Tension at intercellular junctions is necessary for accurate orientation of cell division in the epithelium plane

Abstract

The direction in which a cell divides is set by the orientation of its mitotic spindle and is important for determining cell fate, controlling tissue shape, and maintaining tissue architecture. Divisions parallel to the epithelial plane sustain tissue expansion. By contrast, divisions perpendicular to the plane promote tissue stratification and lead to the loss of epithelial cells from the tissue—an event that has been suggested to promote metastasis. Much is known about the molecular machinery involved in orienting the spindle, but less is known about the contribution of mechanical factors, such as tissue tension, in ensuring spindle orientation in the plane of the epithelium. This is important as epithelia are continuously subjected to mechanical stresses. To explore this further, we subjected suspended epithelial monolayers devoid of extracellular matrix to varying levels of tissue tension to study the orientation of cell divisions relative to the tissue plane. This analysis revealed that lowering tissue tension by compressing epithelial monolayers or by inhibiting myosin contractility increased the frequency of out-of-plane divisions. Reciprocally, increasing tissue tension by elevating cell contractility or by tissue stretching restored accurate in-plane cell divisions. Moreover, a characterization of the geometry of cells within these epithelia suggested that spindles can sense tissue tension through its impact on tension at subcellular surfaces, independently of their shape. Overall, these data suggest that accurate spindle orientation in the plane of the epithelium relies on a threshold level of tension at intercellular junctions.

Oncogenic Ras deregulates cell-substrate interactions during mitotic rounding and respreading to alter cell division orientation

“…While pseudo-stratified epithelia have been shown to maintain attachment to the basal lamina during mitotic rounding via thin basal processes which direct cleavage plane orientation (Kosodo et al ., 2008; Nakajima et al ., 2013), the extent to which these retraction fibres contribute to division orientation in tissues where additional cell-to-cell adhesions and polarity complexes are also at play remains to be determined (Bosveld et al ., 2016). Changes to division orientation in this context have important implications, as they facilitate stress relaxation, maintain cell packing (Wyatt et al ., 2015; Lisica et al ., 2022) and epithelial architecture (Lechler and Mapelli, 2021). While errors in division orientation are tolerated in some tissues (Bergstralh, Lovegrove and St. Johnston, 2015), departure from planar divisions can disrupt epithelial organisation (Zheng et al ., 2010; Bergstralh, Dawney and St Johnston, 2017), leading to the idea that spindle misorientation might contribute to oncogenesis (Macara and Seldin, 2017).…”

Claudin-4 modulates autophagy via SLC1A5/LAT1 as a tolerance mechanism for genomic instability in ovarian cancer

“…Cell cycle progression involves the remodeling of the nucleus as it advances through each phase, and its proper control is key to avoiding genomic instability. [27][28][29][30][31][32][33] Cancer development is related to significant changes in the morphology of the nucleus, which are intimately linked with genome instability. Particularly in ovarian cancer, there is a positive correlation between the nuclei size and chromosomic amplifications, a type of genomic instability.…”

Onsager’s variational principle in proliferating biological tissues, in presence of activity and anisotropy

“…Misorientation of the division axis could contribute to cancer development by disorganising the tissue and provoking tissue metastasis [46]. Orientation of the mitotic spindle requires mechanical cues [47].…”