Modelling FA cancer development

Cancer progression is a dynamical process ranging from early, mostly clinically asymptomatic, to late stages that are difficult to reverse. Each stage is characterized by a particular configuration (emergent behavior) of the tissue, such as infiltration of immune cells, the microbiome, cell cycle speed and the grade of cell dysplasia (Fig. 3A). Disease onset and aggravation emerge from the dynamic interplay between hallmarks of SCC in FA (Fig. 2B). The hallmarks are connected mechanistically by complex, multi-level regulatory networks that under homeostatic conditions maintain a healthy phenotype (Fig. 3B). At the cellular level, the stratified epithelium underlying the epithelial barrier function interplays with the oral microbiome and the infiltration of immune cells, which together shape the micro-environment of tumor cells. At the sub-cellular level, genetic factors such as mutations in FANC genes, copy number variations and epigenetic reprogramming, together with micro-environmental perturbations, such as chronic inflammation and exposure to pathogens or a disturbed microbiome, can lead to altered cell fate decisions. These factors can be intrinsically disturbed,e.g ., by aldehydes, but also influenced by lifestyle decisions, such as physical exercise, antibiotic treatment, immunosuppressants or chemotherapy. The complex interplay between these processes makes prevention but also optimal treatment protocols and individual patient assessments extremely challenging without a dynamical computational framework as an aid.
Based on the hallmarks of FA SCC and known underlying cellular and subcellular regulatory networks, we developed a blueprint for modelling SCC development in FA individuals (Fig. 3C). Biological processes comprising the blueprint include: (i) microbial interactions in the oral cavity (pink inset), (ii) circulating immune cells and immune response (orange inset), (iii) metabolites affected by food intake or endogenously generated within a cell (yellow inset), (iv) DNA damage sensing and repair (red inset), (v) epigenetic reprogramming (green inset), (vi) Stratified epithelial dynamics (brown inset), and (vii) loss of epithelial function through EMT (epithelial-mesenchymal transition) (dark blue inset). Together, these tissue-level processes are sensed and integrated by the cells and their inner regulatory networks (black inset), resulting in (viii) stress response and (xi) cell cycle progression or senescence, (x) leading finally to cell fate decisions, including survival, proliferation, cell death/apoptosis. The blueprint amounts to a preliminary wiring diagram connecting these processes and will act as a template for an executable computational model the dynamical multi-level dynamical network underlying the tumorigenesis in FA individuals.