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ResearchIn-Press PreviewClinical ResearchOncology Open Access | 10.1172/jci.insight.201872

Deep learning–based histologic classifiers enable molecular subtyping of metastatic prostate cancer

Zhijun Chen,1 Erolcan Sayar,2 Daniela Guevara,3 Helen Richards,2 Haoyue Zhang,1 Radhika A. Patel,2 Agnes C. Gawne,2 Lucas J. Liu,2 Ilsa Coleman,2 Ruth Dumpit,2 Colm Morrissey,4 Michael T. Schweizer,2 Ruben Raychaudhuri,4 Laura S. Graham,4 Evan Y. Yu,2 Heather H. Cheng,2 Chien-Kuang C. Ding,5 Yuzhuo Wang,6 Peter Choyke,1 Baris Turkbey,1 Chantal Chanel-Vos,3 Christina Fedorov,3 John R. Otilano III,3 Troy Kane,3 Jyothi Manohar,3 Michael Sigouros,3 Jones T. Nauseef,3 Ana Molina,3 David Nanus,3 Scott T. Tagawa,3 Juan Miguel Mosquera,3 Himisha P. Beltran,3 Ruth Etzioni,2 Peter S. Nelson,2 Rama Soundararajan,7 Ana M. Aparicio,7 Cora N. Sternberg,3 Michael C. Haffner,2 and Stephanie A. Harmon1

1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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1National Cancer Institute, NIH, Bethesda, United States of America

2Fred Hutchinson Cancer Center, Seattle, United States of America

3Englander Institute for Precision Medicine and Weill Cornell Medicine, New York, United States of America

4University of Washington, Seattle, United States of America

5UCSF, San Francisco, United States of America

6University of British Columbia, Vancouver, Canada

7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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6University of British Columbia, Vancouver, Canada

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7The University of Texas MD Anderson Cancer Center, Houston, United States of America

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Published August 6, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.201872.
Copyright © 2026, Chen et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 6, 2026 - Version history
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Abstract

Metastatic prostate cancer is a clinically and molecularly heterogeneous disease. Under the selective pressure of androgen receptor (AR)–directed therapies, resistant phenotypes frequently emerge, posing significant diagnostic and therapeutic challenges. Neuroendocrine prostate cancer (NEPC) is a clinically important phenotype characterized by lineage plasticity, neuroendocrine features, visceral metastases and poor prognosis. Accurately diagnosing NEPC remains difficult due to its histologic and molecular complexity but has high clinical relevance. In this study, we developed a deep learning model that leverages interpretable cellular features to improve feature extraction from H&E-stained tissue sections (NEURAL-PC). By incorporating a multiple instance learning (MIL) framework, NEURAL-PC enables robust NEPC classification solely from H&E tumor images, achieving an area under the receiver operating characteristic curve (AUROC) of 0.921 in independent external validation. In addition to its diagnostic utility, NEURAL-PC provides prognostic information that enables further subclassification of advanced prostate cancer across diverse datasets supporting its strong prognostic value and generalizability. Broadly, our work highlights a hybrid approach that integrates features across different domains, offering a promising strategy for developing reliable deep learning tools in pathology. Built on this framework, NEURAL-PC represents an extensively validated diagnostic and prognostic model for advanced prostate cancer.

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