Abstract 5120: Deciphering melanoma CTC signatures leading to immune escape and brain metastasis: The first MRI CTC xenograft model

Abstract

Abstract Melanoma brain metastasis (MBM) is a devastating disease which is diagnosed in up to 60% of melanoma patients and 80% of patients at autopsy. While microarray studies identified many genes differentially expressed between MBM and extracranial metastasis, magnetic resonance imaging (MRI) is the established technology to evaluate clinical MBM. Circulating Tumor Cells (CTCs) are “seeds” of fatal metastasis and smallest functional units of cancer. Defining mechanisms which regulate the spatial and temporal competence of patient-isolated CTCs driving MBM thus presents the opportunity to suppress its occurrence. Hypothesis is that MRI has fundamental translational relevance to validate preclinical CTC models and that MBM onset depends upon the absence or presence of human immune system cells (Hu-mice), and mice gender and age. We isolated CTCs from blood of primary/metastatic melanoma patients, and confirmed CTC detection by CellSearch࣪, Parsortix࣪, high-definition microscopy and RNA-Seq profiling. Second, we injected melanoma CTCs in immunodeficient but also immunocompetent xenografts (NBSGW female/male mice generated by multiple donors CD34+ cells), and assessed tumor progression by IVIS and MRI with parallel monitoring of CTC gene-specific transcriptional activation. Third, we discovered specific differences in number of CTCs/CTC clustering patterns and CTC signatures which were dependent upon MBM status. Quantitation of melanoma CTC-derived signatures enabled serial noninvasive monitoring of tumor burden. Lastly, we found that these differences and the occurrence, severity and spatial distribution of MBM highly depended from gender, age, and immunocompetency status of injected animals. Thus, by reporting the first MRI CTC xenograft model, its use for melanoma CTC interrogation can provide a platform for early monitoring of response to immunotherapeutic and/or targeted interventions in melanoma, and contribute to rational therapy applications, notably for MBM prediction or prevention. Citation Format: Tetiana Bowley, Dario Marchetti. Deciphering melanoma CTC signatures leading to immune escape and brain metastasis: The first MRI CTC xenograft model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5120.