Spatial biomarker discovery via interpretable semantic learning in histopathology
Cancer Cell, vol. 44, pp. 1605–1622.e7
Abstract
Spatial biomarkers are critical for precision oncology but remain challenging to systematically discover due to the complexity of whole-slide images. We present PathPrism, an interpretable AI framework for spatial biomarker discovery and virtual experimentation. Unlike black-box models, PathPrism encodes tissue architecture into pathologically informed spatial features, enabling transparent modeling of prognosis, molecular alterations, and therapy response. Applied to 7,000 patients with colorectal cancer across 11 cohorts, PathPrism uncovered hundreds of biomarkers predictive of survival, MSI, BRAF, and TP53 mutations, and stratified chemotherapy benefit in stage II/III disease. Building on these interpretable findings, PathPrism uses large language models as auxiliary tools to generate hypotheses grounded in spatial semantics. We further introduce VirtualWSI, a platform for semantic perturbation within an interpretable spatial biomarker atlas. PathPrism provides a scalable and interpretable framework for spatial biomarker discovery.
Authors 40
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Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden · Tsinghua University
Affiliation as printed
Else Kroener Fresenius Center for Digital Health, Faculty of Medicine, TUD Dresden University of Technology, Dresden, Germany; State Key Laboratory of Precision Measurement Technology and Instruments, Department of Precision Instrument, Tsinghua University, Beijing 100084, China
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University of Electronic Science and Technology of China · Sichuan Cancer Hospital
Affiliation as printed
Department of Thoracic Surgery, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, University of Electronic Science and Technology of China (UESTC), Chengdu, China
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University of Augsburg · Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden
Affiliation as printed
Else Kroener Fresenius Center for Digital Health, Faculty of Medicine, TUD Dresden University of Technology, Dresden, Germany; Pathology, Faculty of Medicine, University of Augsburg, Augsburg, Germany; Bavarian Center for Cancer Research, BZKF, Augsburg, Germany
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Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden
Affiliation as printed
Else Kroener Fresenius Center for Digital Health, Faculty of Medicine, TUD Dresden University of Technology, Dresden, Germany
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Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden
Affiliation as printed
Else Kroener Fresenius Center for Digital Health, Faculty of Medicine, TUD Dresden University of Technology, Dresden, Germany
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Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden
Affiliation as printed
Else Kroener Fresenius Center for Digital Health, Faculty of Medicine, TUD Dresden University of Technology, Dresden, Germany
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Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden
Affiliation as printed
Else Kroener Fresenius Center for Digital Health, Faculty of Medicine, TUD Dresden University of Technology, Dresden, Germany
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Helmholtz-Zentrum Dresden-Rossendorf · University Hospital Carl Gustav Carus · Nationales Centrum für Tumorerkrankungen Dresden · Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden
Affiliation as printed
Else Kroener Fresenius Center for Digital Health, Faculty of Medicine, TUD Dresden University of Technology, Dresden, Germany; Department for Visceral, Thoracic and Vascular Surgery, University Hospital and Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany; National Center for Tumor Diseases Dresden (NCT/UCC), A Partnership Between DKFZ, Faculty of Medicine and University Hospital Carl Gustav Carus, TU Dresden University of Technology, and Helmholtz-Zentrum Dresden - Rossendorf (HZDR), Dresden, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden
Affiliation as printed
Else Kroener Fresenius Center for Digital Health, Faculty of Medicine, TUD Dresden University of Technology, Dresden, Germany
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German Cancer Research Center · Universitätsklinikum Aachen · Else Kröner Fresenius Center for Digital Health · German Cancer Consortium (DKTK) Dresden · Technische Universität Dresden · RWTH Aachen University
Affiliation as printed
Else Kroener Fresenius Center for Digital Health, Faculty of Medicine, TUD Dresden University of Technology, Dresden, Germany; German Cancer Consortium (DKTK), Partner Site Dresden, German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Internal Medicine III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany
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Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden
Affiliation as printed
Else Kroener Fresenius Center for Digital Health, Faculty of Medicine, TUD Dresden University of Technology, Dresden, Germany
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Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden
Affiliation as printed
Else Kroener Fresenius Center for Digital Health, Faculty of Medicine, TUD Dresden University of Technology, Dresden, Germany
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Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden
Affiliation as printed
Else Kroener Fresenius Center for Digital Health, Faculty of Medicine, TUD Dresden University of Technology, Dresden, Germany
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Affiliation as printed
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
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Affiliation as printed
Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
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Affiliation as printed
Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA
