Data driven modeling of pseudopalisade pattern formation

Pseudopalisading is an interesting phenomenon where cancer cells arrange themselves to form a dense garland-like pattern. Unlike the palisade structure, a similar type of pattern first observed in schwannomas by pathologist J.J. Verocay (Wippold et al. in AJNR Am J Neuroradiol 27(10):2037-2041, 2006), pseudopalisades are less organized and associated with a necrotic region at their core. These structures are mainly found in glioblastoma (GBM), a grade IV brain tumor, and provide a way to assess the aggressiveness of the tumor. Identification of the exact bio-mechanism responsible for the formation of pseudopalisades is a difficult task, mainly because pseudopalisades seem to be a consequence of complex nonlinear dynamics within the tumor. In this paper we propose a data-driven methodology to gain insight into the formation of different types of pseudopalisade structures. To this end, we start from a state of the art macroscopic model for the dynamics of GBM, that is coupled with the dynamics of extracellular pH, and formulate a terminal value optimal control problem. Thus, given a specific, observed pseudopalisade pattern, we determine the evolution of parameters (bio-mechanisms) that are responsible for its emergence. Random histological images exhibiting pseudopalisade-like structures are chosen to serve as target pattern. Having identified the optimal model parameters that generate the specified target pattern, we then formulate two different types of pattern counteracting ansatzes in order to determine possible ways to impair or obstruct the process of pseudopalisade formation. This provides the basis for designing active or live control of malignant GBM. Furthermore, we also provide a simple, yet insightful, mechanism to synthesize new pseudopalisade patterns by linearly combining the optimal model parameters responsible for generating different known target patterns. This particularly provides a hint that complex pseudopalisade patterns could be synthesized by a linear combination of parameters responsible for generating simple patterns. Going even further, we ask ourselves if complex therapy approaches can be conceived, such that some linear combination thereof is able to reverse or disrupt simple pseudopalisade patterns; this is investigated with the help of numerical simulations.