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ResearchIn-Press PreviewGeneticsOncology Open Access | 10.1172/JCI199454

Polycomb Scaffolding Subunit EED Supports the SCLC Neuroendocrine Identity and EGFR-Mutant LUAD to SCLC Transformation

Yixiang Li,1 Yasmin N. Laimon,2 Hyeonseo Cho,1 Marina Vivero,2 Gabriel Roberti de Oliveira,2 Maxwell D. Seager,2 Andrew Delcea,2 Varunika Savla,2 Yuting Chen,3 Yavuz T. Durmaz,1 Xintao Qiu,1 Shweta Kukreja,1 Rong Li,1 Talal El Zarif,1 Wesley Lu,1 McKayla Van Orden,1 Jacob E. Berchuck,4 Roderick T. Bronson,5 Shuqiang Li,1 Hongbin Ji,3 David A. Barbie,1 Katerina Politi,6 Matthew L. Freedman,1 Henry W. Long,1 Sabina Signoretti,2 and Matthew G. Oser1

1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

Find articles by Li, Y. in: PubMed | Google Scholar

1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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1Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

2Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, United States of America

3State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China

4Winship Cancer Institute, Emory University School of Medicine, Atlanta, United States of America

5Division of Immunology, Department of Microbiology and Immunobiology, Harvard Medical School, Boston, United States of America

6Departments of Pathology and Internal Medicine (Section of Medical Oncology, Yale School of Medicine and Yale Cancer Center, New Haven, United States of America

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Published August 18, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI199454.
Copyright © 2026, Li 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 18, 2026 - Version history
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Abstract

Lung cancer histological subtypes include lung adenocarcinoma (LUAD) and small cell lung cancer (SCLC). Although usually distinct, rare combined LUAD/SCLC tumors occur, and LUAD can transform into SCLC as a mechanism of resistance to targeted therapies, particularly in EGFR-Mutant LUADs with RB1/TP53 inactivation. Although PRC2 complex expression increases during this transformation, its functional role remains unclear. Using CRISPR-based autochthonous immunocompetent GEMMs, we found that inactivation of EED, the core PRC2 scaffolding subunit, impaired SCLC tumorigenesis and promoted LUAD histological identity likely through a NEUROD1-positive intermediate state. Mechanistically, EED loss derepressed bivalent genes co-marked by H3K27me3 and H3K4me3, including LUAD oncogenic RAS, PI3K, and MAPK pathway genes and NEUROD1. These same LUAD oncogenic signaling genes were bivalently repressed in human SCLC patient-derived xenografts, suggesting a conserved PRC2-dependent mechanism that represses LUAD oncogenic signaling and thereby supports the SCLC neuroendocrine identity. In a complementary EGFR-Mutant LUAD GEMM with Rb1 and Trp53 inactivation, EED inactivation at tumor initiation prevented the emergence of SCLC histology after EGFR oncogene withdrawal and redirected recurrent tumors toward mucinous LUAD states with reduced spontaneous metastasis. These findings identify PRC2/EED as a regulator of SCLC neuroendocrine identity and nominate pharmacologic EED inhibition for future investigation in therapy-associated LUAD-to-SCLC transformation.

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