The tumor microenvironment plays an important role on tumor drug sensitivity; thus the incorporation of microenvironment features on cancer models is expected to improve their predictive power. Patient-Derived Explants (PDE) have been proposed as potential models; however there are typically short term cultures. Our goal was to improve culture longevity and vitality to evaluate efficacy of repeated drug treatments, taking advantage of dynamic culture systems.

Fresh ovarian and colorectal cancer (OC and CRC, respectively) samples were mechanically dissociated into PDE and cultured in dynamic conditions. The cell population dynamics, cell viability and proliferation were assessed by a panel of readouts, e.g. immunohistochemistry, rezasurin reduction capacity, PDE concentration and morphometric measurements.

To this date, 20 OC and 18 CRC were successfully cultured as PDE, retaining the original tumor architecture and main cellular components: epithelial cells, fibroblasts and immune cells for at least 28 days (OC) or 7 days (CRC). OC samples included all main malignant ovarian carcinoma types (endometrioid, clear cell, mucinous, undifferentiated, serous low and high grade) and CRC samples included adenocarcinomas' stage I to IIIB. Epithelial, stromal and immune cells were maintained for the duration of OC PDE cultures For CRC, epithelial neoplastic cells were preserved, in some cases up to 3 months, and stromal components were progressively lost along culture. The status of the original tumors was preserved for the majority of cases in terms of driver mutations of CRC and of microsatellite stability. To validate the model, OC-PDE cultures were exposed to cyclic chemotherapy treatment (paclitaxel, carboplatin and the combination of both). After two cycles (1 cycle of 24h per week), PDE showed low cellularity and cell viability, compared to untreated controls, reflecting the action of the compounds.

Altogether, we established PDE dynamic cultures in which tumor architecture and heterogeneity is preserved, replicating the original tumor features. Moreover, we demonstrated the feasibility of performing ex vivo drug efficacy studies employing cyclic drug exposure regimens.

This work was partially supported by FCT (iNOVA4Health – UID/Multi/04462/2013, PD/BD/105768/2014 and SFRH/BD/52208/2013).

Citation Format: Sofia Abreu, Fernanda Silva, Sara da Mata, Teresa F. Mendes, Marta Teixeira, Bruno Filipe, Sónia Morgado, Inês Francisco, Marta Mesquita, Cristina Albuquerque, Paula Chaves, Ricardo Fonseca, Jacinta Serpa, Isadora Rosa, Ana Felix, Erwin R. Boghaert, Vítor E. Santo, Catarina Brito. Preservation of tumor architecture and heterogeneity in long-term cultures of patient-derived explants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1048.