External forces control mitotic spindle positioning

Abstract

The response of cells to forces is essential for tissue morphogenesis and homeostasis. This response has been extensively investigated in interphase cells, but it remains unclear how forces affect dividing cells. We used a combination of micro-manipulation tools on human dividing cells to address the role of physical parameters of the micro-environment in controlling the cell division axis, a key element of tissue morphogenesis. We found that forces applied on the cell body direct spindle orientation during mitosis. We further show that external constraints induce a polarization of dynamic subcortical actin structures that correlate with spindle movements. We propose that cells divide according to cues provided by their mechanical micro-environment, aligning daughter cells with the external force field.

The metastatic cancer cell cortex: An adaptation to enhance robust cell division in novel environments?

“…As adherent cells round up upon entry into mitosis, they maintain attachment to this underlying substrate through actin-rich retraction fibers [6]. This integrin-mediated attachment to the ECM has been shown to guide spindle positioning [7,8]. Furthermore, disruption of integrin signaling in mitosis results in defects in centrosome separation and bipolar spindle assembly [9], as well as impaired cytokinesis [9,10].…”

“…Moreover, circulating tumor cells have been reported to express proliferation markers [13]. Then, in order to form metastases, cells must undergo a process of extravasation to leave the blood/lymphatic system to colonize a new tissue environment, where they must proliferate despite differences in matrix composition and mechanics compared with their tissue of origin.microenvironment affect spindle positioning and division [7][8][9][10][11] it is likely that mitosis in a foreign environment presents a challenge. This may explain, in part, why metastasized cells often initially enter a dormant non-proliferative phase when introduced to a new environment [12].…”

FAK transduces extracellular forces that orient the mitotic spindle and control tissue morphogenesis

“…Several factors have been shown to influence mitotic spindle orientation including cell polarity, cell shape and, more recently, external forces 6,7 . Fink et al 7 , elegantly showed that external forces transmitted through the retraction fibres (RFs) can guide mitotic spindle orientation in adherent cells, whereas external forces have also been shown to control spindle orientation in vivo in the zebrafish EVL 8 .…”

Coordinating cell polarity with cell division in space and time

“…These cues originate in interphase cells and are maintained during mitosis where they associate with retraction fibers, membrane tubes that maintain cell connections with the ECM at cell rounding. The forces applied by retraction fibers provide a cortical polarizing signal that is essential to orient the spindle [23].…”