Patient-Derived Ovarian Cancer Organoids Mimic Clinical Response and Exhibit Heterogeneous Inter- and Intrapatient Drug Responses
Chris Jenske de Witte,
Jose Espejo Valle-Inclan,
Nizar Hami,
Kadi Lõhmussaar,
Oded Kopper,
Celien Philomena Henrieke Vreuls,
Geertruida Nellie Jonges,
Paul van Diest,
Luan Nguyen,
Hans Clevers,
Wigard Pieter Kloosterman,
Edwin Cuppen,
Hugo Johannes Gerhardus Snippert,
Ronald Peter Zweemer,
Petronella Oda Witteveen,
Ellen Stelloo
Affiliations
Chris Jenske de Witte
Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands
Jose Espejo Valle-Inclan
Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands
Nizar Hami
Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
Kadi Lõhmussaar
Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
Oded Kopper
Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
Celien Philomena Henrieke Vreuls
Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
Geertruida Nellie Jonges
Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
Paul van Diest
Department of Pathology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
Luan Nguyen
Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands
Hans Clevers
Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands; Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands
Wigard Pieter Kloosterman
Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
Edwin Cuppen
Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands; Hartwig Medical Foundation, Science Park 408, 1098 XH Amsterdam, the Netherlands
Hugo Johannes Gerhardus Snippert
Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands; Molecular Cancer Research, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands
Ronald Peter Zweemer
Division of Imaging and Oncology, Department of Gynecological Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
Petronella Oda Witteveen
Department of Medical Oncology, Cancer Center, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands
Ellen Stelloo
Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands; Oncode Institute, Jaarbeursplein 6, 3521 AL Utrecht, the Netherlands; Corresponding author
Summary: There remains an unmet need for preclinical models to enable personalized therapy for ovarian cancer (OC) patients. Here we evaluate the capacity of patient-derived organoids (PDOs) to predict clinical drug response and functional consequences of tumor heterogeneity. We included 36 whole-genome-characterized PDOs from 23 OC patients with known clinical histories. OC PDOs maintain the genomic features of the original tumor lesion and recapitulate patient response to neoadjuvant carboplatin/paclitaxel combination treatment. PDOs display inter- and intrapatient drug response heterogeneity to chemotherapy and targeted drugs, which can be partially explained by genetic aberrations. PDO drug screening identifies high responsiveness to at least one drug for 88% of patients. PDOs are valuable preclinical models that can provide insights into drug response for individual patients with OC, complementary to genetic testing. Generating PDOs of multiple tumor locations can improve clinical decision making and increase our knowledge of genetic and drug response heterogeneity.
