Another nice benefit of our approach is that we can combine the model grammar with graphical interfaces to easily write and test new models without writing code. This opens the world of simulation modeling to new communities. (Preprint by @rheiland soon!) 16/19

In this work, we found that applying combination immunotherapy to our model improved clearance of virtual tumors. 14/19

Example 5 extends our model to simulate combination immunotherapy strategies in pancreatic cancer based on these genomics-derived rules of immune cell interactions in immunotherapy response to provide a platform for virtual clinical trials. 13/19

This example demonstrates the power of the simulation to model emergent cell behaviors, as a population of protective M2-like macrophages emerges as the simulation progresses and protects the remaining tumor from destruction. 11/19

With the immune cells in place, example 4 uses extensive literature-derived rules of tumor-immune interactions to simulate T cell activation in response to tumor contact. 10/19

This model allowed us to forecast PDAC microenvironment dynamics from RNA and imaging information. We saw isolated tumor cells transition predominantly to the mesenchymal phenotype and then formulate nests of epithelial tumor cells invade during carcinogenesis. 8/19

Example 2 models human pancreatic tumor progression to invasion by initializing mathematical agents from spatial transcriptomics coordinates of epithelial cells and fibroblasts the hypothesis grammar to encode our genomics-inferred rules of their cell-cell interactions. 7/19

Recently, integrating single-cell data from human pancreatic cancer tumors and organoid co-culture demonstrated a trade-off between tumor cell proliferation and fibroblast-associated EMT in epithelial cells. 6/19  doi.org/10.1101/2022...

Example 1 simulates unchecked cell growth in cancer, which exhausts oxygen in non-vascularized tumors. Modeling this resource consumption problem has provided a foundation for mathematical modeling of tumors, and this serves as the base example of tumor cell behavior. 5/19

To allow for human-readable encoding of equations, we define a new concept of hypothesis grammar and demonstrate its use in 5 real-world biological examples. 4/19