Establishing patient-derived tumor organoids of bone metastasis from lung adenocarcinoma reveals the transcriptomic changes underlying denosumab treatment

Abstract

Patient-derived tumor organoids (PDTOs) models have been widely used to investigate the response of primary cancer tissues to anti-cancer agents. Nonetheless, only few case study tried to establish PDTOs and test treatment response based on bone metastasis (BoM) tissues. Fresh BoM tissues were obtained from lung cancer (LC) patients who underwent spinal metastatic tumor surgery for PDTOs culture. Morphology of LC-BoM-PDTOs were characterized during the process: they were high-efficient in self-assembly and regeneration, forming mature 3D-multicellular structures in 2-3 weeks. To be more specific, organoids of BoM derived from patients with EGFR mutation tended to be follicular conglomeration and resembled "a bunch of grapes", while organoids of BoM derived from patients without driver gene mutation were featured with full sphere and "a ripe sunflower". PDTOs of BoM retained good consistencies of HE morphology and immunohistochemical markers expression with their parental BoM tissues. Down-regulation of receptor activator of nuclear factor kappa-B ligand (RANKL) expression in LC-BoM-PDTOs after in vitro DMAb intervention was associated with earlier clinical ossification efficacy of DMAb on BoM (median time: 5 vs. 8 months, P = 0.049). Accordingly, BoM-PDTOs can be expected to be a preferred model for predicting treatment response of bone metastatic tumors, considering its high-efficient expansion and good biological consistency with parental bone tumor tissues.

Keywords: Bone metastasis; Denosumab; Lung cancer; Organoids.