Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites

Talya L Dayton; Nicolas Alcala; Laura Moonen; Lisanne den Hartigh; Veerle Geurts; Lise Mangiante; Lisa Lap; Antonella F M Dost; Joep Beumer; Sonja Levy; Rachel S van Leeuwaarde; Wenzel M Hackeng; Kris Samsom; Catherine Voegele; Alexandra Sexton-Oates; Harry Begthel; Jeroen Korving; Lisa Hillen; Lodewijk A A Brosens; Sylvie Lantuejoul; Sridevi Jaksani; Niels F M Kok; Koen J Hartemink; Houke M Klomp; Inne H M Borel Rinkes; Anne-Marie Dingemans; Gerlof D Valk; Menno R Vriens; Wieneke Buikhuisen; José van den Berg; Margot Tesselaar; Jules Derks; Ernst Jan Speel; Matthieu Foll; Lynnette Fernández-Cuesta; Hans Clevers

doi:10.1016/j.ccell.2023.11.007

Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites

Talya L Dayton^*, Nicolas Alcala, Laura Moonen, Lisanne den Hartigh, Veerle Geurts, Lise Mangiante, Lisa Lap, Antonella F M Dost, Joep Beumer, Sonja Levy, Rachel S van Leeuwaarde, Wenzel M Hackeng, Kris Samsom, Catherine Voegele, Alexandra Sexton-Oates, Harry Begthel, Jeroen Korving, Lisa Hillen, Lodewijk A A Brosens, Sylvie LantuejoulSridevi Jaksani, Niels F M Kok, Koen J Hartemink, Houke M Klomp, Inne H M Borel Rinkes, Anne-Marie Dingemans, Gerlof D Valk, Menno R Vriens, Wieneke Buikhuisen, José van den Berg, Margot Tesselaar, Jules Derks, Ernst Jan Speel, Matthieu Foll, Lynnette Fernández-Cuesta^*, Hans Clevers^*

^*Corresponding author for this work

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Abstract

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.

Original language	English
Pages (from-to)	2083-2099.e9
Journal	Cancer Cell
Volume	41
Issue number	12
DOIs	https://doi.org/10.1016/j.ccell.2023.11.007
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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Dayton, T. L., Alcala, N., Moonen, L., den Hartigh, L., Geurts, V., Mangiante, L., Lap, L., Dost, A. F. M., Beumer, J., Levy, S., van Leeuwaarde, R. S., Hackeng, W. M., Samsom, K., Voegele, C., Sexton-Oates, A., Begthel, H., Korving, J., Hillen, L., Brosens, L. A. A., ... Clevers, H. (2023). Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites. Cancer Cell, 41(12), 2083-2099.e9. https://doi.org/10.1016/j.ccell.2023.11.007

@article{a85f81a483e04cebbeffa86ab6d04dbe,

title = "Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites",

abstract = "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.",

keywords = "biomarker, cancer, cell neuroendocrine carcinoma, genomics, growth factor depenencies, intra-tumor heterogeneity, lung cancer, neuroendocrine tumorlarge, organoids, tumor evolution",

author = "Dayton, {Talya L} and Nicolas Alcala and Laura Moonen and {den Hartigh}, Lisanne and Veerle Geurts and Lise Mangiante and Lisa Lap and Dost, {Antonella F M} and Joep Beumer and Sonja Levy and {van Leeuwaarde}, {Rachel S} and Hackeng, {Wenzel M} and Kris Samsom and Catherine Voegele and Alexandra Sexton-Oates and Harry Begthel and Jeroen Korving and Lisa Hillen and Brosens, {Lodewijk A A} and Sylvie Lantuejoul and Sridevi Jaksani and Kok, {Niels F M} and Hartemink, {Koen J} and Klomp, {Houke M} and {Borel Rinkes}, {Inne H M} and Anne-Marie Dingemans and Valk, {Gerlof D} and Vriens, {Menno R} and Wieneke Buikhuisen and {van den Berg}, Jos{\'e} and Margot Tesselaar and Jules Derks and Speel, {Ernst Jan} and Matthieu Foll and Lynnette Fern{\'a}ndez-Cuesta and Hans Clevers",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2023",

month = dec,

day = "11",

doi = "10.1016/j.ccell.2023.11.007",

language = "English",

volume = "41",

pages = "2083--2099.e9",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "12",

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Dayton, TL, Alcala, N, Moonen, L, den Hartigh, L, Geurts, V, Mangiante, L, Lap, L, Dost, AFM, Beumer, J, Levy, S, van Leeuwaarde, RS, Hackeng, WM, Samsom, K, Voegele, C, Sexton-Oates, A, Begthel, H, Korving, J, Hillen, L, Brosens, LAA, Lantuejoul, S, Jaksani, S, Kok, NFM, Hartemink, KJ, Klomp, HM, Borel Rinkes, IHM, Dingemans, A-M, Valk, GD , Vriens, MR, Buikhuisen, W, van den Berg, J, Tesselaar, M, Derks, J, Speel, EJ, Foll, M, Fernández-Cuesta, L & Clevers, H 2023, 'Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites', Cancer Cell, vol. 41, no. 12, pp. 2083-2099.e9. https://doi.org/10.1016/j.ccell.2023.11.007

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

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 - 10.1016/j.ccell.2023.11.007

DO - 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 -

Druggable growth dependencies and tumor evolution analysis in patient-derived organoids of neuroendocrine neoplasms from multiple body sites

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Keywords

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