Dina ElHarouni, Mushriq Al‐Jazrawe, Seongmin Choi, Merve Dede, Toshinori Hinoue, Sean A. Misek, Heeju Noh, Luca Zanella, Yuen-Yi Tseng, Hayley E. Francies, Dennis Plenker, Cindy W. Kyi, Julyann Pérez‐Mayoral, Megan J. Stine, Eva Tonsing-Carter, Rachana Agarwal, Jean C. Zenklusen, James M. Clinton, Jennifer M Shelton, Timothy R. Chu, William F. Hooper, Xavi Loinaz, Paula Keskula, Jordan Lee, Peyton C. Kuhlers, Bahar Tercan, Sylvia F. Boj, Alessandro Vasciaveo, Lorenzo Tomassoni, James M. Crawford, Shawna Walsh, Claire Sinai, Sonam Bhatia, Priya Sridevi, Hardik Patel, Maria Antonietta Cerone, The HCMI Network, Mubarak Akadri, Andrew J. Aguirre, Rehan Akbani, Majd Al Assaad, Wael Al Zoughbi, Alyaa Al‐Ibraheemi, Sahar Alkhairy, Nasser Altorki, Silvia Andreani, Joshua Araya, Gayatri Arun, Adel Atari, Stefanie Avril, Toby M. Baker, Metin Balaban, Michael Barnes, Caitlyn W. Barrett, Adam Bass, Alexandra E. Beck, Pascal Belleau, Christopher C. Benz, Bhavneet Bhinder, Shriram G. Bhosle, Julie Boerner, Jay Bowen, Lauren Brais, Bradley M. Broom, Catherine A. Bullen, Jonathan M. Buscaglia, Thomas Anthony Caiazza, Joshua C. Campbell, Evelyn Cantillo, Song Cao, Jared A. Capuano, Mauro A. A. Castro, Eloise Chapman‐Davis, Kami Chiotti, Toni K. Choueiri, Kin-Hoe Chow, Wolu Chukwu, Alanna J. Church, Hans Clevers, Catherine Clinton, Isidro Cortés‐Ciriano, Daniel B. Costa, Gregory M. Cote, Brian D. Crompton, Sabrina D’Agosto, Simona Dalin, Melissa Davis, Frederik De Smet, Rebecca Deasy, Mimoun Delmar, Paula Denoya, Astrid Deschênes, Li Ding, Elizabeth R. Duffy, Ruvimbo Dzvurumi, Kenneth Eng, Jose Espejo Valle-Inclán, Bishoy M. Faltas, Michelle Feenstra, Idhaliz Flores
Abstract The development of new therapeutics and the validation of pathogenetic cancer mechanisms require representative laboratory models 1,2 . However, existing collections represent only a fraction of the diversity observed in human cancer 2–4 . Recent technologies have enabled efficient in vitro model derivation (for example, tumour organoids) 5 . However, whether these maintain essential properties of patient tumours during long-term expansion has not been systematically investigated. Here we present results of a large-scale international programme—the Human Cancer Models Initiative—which involved the generation of a resource of 665 next-generation models from 2,780 donors with 25 cancer types and integrated tumour–model whole genome, exome, methylome and transcriptome analyses. The resource provides 522 models with comprehensive clinical data, 153 models of rare cancers and 71 models from participants with non-European ancestry. Analyses of 421 matched tumour–model pairs reveal high genetic (97.8%) and epigenetic (95%) concordance and define correlates of model discordance. Single-nucleus RNA sequencing of tumour–model pairs reveals subsets of models in which culture conditions significantly influence cell states. Finally, we characterize model preservation of extrachromosomal DNA and post-treatment mutational signatures to provide opportunities to study therapeutic resistance. This model repository is being made available to the community—including multimodal molecular profiling, clinical information and integrative software tools—thus providing a valuable resource for preclinical investigation of cancer pathogenesis and treatment response.