A comprehensive PDX gastric cancer collection captures cancer cell–intrinsic transcriptional MSI traits

Simona Corso, Claudio Isella, Sara E. Bellomo, Maria Apicella, Stefania Durando, Cristina Migliore, Stefano Ughetto, Laura D'Errico, Silvia Menegon, Daniel Moya-Rull, Marilisa Cargnelutti, Tânia Capelôa, Daniela Conticelli, Jessica Giordano, Tiziana Venesio, Antonella Balsamo, Caterina Marchio, Maurizio Degiuli, Rossella Reddavid, Uberto FumagalliStefano de Pascale, Giovanni Sgroi, Emanuele Rausa, Gian Luca Baiocchi, Sarah Molfino, Filippo Pietrantonio, Federica Morano, Salvatore Siena, Andrea Sartore-Bianchi, Maria Bencivenga, Valentina Mengardo, Riccardo Rosati, Daniele Marrelli, Paolo Morgagni, Stefano Rausei, Giovanni Pallabazzer, Michele de Simone, Dario Ribero, Silvia Marsoni, Antonino Sottile, Enzo Medico, Paola Cassoni, Anna Sapino, Eirini Pectasides, Aaron R. Thorner, Anwesha Nag, Samantha D. Drinan, Bruce M. Wollison, Adam J. Bass, Silvia Giordano

Research output: Contribution to journalArticle

Abstract

Gastric cancer is the world's third leading cause of cancer mortality. In spite of significant therapeutic improvements, the clinical outcome for patients with advanced gastric cancer is poor; thus, the identification and validation of novel targets is extremely important from a clinical point of view. We generated a wide, multilevel platform of gastric cancer models, comprising 100 patient-derived xenografts (PDX), primary cell lines, and organoids. Samples were classified according to their histology, microsatellite stability, Epstein–Barr virus status, and molecular profile. This PDX platform is the widest in an academic institution, and it includes all the gastric cancer histologic and molecular types identified by The Cancer Genome Atlas. PDX histopathologic features were consistent with those of patients' primary tumors and were maintained throughout passages in mice. Factors modulating grafting rate were histology, TNM stage, copy number gain of tyrosine kinases/KRAS genes, and microsatellite stability status. PDX and PDX-derived cells/organoids demonstrated potential usefulness to study targeted therapy response. Finally, PDX transcriptomic analysis identified a cancer cell–intrinsic microsatellite instability (MSI) signature, which was efficiently exported to gastric cancer, allowing the identification, among microsatellite stable (MSS) patients, of a subset of MSI-like tumors with common molecular aspects and significant better prognosis. In conclusion, we generated a wide gastric cancer PDX platform, whose exploitation will help identify and validate novel "druggable" targets and optimize therapeutic strategies. Moreover, transcriptomic analysis of gastric cancer PDXs allowed the identification of a cancer cell–intrinsic MSI signature, recognizing a subset of MSS patients with MSI transcriptional traits, endowed with better prognosis.

Original languageEnglish
Pages (from-to)5884-5896
Number of pages13
JournalCancer Research
Volume79
Issue number22
DOIs
Publication statusPublished - Nov 15 2019

Fingerprint

Microsatellite Instability
Heterografts
Stomach Neoplasms
Neoplasms
Microsatellite Repeats
Organoids
Histology
Atlases
Protein-Tyrosine Kinases
Therapeutics
Genome

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A comprehensive PDX gastric cancer collection captures cancer cell–intrinsic transcriptional MSI traits. / Corso, Simona; Isella, Claudio; Bellomo, Sara E.; Apicella, Maria; Durando, Stefania; Migliore, Cristina; Ughetto, Stefano; D'Errico, Laura; Menegon, Silvia; Moya-Rull, Daniel; Cargnelutti, Marilisa; Capelôa, Tânia; Conticelli, Daniela; Giordano, Jessica; Venesio, Tiziana; Balsamo, Antonella; Marchio, Caterina; Degiuli, Maurizio; Reddavid, Rossella; Fumagalli, Uberto; de Pascale, Stefano; Sgroi, Giovanni; Rausa, Emanuele; Baiocchi, Gian Luca; Molfino, Sarah; Pietrantonio, Filippo; Morano, Federica; Siena, Salvatore; Sartore-Bianchi, Andrea; Bencivenga, Maria; Mengardo, Valentina; Rosati, Riccardo; Marrelli, Daniele; Morgagni, Paolo; Rausei, Stefano; Pallabazzer, Giovanni; de Simone, Michele; Ribero, Dario; Marsoni, Silvia; Sottile, Antonino; Medico, Enzo; Cassoni, Paola; Sapino, Anna; Pectasides, Eirini; Thorner, Aaron R.; Nag, Anwesha; Drinan, Samantha D.; Wollison, Bruce M.; Bass, Adam J.; Giordano, Silvia.

