Epithelial Cell Polarity Signaling in Cancer

Epithelial cell polarity is established along an apico-basal axis through coordinated activity of conserved protein complexes, notably the Par, Crumbs and Scribble modules. These complexes interface with phosphoinositide gradients, small Rho GTPases and atypical protein kinase C (aPKC) to organise junctional structures, cytoskeletal architecture and directional transport. In healthy epithelia, this polarity underpins barrier function, tissue homeostasis and regulated proliferation. During tumour initiation and progression, disruption of polarity signalling contributes to loss of cell–cell adhesion, ectopic activation of growth pathways and epithelial–mesenchymal transition (EMT). Alterations in Par complex components or mislocalisation of their binding partners give rise to defective spindle orientation, genomic instability and aberrant mechanical stresses. Emerging evidence further implicates polarity proteins in the modulation of key oncogenic circuits—such as NFκB, Hippo–YAP and Notch—linking spatial organisation at the cortex to transcriptional programmes that drive proliferation, invasion and metastatic dissemination. Understanding how polarity determinants cross-talk with signalling networks offers routes to novel biomarkers and therapeutic targets across diverse carcinomas.

Research from Nature Portfolio

Studies of atypical protein kinase C ζ (PKCζ) have revealed its dual role in breast cancer progression, whereby elevated PKCζ–NFκB-p65 signalling suppresses adherens and tight junction proteins (E-cadherin, ZO-1) to promote invasive behaviour. Manipulation of this axis restores epithelial characteristics and impairs metastasis, highlighting the context-dependent nature of polarity kinases. In parallel, analysis of circulating tumour cells has uncovered a form of single-cell polarity maintained in fluid environments; this polarity facilitates initial attachment to endothelium, enhancing transmigration and colonisation of distant sites. Modulating regulators of this “sc polarity” alters metastatic potential in vitro and in vivo, underscoring the importance of cortical asymmetry even outside structured epithelia.

Epithelial Cell Polarity Signaling in Cancer publication trend

The graph below shows the total number of articles in epithelial cell polarity signaling in cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Apico-basal polarity: Organisation of epithelial cells into distinct apical (facing lumen) and basal (facing extracellular matrix) domains.

Par complex: A core polarity module comprising Par3, Par6 and aPKC that orchestrates junction assembly and cortical asymmetry.

aPKC: Atypical protein kinase C isoforms that phosphorylate polarity substrates and regulate cytoskeletal dynamics.

EMT: Epithelial–mesenchymal transition, a process whereby epithelial cells adopt mesenchymal traits to enhance motility and invasiveness.

Hippo signalling: A kinase cascade that controls organ size and tumour suppressive functions through regulation of YAP/TAZ transcriptional co-activators.

Single-cell polarity (sc polarity): Cortical asymmetry maintained by detached tumour cells in suspension, promoting adhesion and metastatic colonisation.

References

1. Cell polarity changes in cancer initiation and progression. Journal of Cell Biology (2023).
2. PKCζ Promotes Breast Cancer Invasion by Regulating Expression of E-cadherin and Zonula Occludens-1 (ZO-1) via NFκB-p65. Scientific Reports (2015).
3. Single cell polarity in liquid phase facilitates tumour metastasis. Nature Communications (2018).
4. SCRIB Promotes Proliferation and Metastasis by Targeting Hippo/YAP Signalling in Colorectal Cancer. Frontiers in Cell and Developmental Biology (2021).