Peripheral blood MФ–cancer cell fusion hybrids identified in cancer patients correlate with disease stage and overall survival.

Biologists have long recognized that dramatic bending of a cell sheet may be driven by even modest shrinking of the apical sides of cells. Cell shape changes and tissue movements like these are at the core of many of the morphogenetic movements that shape animal form during development, driving processes such as gastrulation, tube formation and neurulation. The mechanisms of such cell shape changes must integrate developmental patterning information in order to spatially and temporally control force production -- issues that touch on fundamental aspects of both cell and developmental biology and on birth defects research. How does developmental patterning regulate force-producing mechanisms, and what roles do such mechanisms play in development? Work on apical constriction from multiple systems including Drosophila, C. elegans, sea urchin, Xenopus, chick and mouse has begun to illuminate these issues. Here, we review this effort to explore the diversity of mechanisms of apical constriction, the diversity of roles that apical constriction plays in development, and the common themes that emerge from comparing systems.

Apical constriction changes cell shapes, driving critical morphogenetic events including gastrulation in diverse organisms and neural tube closure in vertebrates. Apical constriction is thought to be triggered by contraction of apical actomyosin networks. We found that apical actomyosin contractions began before cell shape changes in both C. elegans and Drosophila. In C. elegans, actomyosin networks were initially dynamic, contracting and generating cortical tension without significant shrinking of apical surfaces. Apical cell-cell contact zones and actomyosin only later moved increasingly in concert, with no detectable change in actomyosin dynamics or cortical tension. Thus, apical constriction appears to be triggered not by a change in cortical tension but by dynamic linking of apical cell-cell contact zones to an already contractile apical cortex.

Most cancer patients die as a result of metastasis, thus it is important to understand the molecular mechanisms of dissemination, including intra- and extravasation. Although the mechanisms of extravasation have been vastly studied in vitro and in vivo, the process of intravasation is still unclear. Furthermore, how cells in the tumor microenvironment facilitate tumor cell intravasation is still unknown. Using high-resolution imaging, we found that macrophages enhance tumor cell intravasation upon physical contact. Macrophage and tumor cell contact induce RhoA activity in tumor cells, triggering the formation of actin-rich degradative protrusions called invadopodia, enabling tumor cells to degrade and break through matrix barriers during tumor cell transendothelial migration. Interestingly, we show that macrophage-induced invadopodium formation and tumor cell intravasation also occur in patient-derived tumor cells and in vivo models, revealing a conserved mechanism of tumor cell intravasation. Our results illustrate a novel heterotypic cell contact mediated signaling role for RhoA, as well as yield mechanistic insight into the ability of cells within the tumor microenvironment to facilitate steps of the metastatic cascade.