Colorectal cancer (CRC) is among the three most commonly diagnosed cancers and one of the major causes of cancer-related morbidity and mortality. Despite the discovery of several predictive biomarkers, the 5-year survival rate for metastatic CRC is 15%. A hallmark of CRC is inter- and intra-patient heterogeneity. Moreover, chemo-radiation and targeted therapies often result in producing resistant clonal populations that are unresponsive to the ongoing treatment. Revealing a comprehensive landscape of primary and metastatic CRC cell states and their evolution during chemotherapy treatment provides the potential for tackling this problem. Patient-derived organoids are a valuable research tool to study the biology of the disease as well as for drug screening in personalized medicine. To that end, we have collected a biobank of 90 PDOs from primary and metastatic CRC patients, as well as autologous cancer-associated fibroblasts (CAFs) and tumor infiltrating lymphocytes (TILs). We have performed whole-exome sequencing (WES), scRNA-seq and bulk RNA-seq of original tumors and PDOs, with and without chemotherapy treatment. We have discovered specific and common transcriptional cell states within PDOs and tumors, as well as the multiple responses to treatment confirming high heterogeneity of CRC. Combination of these results with clinical data can predict new biomarkers. Maxim Norkin, Pablo Hernandez Lopez, Cinzia Esposito, George Ramzy, Mireia Andreu Carbo, Paloma Ordóñez-Morán, Patrycja Nowak-Sliwinska, Salvatore Piscuoglio, Krisztian Homicsko, Joerg Huelsken. Cell states and resistance in colorectal cancer: What can we learn from patient-derived organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4588.