Several studies point to possible functional roles for stochastic heterogeneity in epithelia. For instance, the patchy arrangement of cilia in the mouse airway epithelium generates a locally heterogeneous flow of airway clearance that is globally efficient³⁹. Heterogeneity and stochastic growth have also been proposed to regulate biliary epithelial tissue remodelling, which is central to liver regeneration¹¹. Further, T cells can infiltrate through the endothelial Basement membrane containing Laminin 4 but not through endothelial BM containing Laminin 5⁴⁰ during Experimental Autoimmune Encephalomyelitis (EAE) (Fig.1c). Heterogeneity is also associated with pathological conditions such as ageing^41,42. For instance, cell-cell variations in levels of protein expression is higher in old mice as compared to young mice⁴³. Additionally, stochastic physical heterogeneity is shown to regulate essential physiological functions of the tissues. For instance, mechanical heterogeneity regulates collective cell migration during epithelial wound closure^44,45. Another evidence was reported in developing zebrafish where fluctuations in cellular stresses regulates anteroposterior body axis formation^46,47. Studies also implicate physical heterogeneity in pathological situations such as Asthma⁴⁸, pulmonary fibrosis⁴⁹ and cancer metastasis^50,51.

Overall, these studies indicate functional relevance of heterogeneity in biological tissues. The relevance of inherent heterogeneity on disease initiation remains largely unexplored. In the next section, we summarize reports suggesting that inherent tissue heterogeneity might regulate both the initiation and progression of diseases, emphasizing on cancer initiation.