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Patient-derived cancer organoids (PDCOs) faithfully recapitulate the morphology and molecular profiles of the primary tumors from which they are derived, making them attractive preclinical models for predicting response to standard therapies, and thus, for use in drug development assays. Methods: Here, we investigate the hidden subclonal driver mutations in CRC PDCOs and the importance of individual PDCO-level heterogeneity when addressing PDCO treatment responses using changes in diameter and optical redox imaging. PDCO response is then compared to clinical response across a cohort of subjects with CRC receiving chemotherapy and\/or chemoradiation. Results: Change in diameter and optical redox imaging are more sensitive to detecting therapeutic response than endpoint and well-level measurements. These measurements accurately reflect clinical responses to chemotherapy and chemoradiation. Conclusions: Overall, these studies demonstrate the importance of PDCO-level methods of PDCO assessment and further establish PDCOs as powerful tools for drug response assessment and developmental therapeutic studies.<\/jats:p>","DOI":"10.3390\/cancers18101587","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T12:46:55Z","timestamp":1778676415000},"page":"1587","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Organoid Level Assessments of Human Primary and Metastatic Colorectal Cancer-Derived Organoids Predict Response to Chemotherapy and Chemoradiation"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1929-8121","authenticated-orcid":false,"given":"Shirsa","family":"Udgata","sequence":"first","affiliation":[{"name":"Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa E.","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amani A.","family":"Gillette","sequence":"additional","affiliation":[{"name":"Morgridge Institute for Research, Madison, WI 53715, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra G.","family":"Sorenson","sequence":"additional","affiliation":[{"name":"Morgridge Institute for Research, Madison, WI 53715, USA"},{"name":"Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremiah M.","family":"Riendeau","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rian","family":"Engeldinger","sequence":"additional","affiliation":[{"name":"Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordan N.","family":"Stoecker","sequence":"additional","affiliation":[{"name":"Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1932-0338","authenticated-orcid":false,"given":"Alyssa K.","family":"Steimle","sequence":"additional","affiliation":[{"name":"Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6335-7782","authenticated-orcid":false,"given":"Katherine A.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Devan","family":"Kittelson","sequence":"additional","affiliation":[{"name":"School of Computer, Data, and Information Sciences, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Isaak","sequence":"additional","affiliation":[{"name":"Morgridge Institute for Research, Madison, WI 53715, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1979-3955","authenticated-orcid":false,"given":"Jeremy D.","family":"Kratz","sequence":"additional","affiliation":[{"name":"Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5536-7761","authenticated-orcid":false,"given":"Evie","family":"Carchman","sequence":"additional","affiliation":[{"name":"University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA"},{"name":"Department of Surgery, William S. Middleton Memorial Veterans Hospital, Madison, WI 53705, USA"},{"name":"Department of Surgery, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randall","family":"Kimple","sequence":"additional","affiliation":[{"name":"University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA"},{"name":"Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9683-7378","authenticated-orcid":false,"given":"Cheri A.","family":"Pasch","sequence":"additional","affiliation":[{"name":"Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6320-7637","authenticated-orcid":false,"given":"Melissa C.","family":"Skala","sequence":"additional","affiliation":[{"name":"Morgridge Institute for Research, Madison, WI 53715, USA"},{"name":"Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dustin A.","family":"Deming","sequence":"additional","affiliation":[{"name":"Division of Hematology, Medical Oncology, and Palliative Care, Department of Medicine, University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI 53705, USA"},{"name":"University of Wisconsin Carbone Cancer Center, Madison, WI 53705, USA"},{"name":"McArdle Laboratory for Cancer Research, Department of Oncology, University of Wisconsin-Madison, Madison, WI 53705, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"ref_1","unstructured":"(2026, January 01). 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