In: Cancer Research, Vol. 79, No. 22, 15.11.2019, p. 5884-5896.

Research output: Contribution to journalArticle

Corso, S, Isella, C, Bellomo, SE, Apicella, M, Durando, S, Migliore, C, Ughetto, S, D'Errico, L, Menegon, S, Moya-Rull, D, Cargnelutti, M, Capelôa, T, Conticelli, D, Giordano, J, Venesio, T, Balsamo, A, Marchio, C, Degiuli, M, Reddavid, R, Fumagalli, U, de Pascale, S, Sgroi, G, Rausa, E, Baiocchi, GL, Molfino, S, Pietrantonio, F, Morano, F, Siena, S, Sartore-Bianchi, A, Bencivenga, M, Mengardo, V, Rosati, R, Marrelli, D, Morgagni, P, Rausei, S, Pallabazzer, G, de Simone, M, Ribero, D, Marsoni, S, Sottile, A, Medico, E, Cassoni, P, Sapino, A, Pectasides, E, Thorner, AR, Nag, A, Drinan, SD, Wollison, BM, Bass, AJ & Giordano, S 2019, 'A comprehensive PDX gastric cancer collection captures cancer cell–intrinsic transcriptional MSI traits', Cancer Research, vol. 79, no. 22, pp. 5884-5896. https://doi.org/10.1158/0008-5472.CAN-19-1166
Corso, Simona ; Isella, Claudio ; Bellomo, Sara E. ; Apicella, Maria ; Durando, Stefania ; Migliore, Cristina ; Ughetto, Stefano ; D'Errico, Laura ; Menegon, Silvia ; Moya-Rull, Daniel ; Cargnelutti, Marilisa ; Capelôa, Tânia ; Conticelli, Daniela ; Giordano, Jessica ; Venesio, Tiziana ; Balsamo, Antonella ; Marchio, Caterina ; Degiuli, Maurizio ; Reddavid, Rossella ; Fumagalli, Uberto ; de Pascale, Stefano ; Sgroi, Giovanni ; Rausa, Emanuele ; Baiocchi, Gian Luca ; Molfino, Sarah ; Pietrantonio, Filippo ; Morano, Federica ; Siena, Salvatore ; Sartore-Bianchi, Andrea ; Bencivenga, Maria ; Mengardo, Valentina ; Rosati, Riccardo ; Marrelli, Daniele ; Morgagni, Paolo ; Rausei, Stefano ; Pallabazzer, Giovanni ; de Simone, Michele ; Ribero, Dario ; Marsoni, Silvia ; Sottile, Antonino ; Medico, Enzo ; Cassoni, Paola ; Sapino, Anna ; Pectasides, Eirini ; Thorner, Aaron R. ; Nag, Anwesha ; Drinan, Samantha D. ; Wollison, Bruce M. ; Bass, Adam J. ; Giordano, Silvia. / A comprehensive PDX gastric cancer collection captures cancer cell–intrinsic transcriptional MSI traits. In: Cancer Research. 2019 ; Vol. 79, No. 22. pp. 5884-5896.
@article{ef582a1f7ad244cdab204d91a88a1bd3,
title = "A comprehensive PDX gastric cancer collection captures cancer cell–intrinsic transcriptional MSI traits",
abstract = "Gastric cancer is the world's third leading cause of cancer mortality. In spite of significant therapeutic improvements, the clinical outcome for patients with advanced gastric cancer is poor; thus, the identification and validation of novel targets is extremely important from a clinical point of view. We generated a wide, multilevel platform of gastric cancer models, comprising 100 patient-derived xenografts (PDX), primary cell lines, and organoids. Samples were classified according to their histology, microsatellite stability, Epstein–Barr virus status, and molecular profile. This PDX platform is the widest in an academic institution, and it includes all the gastric cancer histologic and molecular types identified by The Cancer Genome Atlas. PDX histopathologic features were consistent with those of patients' primary tumors and were maintained throughout passages in mice. Factors modulating grafting rate were histology, TNM stage, copy number gain of tyrosine kinases/KRAS genes, and microsatellite stability status. PDX and PDX-derived cells/organoids demonstrated potential usefulness to study targeted therapy response. Finally, PDX transcriptomic analysis identified a cancer cell–intrinsic microsatellite instability (MSI) signature, which was efficiently exported to gastric cancer, allowing the identification, among microsatellite stable (MSS) patients, of a subset of MSI-like tumors with common molecular aspects and significant better prognosis. In conclusion, we generated a wide gastric cancer PDX platform, whose exploitation will help identify and validate novel {"}druggable{"} targets and optimize therapeutic strategies. Moreover, transcriptomic analysis of gastric cancer PDXs allowed the identification of a cancer cell–intrinsic MSI signature, recognizing a subset of MSS patients with MSI transcriptional traits, endowed with better prognosis.",
author = "Simona Corso and Claudio Isella and Bellomo, {Sara E.} and Maria Apicella and Stefania Durando and Cristina Migliore and Stefano Ughetto and Laura D'Errico and Silvia Menegon and Daniel Moya-Rull and Marilisa Cargnelutti and T{\^a}nia Capel{\^o}a and Daniela Conticelli and Jessica Giordano and Tiziana Venesio and Antonella Balsamo and Caterina Marchio and Maurizio Degiuli and Rossella Reddavid and Uberto Fumagalli and {de Pascale}, Stefano and Giovanni Sgroi and Emanuele Rausa and Baiocchi, {Gian Luca} and Sarah Molfino and Filippo Pietrantonio and Federica Morano and Salvatore Siena and Andrea Sartore-Bianchi and Maria Bencivenga and Valentina Mengardo and Riccardo Rosati and Daniele Marrelli and Paolo Morgagni and Stefano Rausei and Giovanni Pallabazzer and {de Simone}, Michele and Dario Ribero and Silvia Marsoni and Antonino Sottile and Enzo Medico and Paola Cassoni and Anna Sapino and Eirini Pectasides and Thorner, {Aaron R.} and Anwesha Nag and Drinan, {Samantha D.} and Wollison, {Bruce M.} and Bass, {Adam J.} and Silvia Giordano",
year = "2019",
month = "11",
day = "15",
doi = "10.1158/0008-5472.CAN-19-1166",
language = "English",
volume = "79",
pages = "5884--5896",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "22",

