TY - JOUR
T1 - Patient-derived pancreatic tumour organoids identify therapeutic responses to oncolytic adenoviruses
AU - Raimondi, Giulia
AU - Mato-Berciano, Ana
AU - Pascual-Sabater, Silvia
AU - Rovira-Rigau, Maria
AU - Cuatrecasas, Miriam
AU - Fondevila, Constantino
AU - Sánchez-Cabús, Santiago
AU - Begthel, Harry
AU - Boj, Sylvia F
AU - Clevers, Hans
AU - Fillat, Cristina
N1 - Funding Information:
GR and MRR are recipients of an FPI predoctoral contract ( BES-2015-071612 and BES-2012-053726 respectively) from MINECO , and AM was recipient of an FPU predoctoral contract from Ministry of Education, Spain. This work was supported by grants to CF from the Spanish Ministry of Economia y Competitividad BIO2014-57716-C2-R , BIO2017-89754-C2-2R with partial support from the Generalitat de Catalunya SGR17/861 . CIBERER and CIBERehd are initiatives of the ISCIII. The CF group was partially financed by the Instituto de Salud Carlos III ( IIS10/00014 ) and co-financed by Fondo Europeo de Desarrollo Regional (FEDER); it also acknowledges the support of COST Action BM1204 EUPancreas and the Spanish Adenovirus Network (AdenoNet, BIO2015-68990-REDT ).
Funding Information:
We thank Jordi Camps and Elena Asensio for the help with organoid karyotyping. This work was developed at the Centro Esther Koplowitz, Barcelona, Spain. We are indebted to the Banc de Tumors-Biobank core facility of the Hospital-Clínic-IDIBAPS for technical help (work supported by the Xarxa de Bancs de Tumors de Catalunya - XBTC). We also acknowledge the support of CERCA Programme/Generalitat de Catalunya. GR and MRR are recipients of an FPI predoctoral contract (BES-2015-071612 and BES-2012-053726 respectively) from MINECO, and AM was recipient of an FPU predoctoral contract from Ministry of Education, Spain. This work was supported by grants to CF from the Spanish Ministry of Economia y Competitividad BIO2014-57716-C2-R, BIO2017-89754-C2-2R with partial support from the Generalitat de Catalunya SGR17/861. CIBERER and CIBERehd are initiatives of the ISCIII. The CF group was partially financed by the Instituto de Salud Carlos III (IIS10/00014) and co-financed by Fondo Europeo de Desarrollo Regional (FEDER); it also acknowledges the support of COST Action BM1204 EUPancreas and the Spanish Adenovirus Network (AdenoNet, BIO2015-68990-REDT). The funders had no role in study design, data collection, interpretation, or the decision to submit the work for publication, CF and GR conceived and designed the experiments. GR conducted most of the in vitro and in vivo experiments. MR-R contributed with the generation of adenoviral genomes. AM-B established organoids cultures in the lab. SB trained AM-B and helped to establish organoids generation. SB and HC provided some organoid samples. SP helped with organoid karyotyping and characterization. MC and HB helped with histological analysis. CF and SS-C provided surgical specimens. CF supervised the project and wrote the manuscript, with input from all other authors. HC designed experiments and revised the manuscript.
Publisher Copyright:
© 2020 The Author(s)
PY - 2020/6
Y1 - 2020/6
N2 - BACKGROUND: Pancreatic patient-derived organoids (PDOs) are a well-established model for studying pancreatic ductal adenocarcinoma (PDAC) carcinogenesis and are potential predictors of clinical responses to chemotherapy. Oncolytic virotherapy is envisioned as a novel treatment modality for pancreatic cancer, and candidate viruses are being tested in clinical trials. Here, we explore the feasibility of using PDOs as a screening platform for the oncolytic adenovirus (OA) response.METHODS: Organoids were established from healthy pancreas and PDAC tissues and assessed for infectivity, oncoselectivity, and patient-dependent sensitivity to OA. Antitumour effects were studied in vivo in organoid xenografts. Further evaluation of oncolytic responses was conducted in organoids derived from orthotopic models or metastastic tissues.FINDINGS: Oncolytic adenoviruses display good selectivity, with replication only in organoids derived from PDAC tumours. Furthermore, responses of PDOs to a set of OAs reveal individual differences in cytotoxicity as well as in synergism with standard chemotherapy. Adenoviral cytotoxicity in PDOs is predictive of antitumour efficacy in a subcutaneous xenograft setting. Organoids from orthotopic tumours and metastases in nude mice mirror the viral preference of PDOs, indicating that PDO sensitivity to OAs could be informative about responses in both primary tumours and metastatic foci.INTERPRETATION: Our data imply that pancreatic PDOs can serve as predictive tools for screening for sensitivity to OA.
AB - BACKGROUND: Pancreatic patient-derived organoids (PDOs) are a well-established model for studying pancreatic ductal adenocarcinoma (PDAC) carcinogenesis and are potential predictors of clinical responses to chemotherapy. Oncolytic virotherapy is envisioned as a novel treatment modality for pancreatic cancer, and candidate viruses are being tested in clinical trials. Here, we explore the feasibility of using PDOs as a screening platform for the oncolytic adenovirus (OA) response.METHODS: Organoids were established from healthy pancreas and PDAC tissues and assessed for infectivity, oncoselectivity, and patient-dependent sensitivity to OA. Antitumour effects were studied in vivo in organoid xenografts. Further evaluation of oncolytic responses was conducted in organoids derived from orthotopic models or metastastic tissues.FINDINGS: Oncolytic adenoviruses display good selectivity, with replication only in organoids derived from PDAC tumours. Furthermore, responses of PDOs to a set of OAs reveal individual differences in cytotoxicity as well as in synergism with standard chemotherapy. Adenoviral cytotoxicity in PDOs is predictive of antitumour efficacy in a subcutaneous xenograft setting. Organoids from orthotopic tumours and metastases in nude mice mirror the viral preference of PDOs, indicating that PDO sensitivity to OAs could be informative about responses in both primary tumours and metastatic foci.INTERPRETATION: Our data imply that pancreatic PDOs can serve as predictive tools for screening for sensitivity to OA.
KW - Oncolytic adenovirus (OA)
KW - Orthotopic tumours
KW - Pancreatic ductal adenocarcinoma (PDAC)
KW - Patient-derived organoids (PDO)
UR - http://www.scopus.com/inward/record.url?scp=85084967875&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2020.102786
DO - 10.1016/j.ebiom.2020.102786
M3 - Article
C2 - 32460166
SN - 2352-3964
VL - 56
SP - 1
EP - 13
JO - EBioMedicine
JF - EBioMedicine
M1 - 102786
ER -