Heterogeneity and transcriptional drivers of triple-negative breast cancer.

CP: Cancer triple-negative breast cancer tumor heterogeneity

Journal

Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691

Informations de publication

Date de publication:
13 Dec 2023
Historique:
received: 01 06 2023
revised: 05 10 2023
accepted: 22 11 2023
medline: 15 12 2023
pubmed: 15 12 2023
entrez: 15 12 2023
Statut: aheadofprint

Résumé

Triple-negative breast cancer (TNBC) is a heterogeneous disease with limited treatment options. To characterize TNBC heterogeneity, we defined transcriptional, epigenetic, and metabolic subtypes and subtype-driving super-enhancers and transcription factors by combining functional and molecular profiling with computational analyses. Single-cell RNA sequencing revealed relative homogeneity of the major transcriptional subtypes (luminal, basal, and mesenchymal) within samples. We found that mesenchymal TNBCs share features with mesenchymal neuroblastoma and rhabdoid tumors and that the PRRX1 transcription factor is a key driver of these tumors. PRRX1 is sufficient for inducing mesenchymal features in basal but not in luminal TNBC cells via reprogramming super-enhancer landscapes, but it is not required for mesenchymal state maintenance or for cellular viability. Our comprehensive, large-scale, multiplatform, multiomics study of both experimental and clinical TNBC is an important resource for the scientific and clinical research communities and opens venues for future investigation.

Identifiants

DOI: 10.1016/j.celrep.2023.113564 PMID: 38100350
pubmed: 38100350
pii: S2211-1247(23)01576-0
doi: 10.1016/j.celrep.2023.113564
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

113564

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests The following authors report current employment: Eli Lilly (B.J.), Shasqi, Inc (M.A.), GenieUsGenomics (A.T.), Morrison & Foerster LLP (A.G.), AstraZeneca (M.B.E. and L.E.S.), Odyssey Therapeutics (J.D.J.). K.P. serves on the Scientific Advisory Boards (SABs) of Novartis, Ideaya Biosciences, and Scorpion Therapeutics; holds equity options in Scorpion Therapeutics and Ideaya Biosciences; and receives sponsored research funding from Novartis, where she consults. F.M. is a cofounder of and has equity in Harbinger Health, has equity in Zephyr AI, and consults for Harbinger Health and Zephyr AI. She is on the board of directors of Exscientia Plc. She declares that none of these relationships are directly or indirectly related to the content of this manuscript. P.S. is a consultant for Novartis, Genovis, Guidepoint, The Planning Shop, ORIC Pharmaceuticals, Cedilla Therapeutics, Syros Pharmaceuticals, Blueprint Medicines, Curie Bio, Differentiated Therapeutics, Excientia, Ligature Therapeutics, Merck, Redesign Science, Sibylla Biotech, and Exo Therapeutics; he receives research funding from Novartis. A.G.L. serves on the SAB of Flash Therapeutics, Zentalis Pharmaceuticals, and Trueline Therapeutics and consults for AbbVie. M.B. receives research funding from Novartis, where he also serves on the SAB and acts as a consultant. He is a member of the SAB for Kronos Bio and GV20 Therapeutics and holds equity in both companies. He also serves on the SAB for FibroGen and is a consultant for Belharra Therapeutics. K.W.W. serves on the SAB of TScan Therapeutics, SQZ Biotech, Bisou Bioscience Company, DEM BioPharma, and Nextechinvest; receives sponsored research funding from Novartis; and is a co-founder, stockholder, and advisory board member of Immunitas Therapeutics. D.D. receives research support from Canon, Inc. H.W.L. receives research funding from Novartis.

Auteurs

Bojana Jovanović (B)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Daniel Temko (D)

Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.

Laura E Stevens (LE)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Marco Seehawer (M)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Anne Fassl (A)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

Katherine Murphy (K)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Jayati Anand (J)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Kodie Garza (K)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Anushree Gulvady (A)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Xintao Qiu (X)

Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Nicholas W Harper (NW)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Veerle W Daniels (VW)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Huang Xiao-Yun (H)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Jennifer Y Ge (JY)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, MA 02115, USA.

Maša Alečković (M)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Jason Pyrdol (J)

Departments of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.

Kunihiko Hinohara (K)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Shawn B Egri (SB)

The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA.

Malvina Papanastasiou (M)

The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA.

Raga Vadhi (R)

Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Alba Font-Tello (A)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Robert Witwicki (R)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Guillermo Peluffo (G)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Anne Trinh (A)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Shaokun Shu (S)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Benedetto Diciaccio (B)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Muhammad B Ekram (MB)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Ashim Subedee (A)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Zachary T Herbert (ZT)

Department of Molecular Biology Core Facility, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Kai W Wucherpfennig (KW)

Departments of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Departments of Microbiology and Immunobiology, Harvard Medical School, Boston, MA 02115, USA.

Anthony G Letai (AG)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.

Jacob D Jaffe (JD)

The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA.

Piotr Sicinski (P)

Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.

Myles Brown (M)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA.

Deborah Dillon (D)

Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA.

Henry W Long (HW)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA.

Franziska Michor (F)

Department of Data Science, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: michor@jimmy.harvard.edu.

Kornelia Polyak (K)

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA; The Eli and Edythe L. Broad Institute, Cambridge, MA 02142, USA; Ludwig Center at Harvard, Harvard Medical School, Boston, MA 02115, USA; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA 02215, USA. Electronic address: kornelia_polyak@dfci.harvard.edu.

Classifications MeSH