}

TY - JOUR

T1 - A comprehensive PDX gastric cancer collection captures cancer cell–intrinsic transcriptional MSI traits

AU - Corso, Simona

AU - Isella, Claudio

AU - Bellomo, Sara E.

AU - Apicella, Maria

AU - Durando, Stefania

AU - Migliore, Cristina

AU - Ughetto, Stefano

AU - D'Errico, Laura

AU - Menegon, Silvia

AU - Moya-Rull, Daniel

AU - Cargnelutti, Marilisa

AU - Capelôa, Tânia

AU - Conticelli, Daniela

AU - Giordano, Jessica

AU - Venesio, Tiziana

AU - Balsamo, Antonella

AU - Marchio, Caterina

AU - Degiuli, Maurizio

AU - Reddavid, Rossella

AU - Fumagalli, Uberto

AU - de Pascale, Stefano

AU - Sgroi, Giovanni

AU - Rausa, Emanuele

AU - Baiocchi, Gian Luca

AU - Molfino, Sarah

AU - Pietrantonio, Filippo

AU - Morano, Federica

AU - Siena, Salvatore

AU - Sartore-Bianchi, Andrea

AU - Bencivenga, Maria

AU - Mengardo, Valentina

AU - Rosati, Riccardo

AU - Marrelli, Daniele

AU - Morgagni, Paolo

AU - Rausei, Stefano

AU - Pallabazzer, Giovanni

AU - de Simone, Michele

AU - Ribero, Dario

AU - Marsoni, Silvia

AU - Sottile, Antonino

AU - Medico, Enzo

AU - Cassoni, Paola

AU - Sapino, Anna

AU - Pectasides, Eirini

AU - Thorner, Aaron R.

