(F-216) Impact of stroma remodeling on forces experienced by cancer cells and stromal cells

Introduction:: Pancreatic cancer is a common gastrointestinal malignancy, with pancreatic ductal adenocarcinoma (PDAC) being the most prevalent. One of the current limitations with the effectiveness of modern-day drug therapies for PDAC is due to the increased desmoplasia tumor microenvironment. Remodeling the tumor’s stroma can improve the efficiency of the anti-tumor therapies without destroying the stroma, but it is unknown how the remodeling of stromal components is associated with nanoparticle penetration. The current study aims to 1) determine how stromal remodeling alters the stress experienced by cancer cells and their microenvironment and 2) to identify, during remodeling, which stromal component has the highest impact on stresses experienced by cancer cell. A three-dimensional model was developed to investigate the impact of different stages of tumor stroma remodeling by quantifying stresses experienced by the tissue components.


Materials and Methods:: The three-dimensional model was created using COMSOL Multiphysics v. 5.6. The model represented the tumor stroma, consisting of stromal cells (fibroblasts) and PDAC cancer cells (PANC-1), surrounded by the extracellular matrix (ECM). The tumor microenvironment’s mechanical properties were altered with each computational simulation to depict the changes seen during remodeling. This is depicted in Table 1. Cases 1-9 included three cancer cells surrounded by fibroblasts and cases 10-12 contained nine cancer cells surrounded by fibroblasts.


Results, Conclusions, and Discussions:: Our results show that there is fibroblast and ECM impact on the stresses experienced by cancer cells, as seen in Figure 1 and Figure 2. Our results show that Case 5 and Case 10, where ECM is very soft, tumor and its stroma experienced the highest stress regardless of the number of cancer cells. Our study reveals that a tumor stroma with stiffer stroma and softer ECM will exert the highest stress on the tumor tissue including cancer cells. Physical stresses exerted on cancer cells by their microenvironment have been shown to drive cells toward invasive phenotype by altering cells’ motility, proliferation, and apoptosis. Without a distinct identification of the components’ role in the resistance of nanoparticles’ penetration, all attempts to improve drug therapies’ success will remain out of reach. Our study was able to quantify impact of stromal components and their drug-induced alteration on stresses experienced by tumor tissue. This knowledge will assist us with identifying stromal components hindering the reach of nanoparticles deep into cancer cells.


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References (Optional): : Zhang, Y., Jiang, S., Hu, L., Huang, P., Wang, X., Li, J., Zhang, X., Nie, H., & Zhang, Z. (2019). Targeting the tumor microenvironment for pancreatic ductal adenocarcinoma therapy. Chinese Clinical Oncology, 8(2), 18. https://doi.org/10.21037/cco.2019.03.02