RT Journal Article
SR Electronic
T1 Human Organoids Share Structural and Genetic Features with Primary Pancreatic Adenocarcinoma Tumors
JF Molecular Cancer Research
JO Mol Cancer Res
FD American Association for Cancer Research
SP 70
OP 83
DO 10.1158/1541-7786.MCR-18-0531
VO 17
IS 1
A1 Romero-Calvo, Isabel
A1 Weber, Christopher R.
A1 Ray, Mohana
A1 Brown, Miguel
A1 Kirby, Kori
A1 Nandi, Rajib K.
A1 Long, Tiha M.
A1 Sparrow, Samantha M.
A1 Ugolkov, Andrey
A1 Qiang, Wenan
A1 Zhang, Yilin
A1 Brunetti, Tonya
A1 Kindler, Hedy
A1 Segal, Jeremy P.
A1 Rzhetsky, Andrey
A1 Mazar, Andrew P.
A1 Buschmann, Mary M.
A1 Weichselbaum, Ralph
A1 Roggin, Kevin
A1 White, Kevin P.
YR 2019
UL http://mcr.aacrjournals.org/content/17/1/70.abstract
AB 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, primary tumor- and patient-derived xenograft (PDX)-derived organoids, and 2D cultures for in-depth genomic and histopathologic comparisons with the primary tumor were created. Histopathologic features and PDAC representative protein markers (e.g., claudin 4 and CA19-9) showed strong concordance. DNA- and RNA-sequencing (RNAseq) 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. In addition, the in vivo PDX response to FOLFIRINOX and gemcitabine/abraxane treatments were examined, which was recapitulated in vitro with organoids. This study has demonstrated that organoids are potentially invaluable for precision medicine as well as preclinical drug treatment studies because they maintain distinct patient phenotypes and respond differently to drug combinations and dosage.Implications: The patient-specific molecular and histopathologic 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.This article is featured in Highlights of This Issue, p. 1