Abstract
Original language | English |
---|---|
Pages (from-to) | 2083-2099.e9 |
Journal | Cancer cell |
Volume | 41 |
Issue number | 12 |
DOIs | |
Publication status | Published - 11 Dec 2023 |
Keywords
- biomarker
- cancer
- cell neuroendocrine carcinoma
- genomics
- growth factor depenencies
- intra-tumor heterogeneity
- lung cancer
- neuroendocrine tumorlarge
- organoids
- tumor evolution
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In: Cancer cell, Vol. 41, No. 12, 11.12.2023, p. 2083-2099.e9.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites
AU - Dayton, Talya L.
AU - Alcala, Nicolas
AU - Moonen, Laura
AU - den Hartigh, Lisanne
AU - Geurts, Veerle
AU - Mangiante, Lise
AU - Lap, Lisa
AU - Dost, Antonella F. M.
AU - Beumer, Joep
AU - Levy, Sonja
AU - van Leeuwaarde, Rachel S.
AU - Hackeng, Wenzel M.
AU - Samsom, Kris
AU - Voegele, Catherine
AU - Sexton-Oates, Alexandra
AU - Begthel, Harry
AU - Korving, Jeroen
AU - Hillen, Lisa
AU - Brosens, Lodewijk A. A.
AU - Lantuejoul, Sylvie
AU - Jaksani, Sridevi
AU - Kok, Niels F. M.
AU - Hartemink, Koen J.
AU - Klomp, Houke M.
AU - Borel Rinkes, Inne H. M.
AU - Dingemans, Anne-Marie
AU - Valk, Gerlof D.
AU - Vriens, Menno R.
AU - Buikhuisen, Wieneke
AU - van den Berg, José
AU - Tesselaar, Margot
AU - Derks, Jules
AU - Speel, Ernst Jan
AU - Foll, Matthieu
AU - Fernández-Cuesta, Lynnette
AU - Clevers, Hans
N1 - Funding Information: We thank all patients participating in this study as well as the teams approaching patients for consent and collecting tissue, including the Utrecht Portal for Organoid Technology (U-PORT; UMC Utrecht)—in particular Anneta Brousali, Jorieke Salij, Onno Kranenburg, and Renate Bezemer—and the clinical studies department at the NKI—in particular Jan-Nico Ridderbos. We are grateful to the Foundation Hubrecht Organoid Technology (HUB) and employees, including Patrick de Kort and Calinda Dingenouts, for their work supporting ethical regulatory affairs. We thank Utrecht Sequencing for bulk RNA sequencing services. We thank the editor and two anonymous reviewers for their comments and suggestions. We acknowledge financial support from the NET Research Foundation (2017 Petersen Accelerator Award to H.C.), Worldwide Cancer Research (2020 grant round to L.F.-C), NET Research Foundation (2019 Investigator Award to L.F.-C), French National Cancer Institute (INCa, PRT-K 2017 to L.F.-C. and M.F.), Ligue Nationale contre le Cancer (fellowship to L.Ma.), and the Dutch Cancer Foundation (grant number 10956, 2017, to E.J.S.). T.L.D. was supported by an EMBO long-term fellowship (ALTF-21-2017) and a Marie Skłodowska-Curie IF grant 797966 – PNECtumor. A.D. was supported by Accelerate Lung Regeneration Consortium grant BREATH 12.0.18.002 of the Lung Foundation Netherlands (to H.C.). The Oncode Institute is supported by the Dutch Cancer Society . Funding Information: We thank all patients participating in this study as well as the teams approaching patients for consent and collecting tissue, including the Utrecht Portal for Organoid Technology (U-PORT; UMC Utrecht)—in particular Anneta Brousali, Jorieke Salij, Onno Kranenburg, and Renate Bezemer—and the clinical studies department at the NKI—in particular Jan-Nico Ridderbos. We are grateful to the Foundation Hubrecht Organoid Technology (HUB) and employees, including Patrick de Kort and Calinda Dingenouts, for their work supporting ethical regulatory affairs. We thank Utrecht Sequencing for bulk RNA sequencing services. We thank the editor and two anonymous reviewers for their comments and suggestions. We acknowledge financial support from the NET Research Foundation (2017 Petersen Accelerator Award to H.C.), Worldwide Cancer Research (2020 grant round to L.F.-C), NET Research Foundation (2019 Investigator Award to L.F.-C), French National Cancer Institute (INCa, PRT-K 2017 to L.F.-C. and M.F.), Ligue Nationale contre le Cancer (fellowship to L.Ma.), and the Dutch Cancer Foundation (grant number 10956, 2017, to E.J.S.). T.L.D. was supported by an EMBO long-term fellowship (ALTF-21-2017) and a Marie Skłodowska-Curie IF grant 797966 – PNECtumor. A.D. was supported by Accelerate Lung Regeneration Consortium grant BREATH 12.0.18.002 of the Lung Foundation Netherlands (to H.C.). The Oncode Institute is supported by the Dutch Cancer Society. The results shown here are in part based upon data generated by the Rare Cancers Genomics initiative (www.rarecancersgenomics.com) and the TCGA Research Network (https://www.cancer.gov/tcga). We thank E. Reckzeh and Y.M. Soto-Feliciano for critically reading the manuscript and R. Millen for assistance with drug sensitivity assays. T.L.D. N.A. L.F.