ABSTRACT
Patient-derived pancreatic ductal adenocarcinoma (PDAC) organoid systems show great promise for understanding the biological underpinnings of disease and advancing therapeutic precision medicine. Despite the increased use of organoids, the fidelity of molecular features, genetic heterogeneity, and drug response to the tumor of origin remain important unanswered questions limiting their utility. To address this gap in knowledge, we created primary tumor- and PDX-derived organoids, and 2D cultures for in-depth genomic and histopathological comparisons to the primary tumor. Histopathological features and PDAC representative protein markers showed strong concordance. DNA and RNA sequencing of single organoids revealed patient-specific genomic and transcriptomic consistency. Single-cell RNAseq demonstrated that organoids are primarily a clonal population. In drug response assays, organoids displayed patient-specific sensitivities. Additionally, we examined the in vivo PDX response to FOLFIRINOX and Gemcitabine/Abraxane treatments, which was recapitulated in vitro by organoids. The patient-specific molecular and histopathological fidelity of organoids indicate that they can be used to understand the etiology of the patient’s tumor and the differential response to therapies and suggests utility for predicting drug responses.
Footnotes
FINANCIAL SUPPORT IRC, CRW, MR, MMB, KK, SMS, TB, and MMB’s work, as well as all reagents and clinical research expenses, was provided by the Friends of Jack Karp and Barbara Turf. HK is partially supported by NIH U10CA180836. AU and WQ work was partially supported by NCI U54CA193419 and CCSG P30 CA060553.
CONFLICT OF INTEREST Kevin White, Andrey Ugolkov and Yilin Zhang are employees of Tempus labs; Andrew Mazar is the founder of Tactic Pharma, Pamdeca, Actuate Therapeutics, Lung Therapeutics, Inc, and Monopar Therapeutics; All other authors have nothing to disclose.