Disrupted cell polarity is a feature of epithelial cancers. The Crumbs, Par and Scribble polarity complexes function to specify and maintain apical and basolateral membrane domains, which are essential to organize intracellular signaling pathways that maintain epithelial homeostasis. Disruption of apical-basal polarity proteins facilitates rewiring of oncogene and tumor suppressor signaling pathways to deregulate proliferation, apoptosis, invasion and metastasis. Moreover, apical-basal polarity integrates intracellular signaling with the microenvironment by regulating metabolic signaling, extracellular matrix remodeling and tissue level organization. In this review, we discuss recent advances in our understanding of how polarity proteins regulate diverse signaling pathways throughout cancer progression from initiation to metastasis.
Understanding how forces orchestrate tissue formation requires technologies to map internal tissue stress at cellular length scales. Here, we develop ultrasoft mechanosensors that visibly deform under less than 10 Pascals of cell-generated stress. By incorporating these mechanosensors into multicellular spheroids, we capture the patterns of internal stress that arise during spheroid formation. We experimentally demonstrate the spontaneous generation of a tensional ‘skin’, only a few cell layers thick, at the spheroid surface, which correlates with activation of mechanobiological signalling pathways, and balances a compressive stress profile within the tissue. These stresses develop through cell-driven mechanical compaction at the tissue periphery, and suggest that the tissue formation process plays a critically important role in specifying mechanobiological function. The broad applicability of this technique should ultimately provide a quantitative basis to design tissues that leverage the mechanical activity of constituent cells to evolve towards a desired form and function.
Epithelial cancers (carcinoma) account for 80%-90% of all cancers. The development of carcinoma is associated with disrupted epithelial organization and solid ductal structures. The mechanisms underlying the morphological development of carcinoma are poorly understood, but it is thought that loss of cell polarity is an early event. Here we report the characterization of the development of human breast lesions leading to carcinoma. We identified a unique mechanism that generates solid ducts in carcinoma through progressive loss of polarity and collapse of the luminal architecture. This program initiates with asymmetric divisions of polarized cells that generate a stratified epithelium containing both polarized and depolarized cells. Stratified regions form cords that penetrate into the lumen, subdividing it into polarized secondary lumina. The secondary lumina then collapse with a concomitant decrease in RhoA and myosin II activity at the apical membrane and ultimately lose apical-basal polarity. By restoring RhoA activity in mice, ducts maintained lumen and cell polarity. Notably, disrupted tissue architecture through luminal collapse was reversible, and ducts with a lumen were re-established after oncogene suppression in vivo. This reveals a novel and common mechanism that contributes to carcinoma development by progressively disrupting cell and tissue organization.
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