2. Academic Validation
  3. Patient-derived organoids across cancers reveal conserved tumor heterogeneity and actionable therapeutic vulnerabilities

Patient-derived organoids across cancers reveal conserved tumor heterogeneity and actionable therapeutic vulnerabilities

  • Sci Adv. 2026 Jun 26;12(26):eadz3351. doi: 10.1126/sciadv.adz3351.
Hui-Hsuan Kuo 1,  Bhavneet Bhinder 1 2,  Hamza N Gokozan 3,  Kathryn Gorski 1 3,  Pooja Chandra 1 3,  Jyothi Manohar 1,  Daniela Guevara 1,  John Otilano 1,  Jenna Moyer 1,  Marvel Tranquille 1,  Sarah Ackermann 1,  Jared Capuano 1,  Cynthia Cheung 1,  Thomas A Caiazza 1,  Phoebe L Reuben 1,  Anastasia Murray Tsomides 1,  Adriana Irizarry 1,  Michael Sigouros 1,  David Wilkes 1,  Abigail King 1,  Troy Kane 1,  Majd Al Assaad 1 3,  Wael Al Zoughbi 1 3,  Kentaro Ohara 1 3,  Joonghoon Auh 1,  Peter Waltman 1 2,  Florencia P Madorsky Rowdo 1,  Enrique Podaza 1,  Valerie Gallegos 1,  John Nguyen 1,  Raehash Shah 1,  Manish Shah 1,  Allyson Ocean 1,  Douglas Scherr 4,  Nasser Altorki 5,  Melissa Frey 6,  Ana M Molina 7,  Lisa Newman 1,  Vivan Bea 8 9,  Eloise Chapman-Davis 1,  Marcus D Goncalves 7,  Ashish Saxena 1,  Parul J Shukla 8,  Kevin Holcomb 6,  Rachel Simmons 1,  Scott Tagawa 1,  Jonathan H Zippin 1 10,  Evelyn Cantillo 1,  Rohit Chandwani 8 11,  Melissa Davis 1,  Kelly Garrett 8,  Pashtoon M Kasi 1,  Jennifer Marti 1,  David Nanus 12,  Jones T Nauseef,  Elizabeth Popa 1,  Momin T Siddiqui 3,  Alicia Alonso 1,  Cora N Sternberg 1,  Bishoy M Faltas 1,  Olivier Elemento 1 2 13,  Juan Miguel Mosquera 1 3,  Andrea Sboner 1 2 14,  M Laura Martin 1
Affiliations

Affiliations

  • 1 Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
  • 2 Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10021, USA.
  • 3 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY USA 10065.
  • 4 Department of Urology, Weill Cornell Medicine, New York, NY 10065 USA.
  • 5 Department of Cardiothoracic Surgery, Weill Cornell Medicine, New York, NY 10065 USA.
  • 6 Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10065, USA.
  • 7 Department of Medicine, Weill Cornell Medicine, New York, NY 10065 USA.
  • 8 Department of Surgery, Weill Cornell Medicine, New York, NY 10065 USA.
  • 9 NewYork-Presbyterian Weill Cornell Brooklyn Methodist Hospital, Brooklyn, NY 11215 USA.
  • 10 Department of Dermatology, Weill Cornell Medicine, New York, NY 10021, USA.
  • 11 Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY 10065, USA.
  • 12 Division of Hematology and Oncology, Department of Medicine, Weill Cornell Medicine, New York, NY 10065 USA.
  • 13 Department of Physiology, Biophysics and Systems Biology, Weill Cornell Medicine, New York, NY 10021, USA.
  • 14 Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA.
PMID: 42361179 DOI: 10.1126/sciadv.adz3351
Abstract

We developed a pan-cancer patient-derived Organoid (PDO) platform comprising 220 PDOs from 191 patients across 15 Cancer types to advance functional precision oncology. Comprehensive characterization demonstrated high fidelity to parent tumors, with 93% histopathology concordance, 80% median genomic concordance for driver mutations, and a 0.85 median gene expression correlation. Expression profiles remained largely stable over 10 passages, ensuring reproducibility for long-term screening. Clonality analysis showed that 85% of dominant tumor clones were preserved, with genomic concordance directly reflecting clonal similarity. Even PDOs with lower concordance retained key oncogenic drivers, validating their utility as disease models. Functional assays revealed that 58% of PDOs from patients ineligible for US Food and Drug Administration-approved poly(adenosine 5'-diphosphate-ribose) polymerase inhibitors were sensitive to talazoparib, linked to DNA damage repair alterations. Furthermore, combination screens identified agents that overcome resistance, particularly in TP53-mutant models. Our platform enables the investigation of targeted therapies and molecular drivers of drug sensitivity, providing translational insights for personalized treatment beyond current biomarker guidelines.

Figures
Products