An integrated computational model of the bone microenvironment in bone-metastatic prostate cancer.
Bone metastasis will impact most men with advanced prostate cancer. The vicious cycle of bone degradation and formation driven by metastatic prostate cells in bone yields factors that drive cancer growth. Mechanistic insights into this vicious cycle have suggested new therapeutic opportunities, but complex temporal and cellular interactions in the bone microenvironment make drug development challenging. We have integrated biologic and computational approaches to generate a hybrid cellular automata model of normal bone matrix homeostasis and the prostate cancer-bone microenvironment. The model accurately reproduces the basic multicellular unit bone coupling process, such that introduction of a single prostate cancer cell yields a vicious cycle similar in cellular composition and pathophysiology to models of prostate-to-bone metastasis. Notably, the model revealed distinct phases of osteolytic and osteogenic activity, a critical role for mesenchymal stromal cells in osteogenesis, and temporal changes in cellular composition. To evaluate the robustness of the model, we assessed the effect of established bisphosphonate and anti-RANKL therapies on bone metastases. At approximately 100% efficacy, bisphosphonates inhibited cancer progression while, in contrast with clinical observations in humans, anti-RANKL therapy fully eradicated metastases. Reducing anti-RANKL yielded clinically similar results, suggesting that better targeting or dosing could improve patient survival. Our work establishes a computational model that can be tailored for rapid assessment of experimental therapies and delivery of precision medicine to patients with prostate cancer with bone metastases.
Authors' Affiliations: Departments of Integrated Mathematical Oncology and Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
Arturo
A
Araujo
Leah M
LM
Cook
Conor C
CC
Lynch
David
D
Basanta
D001859:Bone Neoplasms / Q000378:metabolism / Q000556:secondary*; D001842:Bone and Bones / Q000473:pathology; D002460:Cell Line; D002465:Cell Movement; D003198:Computer Simulation; D006801:Humans; D008297:Male; D008954:Models, Biological; D010006:Osteoblasts / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D059016:Tumor Microenvironment
D016212:Transforming Growth Factor beta