Agent-based modeling of the prostate tumor microenvironment uncovers spatial tumor growth constraints and immunomodulatory properties

Maisa N G van Genderen, Jeroen Kneppers, Anniek Zaalberg, Elise M Bekers, Andries M Bergman (Corresponding author), Wilbert Zwart (Corresponding author), Federica Eduati (Corresponding author)

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Abstract

Inhibiting androgen receptor (AR) signaling through androgen deprivation therapy (ADT) reduces prostate cancer (PCa) growth in virtually all patients, but response may be temporary, in which case resistance develops, ultimately leading to lethal castration-resistant prostate cancer (CRPC). The tumor microenvironment (TME) plays an important role in the development and progression of PCa. In addition to tumor cells, TME-resident macrophages and fibroblasts express AR and are therefore also affected by ADT. However, the interplay of different TME cell types in the development of CRPC remains largely unexplored. To understand the complex stochastic nature of cell-cell interactions, we created a PCa-specific agent-based model (PCABM) based on in vitro cell proliferation data. PCa cells, fibroblasts, "pro-inflammatory" M1-like and "pro-tumor" M2-like polarized macrophages are modeled as agents from a simple set of validated base assumptions. PCABM allows us to simulate the effect of ADT on the interplay between various prostate TME cell types. The resulting in vitro growth patterns mimic human PCa. Our PCABM can effectively model hormonal perturbations by ADT, in which PCABM suggests that CRPC arises in clusters of resistant cells, as is observed in multifocal PCa. In addition, fibroblasts compete for cellular space in the TME while simultaneously creating niches for tumor cells to proliferate in. Finally, PCABM predicts that ADT has immunomodulatory effects on macrophages that may enhance tumor survival. Taken together, these results suggest that AR plays a critical role in the cellular interplay and stochastic interactions in the TME that influence tumor cell behavior and CRPC development.

Original languageEnglish
Article number20
Number of pages13
Journalnpj Systems Biology and Applications
Volume10
Issue number1
DOIs
Publication statusPublished - 21 Feb 2024

Bibliographical note

© 2024. The Author(s).

Funding

We express gratitude to all members of the Zwart and Bergman lab, and members of the NKI Oncogenomics division for helpful scientific discussion. We would like to thank Margot Passier for testing the code. This work was supported by Prostate Cancer Foundation, Department of Defense, Oncode Institute and Alpe d’HuZes/ KWF Dutch Cancer Society.

FundersFunder number
KWF Dutch Cancer Society
Oncode Institute and Alpe d’HuZes
U.S. Department of Defense
Prostate Cancer Foundation

    Keywords

    • Male
    • Humans
    • Prostatic Neoplasms, Castration-Resistant/metabolism
    • Receptors, Androgen/metabolism
    • Prostate/pathology
    • Androgen Antagonists
    • Tumor Microenvironment
    • Systems Analysis

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