Integrating spatial analysis and agent-based modeling for studies of stroma sheltering effects in NSCLC

Abstract Background: Stroma plays a crucial role in shaping tumor growth dynamics, invasion, and metastasis. High stroma to tumor ratio in the clinic is associated with poor outcomes and shorter remission periods for lung cancer patients. Recent studies suggest that stroma shelters tumor cells during drug administration, but the precise mechanisms to confer this protection remain unclear. We hypothesize that stroma secretes paracrine factors that enhance tumor cells' proliferation rate in proximity, hence outcompeting the death rate due to therapies. In this context, the residual disease is an inherent stage in tumors' eco-evolutionary dynamics under treatment. Therefore, understanding the nature of stroma-tumor cell interactions is crucial for designing effective therapies. Methods: The spatial relationship between the stroma and proliferating tumor cells was interrogated via spatial analysis of 2D samples from mouse xenograft models and subsequent spatial agent-based modeling (ABM). Results: First, we built a pipeline to quantify the spatial extent and amplitude of stroma shielding the presence or absence of treatment. The spatial distributions of tumor cells, their proliferating rates, and the spatial extent of stroma protective effects are used to parametrize the ABM and simulate the spatio-temporal dynamics of tumor growth with and without treatment. Our preliminary results show moderately higher clustering of proliferating and stroma cells than stroma and non-proliferating cells or random distribution in the absence of treatment. In contrast, during therapy, stroma-proliferating tumor cell clustering is considerably higher than stroma-non proliferating tumor cells and stroma-random distribution. Moreover, stroma's protective effect during treatment seems limited to cells either in direct contact with stromal cells or in their immediate proximity. Conclusions: We expect our results to lead to novel therapeutic interventions that aim to shift eco-evolutionary dynamics rather than maximize short-term tumor cell killing efficiency. Citation Format: Tatiana Miti, Anna Miller, Daria Myroshnychenko, Bina Desai, Andriy Marusyk, David Basanta. Integrating spatial analysis and agent-based modeling for studies of stroma sheltering effects in NSCLC [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A032.