Patient-derived organoids from metastatic colorectal cancer mirror tumor heterogeneity and predict patient survival and drug sensitivity

Kushtrim Kryeziu; Solveig K Klokkerud; Max Z Totland; Seyed H Moosavi; Henrik M Reims; Christian H Bergsland; Ina A Eilertsen; Jørgen Smeby; Kristoffer Lassen; Kristoffer K Lundesgaard; Trygve Syversveen; Morten Brændengen; Arild Nesbakken; Tormod K Guren; Sheraz Yaqub; Anita Sveen; Ragnhild A Lothe

doi:10.1016/j.xcrm.2026.102840

Patient-derived organoids from metastatic colorectal cancer mirror tumor heterogeneity and predict patient survival and drug sensitivity

Cell Rep Med. 2026 May 28:102840. doi: 10.1016/j.xcrm.2026.102840. Online ahead of print.

Authors

Kushtrim Kryeziu¹, Solveig K Klokkerud², Max Z Totland³, Seyed H Moosavi³, Henrik M Reims⁴, Christian H Bergsland³, Ina A Eilertsen³, Jørgen Smeby⁵, Kristoffer Lassen⁶, Kristoffer K Lundesgaard⁷, Trygve Syversveen⁷, Morten Brændengen⁸, Arild Nesbakken⁹, Tormod K Guren¹⁰, Sheraz Yaqub¹¹, Anita Sveen², Ragnhild A Lothe¹²

Affiliations

¹ Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway. Electronic address: kushtrim.kryeziu@ous-research.no.
² Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway.
³ Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway.
⁴ Department of Pathology, Oslo University Hospital, 0424 Oslo, Norway.
⁵ Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway; Department of Oncology, Oslo University Hospital, 0424 Oslo, Norway.
⁶ Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, 0424 Oslo, Norway; Institute of Clinical Medicine, UiT, The Arctic University of Norway, 9037 Tromsø, Norway.
⁷ Department of Radiology and Nuclear Medicine, Oslo University Hospital, 0424 Oslo, Norway.
⁸ Center for Cancer Medicine, Diakonhjemmet Hospital, 0370 Oslo, Norway.
⁹ Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway; Department of Gastrointestinal Surgery, Oslo University Hospital, 0424 Oslo, Norway.
¹⁰ Department of Oncology, Oslo University Hospital, 0424 Oslo, Norway.
¹¹ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway; Department of Hepato-Pancreato-Biliary Surgery, Oslo University Hospital, 0424 Oslo, Norway.
¹² Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital, 0424 Oslo, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0316 Oslo, Norway. Electronic address: r.a.lothe@medisin.uio.no.

PMID: 42208542
DOI: 10.1016/j.xcrm.2026.102840

Abstract

This study reports the pharmacogenomic analysis of tumor heterogeneity in a living biobank of 213 organoids derived from liver metastases of 102 patients with metastatic colorectal cancer. Successful organoid establishment reflects poorer chemosensitivity and patient survival. Molecular fidelity is confirmed in tumor-organoid pairs, and multi-modal phenotypes are defined based on organoid morphology. Cystic morphology associates with intestinal stem cell markers and greater drug sensitivity, while solid morphology is linked to markers of plasticity and aggressiveness. The potential to identify treatments less affected by tumor heterogeneity is supported by multi-lesion analyses in 65 patients. Clinical translation is illustrated in two prospective cases of pharmacogenomics-guided treatment, including successful chemotherapy rechallenge and targeted therapy resistance in cancers with low and high heterogeneity. All pharmacogenomic data are openly available as a functional oncology resource to support interpretation of ex vivo drug sensitivities into clinical "actionability."

Keywords: colorectal cancer; drug screening; functional oncology; heterogeneity; metastasis; molecular profiling; patient-derived organoids; pharmacogenomics.