AU - Nag, Anwesha

AU - Drinan, Samantha D.

AU - Wollison, Bruce M.

AU - Bass, Adam J.

AU - Giordano, Silvia

PY - 2019/11/15

Y1 - 2019/11/15

N2 - Gastric cancer is the world's third leading cause of cancer mortality. In spite of significant therapeutic improvements, the clinical outcome for patients with advanced gastric cancer is poor; thus, the identification and validation of novel targets is extremely important from a clinical point of view. We generated a wide, multilevel platform of gastric cancer models, comprising 100 patient-derived xenografts (PDX), primary cell lines, and organoids. Samples were classified according to their histology, microsatellite stability, Epstein–Barr virus status, and molecular profile. This PDX platform is the widest in an academic institution, and it includes all the gastric cancer histologic and molecular types identified by The Cancer Genome Atlas. PDX histopathologic features were consistent with those of patients' primary tumors and were maintained throughout passages in mice. Factors modulating grafting rate were histology, TNM stage, copy number gain of tyrosine kinases/KRAS genes, and microsatellite stability status. PDX and PDX-derived cells/organoids demonstrated potential usefulness to study targeted therapy response. Finally, PDX transcriptomic analysis identified a cancer cell–intrinsic microsatellite instability (MSI) signature, which was efficiently exported to gastric cancer, allowing the identification, among microsatellite stable (MSS) patients, of a subset of MSI-like tumors with common molecular aspects and significant better prognosis. In conclusion, we generated a wide gastric cancer PDX platform, whose exploitation will help identify and validate novel "druggable" targets and optimize therapeutic strategies. Moreover, transcriptomic analysis of gastric cancer PDXs allowed the identification of a cancer cell–intrinsic MSI signature, recognizing a subset of MSS patients with MSI transcriptional traits, endowed with better prognosis.

AB - Gastric cancer is the world's third leading cause of cancer mortality. In spite of significant therapeutic improvements, the clinical outcome for patients with advanced gastric cancer is poor; thus, the identification and validation of novel targets is extremely important from a clinical point of view. We generated a wide, multilevel platform of gastric cancer models, comprising 100 patient-derived xenografts (PDX), primary cell lines, and organoids. Samples were classified according to their histology, microsatellite stability, Epstein–Barr virus status, and molecular profile. This PDX platform is the widest in an academic institution, and it includes all the gastric cancer histologic and molecular types identified by The Cancer Genome Atlas. PDX histopathologic features were consistent with those of patients' primary tumors and were maintained throughout passages in mice. Factors modulating grafting rate were histology, TNM stage, copy number gain of tyrosine kinases/KRAS genes, and microsatellite stability status. PDX and PDX-derived cells/organoids demonstrated potential usefulness to study targeted therapy response. Finally, PDX transcriptomic analysis identified a cancer cell–intrinsic microsatellite instability (MSI) signature, which was efficiently exported to gastric cancer, allowing the identification, among microsatellite stable (MSS) patients, of a subset of MSI-like tumors with common molecular aspects and significant better prognosis. In conclusion, we generated a wide gastric cancer PDX platform, whose exploitation will help identify and validate novel "druggable" targets and optimize therapeutic strategies. Moreover, transcriptomic analysis of gastric cancer PDXs allowed the identification of a cancer cell–intrinsic MSI signature, recognizing a subset of MSS patients with MSI transcriptional traits, endowed with better prognosis.

UR - http://www.scopus.com/inward/record.url?scp=85075062195&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075062195&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-19-1166

DO - 10.1158/0008-5472.CAN-19-1166

M3 - Article

C2 - 31585941

AN - SCOPUS:85075062195

VL - 79

SP - 5884

EP - 5896

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 22

ER -