-C. and H.C. designed and conceived the study. T.L.D. generated the organoids. T.L.D. L.dH. and V.G. cultured and curated organoid lines and performed related experiments. T.L.D. V.G. and A.F.M.D. performed drug sensitivity assays. V.G. and J.V. performed xenotransplantation experiments. J.B. and J.D. contributed to study design. L.Mo. L.L. W.M.H. and L.B. performed histological stains, acquired images, and performed related analyses. N.A. processed the sequencing data. T.L.D. and N.A. analyzed and interpreted the data and generated figures. J.V. and H.B. embedded organoids and cut slides for immunohistochemistry staining. S.J. generated novel reagents. L.H. L.B. and S.L. performed pathological assessments. N.A. C.V. and A.vH. curated sequencing data. L.Ma. contributed to analysis of sequencing data. L.Mo. J.D. S.L. R.S.vL. L.B. and K.S. provided samples, curated patient data, and provided pathology information. N.F.M.K. K.J.H. H.M.K. I.H.M.B.R. A.-M.D. G.V. M.R.V. W.B. J.vdB. and M.T. provided clinical feedback. J.D. M.R.V. G.D.V. J.vdB. and M.T. coordinated clinical aspects of the study. L.F.-C. and M.F. supervised N.A. L.Ma. C.V. and A.S.-O. E.-J.S. and J.D. supervised L.Mo. and L.L. H.C. directed the study. Where authors are identified as personnel of the International Agency for Research on Cancer/World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/World Health Organization. H.C.’s full disclosure is given at https://www.uu.nl/staff/JCClevers/. H.C. is inventor of several patents related to organoid technology, cofounder of Xilis Inc. and currently an employee of Roche, Basel. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: © 2023 The Authors
PY - 2023/12/11
Y1 - 2023/12/11
N2 - Neuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Treatment options for patients with NENs are limited, in part due to lack of accurate models. We establish patient-derived tumor organoids (PDTOs) from pulmonary NETs and derive PDTOs from an understudied subtype of NEC, large cell neuroendocrine carcinoma (LCNEC), arising from multiple body sites. PDTOs maintain the gene expression patterns, intra-tumoral heterogeneity, and evolutionary processes of parental tumors. Through hypothesis-driven drug sensitivity analyses, we identify ASCL1 as a potential biomarker for response of LCNEC to treatment with BCL-2 inhibitors. Additionally, we discover a dependency on EGF in pulmonary NET PDTOs. Consistent with these findings, we find that, in an independent cohort, approximately 50% of pulmonary NETs express EGFR. This study identifies an actionable vulnerability for a subset of pulmonary NETs, emphasizing the utility of these PDTO models.
AB - Neuroendocrine neoplasms (NENs) comprise well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Treatment options for patients with NENs are limited, in part due to lack of accurate models. We establish patient-derived tumor organoids (PDTOs) from pulmonary NETs and derive PDTOs from an understudied subtype of NEC, large cell neuroendocrine carcinoma (LCNEC), arising from multiple body sites. PDTOs maintain the gene expression patterns, intra-tumoral heterogeneity, and evolutionary processes of parental tumors. Through hypothesis-driven drug sensitivity analyses, we identify ASCL1 as a potential biomarker for response of LCNEC to treatment with BCL-2 inhibitors. Additionally, we discover a dependency on EGF in pulmonary NET PDTOs. Consistent with these findings, we find that, in an independent cohort, approximately 50% of pulmonary NETs express EGFR. This study identifies an actionable vulnerability for a subset of pulmonary NETs, emphasizing the utility of these PDTO models.
KW - biomarker
KW - cancer
KW - cell neuroendocrine carcinoma
KW - genomics
KW - growth factor depenencies
KW - intra-tumor heterogeneity
KW - lung cancer
KW - neuroendocrine tumorlarge
KW - organoids
KW - tumor evolution
UR - http://www.scopus.com/inward/record.url?scp=85179067544&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.ccell.2023.11.007
DO - https://doi.org/10.1016/j.ccell.2023.11.007
M3 - Article
C2 - 38086335
SN - 1535-6108
VL - 41
SP - 2083-2099.e9
JO - Cancer cell
JF - Cancer cell
IS - 12
ER -