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

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.

Authors

Institutions

Publication Details

Journal
Science Advances
Published
2026-06-26
DOI
https://doi.org/10.1126/sciadv.adz3351
Primary Topic
Cancer Cells and Metastasis
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

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

Troy Kane, Cora Nanette Sternberg, Phoebe L. Reuben, Scott T. Tagawa et al.
Science Advances
Cancer Cells and Metastasis
article

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

Troy Kane, Cora Nanette Sternberg, Phoebe L. Reuben, Scott T. Tagawa, Ana M. Molina, Jyothi Manohar, Marcus DaSilva Goncalves, Valerie Gallegos, Kathryn Gorski, Anastasia Tsomides, Lisa A. Newman, Majd Al Assaad, Jones T. Nauseef, Michael Sigouros, Florencia P. Madorsky Rowdo, Joonghoon Auh, Bhavneet Bhinder, Parul J. Shukla, Adriana Irizarry, Pooja Chandra, M. Laura Martín, Rohit Chandwani, Evelyn Cantillo, R M Simmons, Bishoy M. Faltas, Kentaro Ohara, Sarah E. Ackermann, Melissa Kristen Frey, Nasser K. Altorki, John Nguyen, Hamza N. Gokozan, Juan Miguel Mosquera, Andrea Sboner, Alicia Alonso, Allyson J. Ocean, Olivier Elemento, Douglas Scherr, Wael Al Zoughbi, Hui–Hsuan Kuo, Momin T. Siddiqui, Pashtoon Murtaza Kasi, David Wilkes, Marvel Tranquille, Jonathan Hale Zippin, Eloise Chapman‐Davis, Daniela E. Guevara, Manish A. Shah, John Otilano, Cynthia Cheung, Jennifer Marti, Thomas Anthony Caiazza, Elizabeth Popa, Kelly Garrett, Enrique Podaza, Jenna Moyer, Abigail King, Ashish Saxena, Melissa Davis, Kevin Holcomb, Vivan Bea, David Nanus, Jared Capuano, Peter Waltman, Raehash Shah
article en

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.

Science AdvancesVol. 12(26)
NewYork–Presbyterian Brooklyn Methodist Hospital (US), Cornell University (US), Weill Cornell Medicine (US)
National Cancer Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, DOD Prostate Cancer Research Program
Openalex Percentile: Top 8%
Cancer Cells and Metastasis
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.