Blueprint for mechanistic modelling of SCC in FA. Disease onset and aggravation emerges as a gradual loss of epithelial tissue function (A). The hallmarks of FA are connected mechanistically through complex multi-level regulatory networks that, under homeostatic conditions, maintain a healthy phenotype (B). The blueprint for modeling SCC development in FA individuals is based on the hallmarks of FA as well as cellular and subcellular regulatory networks. At the cellular level, it includes interplays between the epithelial barrier function, the oral microbiome and the immune responses. Together, these factors shape a microenvironment that is sensed at the sub-cellular level by regulatory networks shaping cell fate decisions. These are targeted by epigenetic and genetic processes including mutations and genomic instability (C).