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- Title
The impact of the spatial heterogeneity of resistant cells and fibroblasts on treatment response.
- Authors
M A, Masud; Kim, Jae-Young; Pan, Cheol-Ho; Kim, Eunjung
- Abstract
A long-standing practice in the treatment of cancer is that of hitting hard with the maximum tolerated dose to eradicate tumors. This continuous therapy, however, selects for resistant cells, leading to the failure of the treatment. A different type of treatment strategy, adaptive therapy, has recently been shown to have a degree of success in both preclinical xenograft experiments and clinical trials. Adaptive therapy is used to maintain a tumor's volume by exploiting the competition between drug-sensitive and drug-resistant cells with minimum effective drug doses or timed drug holidays. To further understand the role of competition in the outcomes of adaptive therapy, we developed a 2D on-lattice agent-based model. Our simulations show that the superiority of the adaptive strategy over continuous therapy depends on the local competition shaped by the spatial distribution of resistant cells. Intratumor competition can also be affected by fibroblasts, which produce microenvironmental factors that promote cancer cell growth. To this end, we simulated the impact of different fibroblast distributions on treatment outcomes. As a proof of principle, we focused on five types of distribution of fibroblasts characterized by different locations, shapes, and orientations of the fibroblast region with respect to the resistant cells. Our simulation shows that the spatial architecture of fibroblasts modulates tumor progression in both continuous and adaptive therapy. Finally, as a proof of concept, we simulated the outcomes of adaptive therapy of a virtual patient with four metastatic sites composed of different spatial distributions of fibroblasts and drug-resistant cell populations. Our simulation highlights the importance of undetected metastatic lesions on adaptive therapy outcomes. Author summary: Tumors are composed of different cancer cells with varying degrees of treatment resistance, which compete for a shared resource. Adaptive therapy exploits this competition. The paradigm employs patient-specific on and off treatment schedules or lower doses to permit a significant number of drug-sensitive cells to survive. The surviving sensitive cells can suppress the growth of drug-resistant cells via intratumor competition. This competition can be modulated by the spatial structure of tumors. For example, resistant cell configuration, carrying capacity, or migration rate may change local spatial competition between drug-resistant cells or between drug-sensitive and drug resistant cells. In addition, the presence of growth factors produced by stromal cells such as fibroblasts promotes the proliferation of cells, enhancing the competition. To understand the impact of forenamed factors on the outcomes of adaptive therapy, we developed a computational model, 2D on-lattice agent-based model. Our findings show that the spatial factors regulate the local competition and may hold back the benefit of adaptive therapy. Further, the impact of fibroblast depends on the respective positioning of fibroblast to the resistant cells. Finally, we simulated the outcomes of adaptive therapy on multiple metastatic lesions of mixed spatial configuration on a virtual patient. In the simulation, we highlight the importance of undetected metastatic lesions on therapy outcomes.
- Subjects
FIBROBLASTS; CANCER cell growth; CELL populations; SIMULATED patients; CANCER invasiveness; STROMAL cells
- Publication
PLoS Computational Biology, 2022, Vol 18, Issue 3, p1
- ISSN
1553-734X
- Publication type
Article
- DOI
10.1371/journal.pcbi.1009919