Patient-derived extracellular matrix from decellularized high-grade serous ovarian carcinoma tissues as a biocompatible support for organoid growth

: High-grade serous ovarian cancer (HGSOC) is the most common clinically diagnosed ovarian cancer, often considered a fatal disease. Although current treatments appear to provide almost complete remission, the recurrence rate is still high. Here we present an innovative tissue engineering approach applied to HGSOC by combining patient-derived decellularized extracellular matrix (dECM) and patient-derived organoids (PDO), intending to provide a three-dimensional (3D) model useful to evaluate treatment response. By histology, immunohistochemistry, immunofluorescence, and second harmonic generation microscopy, we demonstrated that dECM maintains the structural environment of native tumoral tissue. Proteomic analysis performed on isolated dECM compared to the native tumor revealed a dominant set of functionally related proteins associated with ECM assembly, organization and morphology consistent with preservation of a tissue-specific niche for later PDO seeding and infiltration. In parallel, we established a protocol for the PDO derivation with an initiation efficiency of 83.3 %. We compared PDO with its native tumor counterpart using diagnostics markers with a concordance index of 100 % for CK7 and P16 and 66 % for P53mut, PAX8 and WT1. The IC50 concentrations of PDO treated with Paclitaxel and Paclitaxel plus Carboplatin resulted in 37.10 µM and 6.8 µM, respectively, after treatment. The dECM recellularized by injection with PDO, and treated with drugs displayed a reduced sensitivity to standard first-line chemotherapy. This 3D model could be a reliable preclinical patient-specific platform to bridge the gap between in vitro and in vivo drug testing assays. NOVELTY AND IMPACT STATEMENT: The novelty of this research lies in the fact that, for the first time, a three-dimensional preclinical model of ovarian cancer fully derived from the patient has been generated. The patient's decellularized extracellular matrix is capable of supporting the growth of organoids and produces a response to chemotherapy treatment that more closely resembles the actual doses used in vivo compared to organoids grown solely in commercial matrices. We hope that the presented model can have a useful impact in identifying the right drugs to treat patients, and avoiding unnecessary toxicity.