TY - JOUR
T1 - Human organoids share structural and genetic features with primary pancreatic adenocarcinoma tumors
AU - Romero-Calvo, Isabel
AU - Weber, Christopher R.
AU - Ray, Mohana
AU - Brown, Miguel
AU - Kirby, Kori
AU - Nandi, Rajib K.
AU - Long, Tiha M.
AU - Sparrow, Samantha M.
AU - Ugolkov, Andrey
AU - Qiang, Wenan
AU - Zhang, Yilin
AU - Brunetti, Tonya
AU - Kindler, Hedy
AU - Segal, Jeremy P.
AU - Rzhetsky, Andrey
AU - Mazar, Andrew P.
AU - Buschmann, Mary M.
AU - Weichselbaum, Ralph
AU - Roggin, Kevin
AU - White, Kevin P.
N1 - Funding Information:
We would like to thank Drs. Mitchell Posner and Jeffrey Matthews for allowing us to consent patients in their clinics and for providing study guidance; Dr. William Dale for providing direction in human subjects protocol development and clinical research operations; Margaret Eber, Megan Flanagan, and Teresa Barry for consenting patients and coordinating biospecimens; Marlin Amy Halder for assistance with DNA sequencing studies; Shuang Qin Zhang for consulting on therapeutic treatment of PDX models; Bradley Long and Sabah Kadri for assistance with DNA sequencing and data interpretation; and to the Friends of Jack Karp and Barbara Turf for their generous financial support of this work. I. Romero-Calvo, C.R. Weber, M. Ray, M.M. Buschmann, K. Kirby, S.M. Sparrow, T. Brunetti, and M.M. Buschmann's work, as well as all reagents and clinical research expenses, was provided by the Friends of Jack Karp and Barbara Turf. H. Kindler is partially supported by NIH U10CA180836. The work of A. Ugolkov and W. Qiang was partially supported by NCI U54CA193419 and CCSG P30 CA060553.
Publisher Copyright:
2018 American Association for Cancer Research.
PY - 2019/1/1
Y1 - 2019/1/1
N2 - 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.
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.
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U2 - 10.1158/1541-7786.MCR-18-0531
DO - 10.1158/1541-7786.MCR-18-0531
M3 - Article
C2 - 30171177
AN - SCOPUS:85059501235
VL - 17
SP - 70
EP - 83
JO - Cell Growth and Differentiation
JF - Cell Growth and Differentiation
SN - 1541-7786
IS - 1
ER -