation.
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