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<p>The development of new therapeutics and the validation of pathogenetic cancer mechanisms require representative laboratory models<sup><CitationRef CitationID="CR1">1</CitationRef>,<CitationRef CitationID="CR2">2</CitationRef></sup>. However, existing collections represent only a fraction of the diversity observed in human cancer<sup><CitationRef AdditionalCitationIDS="CR3" CitationID="CR2">2</CitationRef>–<CitationRef CitationID="CR4">4</CitationRef></sup>. Recent technologies have enabled efficient in vitro model derivation (for example, tumour organoids)<sup><CitationRef CitationID="CR5">5</CitationRef></sup>. 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.</p>

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A compendium of next-generation patient-derived models for diverse cancers

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年8月5日

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  • 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 Perez-Mayoral,
  • Megan J. Stine,
  • Eva Tonsing-Carter,
  • Rachana Agarwal,
  • Jean Claude Zenklusen,
  • James M. Clinton,
  • Jennifer M. Shelton,
  • Timothy R. Chu,
  • William F. Hooper,
  • Xavi Loinaz,
  • Paula Keskula,
  • Jordan Tagle,
  • 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,
  • 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 D. 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 Cortes-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 I. Denoya,
  • Astrid Deschênes,
  • Li Ding,
  • Elizabeth R. Duffy,
  • Ruvimbo Dzvurumi,
  • Kenneth Eng,
  • Jose Espejo Valle-Inclan,
  • Bishoy M. Faltas,
  • Michelle Feenstra,
  • Idhaliz Flores,
  • Sharon B. Fox,
  • Melissa K. Frey,
  • Marina Frimer,
  • Jack Geduldig,
  • Veerle Geurts,
  • Gad Getz,
  • James G. R. Gilbert,
  • Gary L. Goldberg,
  • Sara Goodwin,
  • Peter K. Gregersen,
  • Evan Grossman,
  • Akansha A. Gupta,
  • Amber N. Habowski,
  • William C. Hahn,
  • Peter Hammerman,
  • D. Neil Hayes,
  • David I. Heiman,
  • Elizabeth P. Henske,
  • Carmen Herranz-Ors,
  • Julian M. Hess,
  • Kevin Holcomb,
  • Andrew L. Hong,
  • Christine Hudson,
  • Victoria Hung,
  • Lora Iliev,
  • Katherine A. Janeway,
  • Julia O. Japo,
  • Grace Johnson,
  • Jihang Ju,
  • Troy J. Kane,
  • Samuel J. Klempner,
  • Melissa Kramer,
  • Anneke Kramm,
  • Alexander Krasnitz,
  • Shwetha V. Kumar,
  • Rita Teresa Lawlor,
  • Gwo-Shu Mary Lee,
  • Siyun Lee,
  • Hongyu Li,
  • Ellen Li,
  • Madison Liistro,
  • Jochen Lorch,
  • Carolina Lucchesi,
  • Claudio Luchini,
  • Seth Malinowski,
  • Jyothi Manohar,
  • Laura A. Martello,
  • Jennifer L. Marti,
  • M. Laura Martin,
  • R. Jay Mashl,
  • W. Richard McCombie,
  • Aaron K. McCormick,
  • Brian W. McSteen,
  • Christine N. Metz,
  • Ana Molina,
  • Juan Miguel Mosquera,
  • Jenna E. Moyer,
  • Anthony Murphy,
  • Payal Naik,
  • Indu Nair,
  • David M. Nanus,
  • Emon Nasajpour,
  • Jones T. Nauseef,
  • Lisa Newman,
  • Kimmie Ng,
  • Samuel Y. Ng,
  • Allyson Ocean,
  • Coyin Oh,
  • Kentaro Ohara,
  • Kadir Ozler,
  • Kila Panchot,
  • Nicole Pavao,
  • Antonio Pea,
  • Kristine Pelton,
  • Anson Peng,
  • Claudia K. Petritsch,
  • Payal Pradhan,
  • Sidharth V. Puram,
  • Meifang Qi,
  • Srivatsan Raghavan,
  • Benjamin J. Raphael,
  • David Requena,
  • Phoebe L. Reuben,
  • Esther Rheinbay,
  • Arvind Rishi,
  • Carmen Rios,
  • A. Gordon Robertson,
  • Peter Ronning,
  • Ashley R. Ruehr,
  • Suzanne Russo,
  • Andrea Ruzzenente,
  • Michael Ryan,
  • Roberto Salvia,
  • David Sandak,
  • Shahab Sarmashghi,
  • Ashish Saxena,
  • Abeer Sayeed,
  • Parul Shukla,
  • Andrea Sboner,
  • Aldo Scarpa,
  • Douglas S. Scherr,
  • Francesco Serafini,
  • Hui Shen,
  • Aniket Shetty,
  • Manish Shah,
  • Ewa Sicinska,
  • Sabina Signoretti,
  • Michael Sigouros,
  • Amber R. Smith,
  • Yizhe Song,
  • Yingduo Song,
  • Conrado T. Soria,
  • Cora Sternberg,
  • Joshua M. Stuart,
  • Cheryl L. Thompson,
  • Natalie Tsang,
  • Aviad Tsherniak,
  • Cristina Valente,
  • Sara Valentini,
  • Johan H. van Es,
  • Barbara Van Hare,
  • Shivakumar Vignesh,
  • Jayne Vogelzang,
  • Abigail Ward,
  • Fiona Watkinson,
  • Sophie Webster,
  • John N. Weinstein,
  • David M. Weinstock,
  • Michael C. Wendl,
  • Brian M. Wolpin,
  • Christopher K. Wong,
  • Maoxin Wu,
  • Matthew A. Wyczalkowski,
  • William P. Wysocki,
  • Alexa Yeagley,
  • Smitha Yerrum,
  • Charles H. Yoon,
  • Jenny Yuan,
  • Brian Yueh,
  • Zhenyu Zhang,
  • Kyle Ellrott,
  • Calvin J. Kuo,
  • Olivier Elemento,
  • Semir Beyaz,
  • Vincenzo Corbo,
  • David L. Spector,
  • Rameen Beroukhim,
  • Martin L. Ferguson,
  • Andrew D. Cherniack,
  • Peter W. Laird,
  • Nicolas Robine,
  • Andrew McPherson,
  • Katherine A. Hoadley,
  • Mathew J. Garnett,
  • David A. Tuveson,
  • Andrea Califano,
  • Paul T. Spellman,
  • Keith L. Ligon,
  • Daniela S. Gerhard,
  • Louis M. Staudt,
  • Jesse S. Boehm

摘要

The development of new therapeutics and the validation of pathogenetic cancer mechanisms require representative laboratory models1,2. However, existing collections represent only a fraction of the diversity observed in human cancer2–4. 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.