Abstract 4124: Patient-derived ex vivo models to test drug responses of disseminated cancer cells in various metastatic niches
Authors: Wöhrl Lukas , Botteron Catherine , Weidele Kathrin , Treitschke Steffi , Das Durdam , Werner-Klein Melanie , Hoffmann Martin , Gužvić Nataša Stojanović , Materna-Reichelt Silvia , Weber Florian , Engelmann Simon , Mayr Roman , Gužvić Miodrag , Haferkamp Sebastian , Seitz Stephan , Klein Christoph A. , Werno Christian 
Published: March 2024

Abstract
Metastases arise from disseminated cancer cells (DCCs) that often lodge to distant organs long before diagnosis of the primary tumor. Unfortunately, the efficacy of (neo-)adjuvant therapies against DCCs remains uncertain. Here, we harnessed novel patient-derived ex vivo models to identify promising candidate therapies targeting DCCs and explored the impact of the unique microenvironment of metastatic target organs on the phenotypes and drug responses of DCCs. We screened disaggregated lymph node (LN) or bone marrow (BM) samples from melanoma, breast, and bladder cancer patients without distant metastasis for the presence of DCCs. Then, we expanded DCCs in patient-derived xenografts, adherent cell culture, or three-dimensional culture. LN and BM suspensions were spiked with allogeneic and autologous tumor cells to unravel the impact of different metastatic niches on DCCs. Automated high-throughput microscopy of disaggregated patient LNs was used to evaluate drug effects on DCCs in the autologous microenvironment. We established 13 cell lines from melanoma DCCs, three organoid models from breast cancer DCCs, and two organoid models from bladder cancer DCCs. The origin of each model was confirmed by assessment of histomorphology, marker expression, and genetic profiles. We screened a comprehensive panel of chemotherapeutics, targeted drugs, and antibody-drug conjugates across these in vitro models, and thereby identified compounds with the potential to eradicate DCCs. We further found that the LN and BM microenvironments differentially affected phenotypes and drug responses of cancer cells particularly when immune modulating drugs were used. Of note, ex vivo drug testing, performed directly on LN suspensions containing DCCs, revealed candidate therapeutics within a time frame acceptable for personalized treatment decisions. In conclusion, we report that the microenvironment of the specific metastatic niche impacts DCC drug responsiveness. Employing DCC-derived in vitro models in drug response assays that include specific niches may help to develop (neo)-adjuvant, personalized therapies and to discover novel therapeutics against metastasis.
Citation Format: Lukas Wöhrl, Catherine Botteron, Kathrin Weidele, Steffi Treitschke, Durdam Das, Melanie Werner-Klein, Martin Hoffmann, Nataša Stojanović Gužvić, Silvia Materna-Reichelt, Florian Weber, Simon Engelmann, Roman Mayr, Miodrag Gužvić, Sebastian Haferkamp, Stephan Seitz, Christoph A. Klein, Christian Werno. Patient-derived ex vivo models to test drug responses of disseminated cancer cells in various metastatic niches [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4124.