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.