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Affiliation as printed
Center for Cancer Research, Medical University of Vienna, Vienna, Austria
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Affiliation as printed
Center for Cancer Research, Medical University of Vienna, Vienna, Austria
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Centre international de recherche sur le cancer · Imperial College London
Affiliation as printed
Nutrition and Metabolism Branch, International Agency for Research on Cancer, World Health Organization, Lyon, France; Cancer Epidemiology and Prevention Research Unit, School of Public Health, Imperial College London, London, UK
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Affiliation as printed
Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA
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University of Washington · Fred Hutch Cancer Center
Affiliation as printed
Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA
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University of Washington · Fred Hutch Cancer Center
Affiliation as printed
Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA
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University of Washington · Fred Hutch Cancer Center
Affiliation as printed
Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA; Department of Epidemiology, University of Washington, Seattle, WA, USA
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Affiliation as printed
Pathology & Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
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Affiliation as printed
Pathology & Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
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Affiliation as printed
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Clinical Epidemiology of Early Cancer Detection, German Cancer Research Center (DKFZ), Heidelberg, Germany
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German Cancer Research Center · Deutsches Konsortium für Translationale Krebsforschung
Affiliation as printed
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Cancer Prevention Graduate School, German Cancer Research Center (DKFZ), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
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Affiliation as printed
Division of Clinical Epidemiology of Early Cancer Detection, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Affiliation as printed
School of Population Health, Faculty of Medicine and Health, UNSW Sydney, Kensington, Sydney, NSW, Australia
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Affiliation as printed
School of Medical Sciences, Faculty of Medicine and Health, UNSW Sydney, Sydney, NSW, Australia
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Affiliation as printed
Faculty of Medicine and Health, The University of Sydney, Camperdown, Sydney, NSW, Australia
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European University Cyprus · St. Luke's Hospital
Affiliation as printed
Department of Medical Oncology, St Luke's Clinic, Thessaloniki, Greece; European University Cyprus, Engomi, Cyprus
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Affiliation as printed
Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Thessaloniki, Greece
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Aristotle University of Thessaloniki
Affiliation as printed
Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Thessaloniki, Greece; Aristotle University of Thessaloniki, Thessaloniki, Greece
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Sorbonne Université · Assistance Publique – Hôpitaux de Paris · Hôpital Saint-Antoine
Affiliation as printed
Medical Oncology, Institut Universitaire de Cancérologie AP-HP Sorbonne Université - Hôpital Saint-Antoine, Paris, France
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Université Paris Cité · Assistance Publique – Hôpitaux de Paris · Hôpital Européen Georges-Pompidou
Affiliation as printed
Department of Gastroenterology and Digestive Oncology, European Georges Pompidou Hospital, Assistance Publique Hôpitaux de Paris, University of Paris Cité, 75015 Paris, France
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Université Paris-Saclay · Assistance Publique – Hôpitaux de Paris · Hôpital Ambroise-Paré · Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie
Affiliation as printed
Paris-Saclay University, Versailles SQY University, EA4340-BECCOH, Assistance Publique-Hôpitaux de Paris, Ambroise-Paré Hospital, Smart Imaging, Service de Pathologie, Boulogne, France
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Inserm · Sorbonne Université · Laboratoire d'Informatique Médicale et d'Ingénierie des Connaissances en e-Santé
Affiliation as printed
Sorbonne Université, LIMICS, INSERM UMRS 1142, Paris, France; Léon Bérard Comprehensive Cancer Center, Department of Pathology, Lyon, France
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Lingjie Kong corresponding
Affiliation as printed
State Key Laboratory of Precision Measurement Technology and Instruments, Department of Precision Instrument, Tsinghua University, Beijing 100084, China; IDG/McGovern Institute for Brain Research, Tsinghua University, Beijing, China. Electronic address: konglj@tsinghua.edu.cn
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Jakob Nikolas Kather corresponding
University of Leeds · Heidelberg University · University Hospital Heidelberg · National Center for Tumor Diseases · Else Kröner Fresenius Center for Digital Health · Technische Universität Dresden
Affiliation as printed
Else Kroener Fresenius Center for Digital Health, Faculty of Medicine, TUD Dresden University of Technology, Dresden, Germany; Pathology & Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK; Department of Medicine I, Faculty of Medicine, TUD Dresden University of Technology, Dresden, Germany; Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany. Electronic address: jakob_nikolas.kather@tu-dresden.de
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