BRD9-SMAD2/3 Orchestrates Stemness and Tumorigenesis in Pancreatic Ductal Adenocarcinoma

Yuliang Feng; Liuyang Cai; Martin Pook; Feng Liu; Chao-Hui Chang; Mai Abdel Mouti; Reshma Nibhani; Stefania Militi; James Dunford; Martin Philpott; Yanbo Fan; Guo-Chang Fan; Qi Liu; Jun Qi; Cheng Wang; Wanzi Hong; Hannah Morgan; Mingyang Wang; Sakthivel Sadayappan; Anil G Jegga; Udo Oppermann; Yigang Wang; Wei Huang; Lei Jiang; Siim Pauklin

doi:10.1053/j.gastro.2023.09.021

BRD9-SMAD2/3 Orchestrates Stemness and Tumorigenesis in Pancreatic Ductal Adenocarcinoma

Gastroenterology. 2024 Jan;166(1):139-154. doi: 10.1053/j.gastro.2023.09.021. Epub 2023 Sep 21.

Authors

Yuliang Feng¹, Liuyang Cai², Martin Pook¹, Feng Liu¹, Chao-Hui Chang¹, Mai Abdel Mouti¹, Reshma Nibhani¹, Stefania Militi¹, James Dunford¹, Martin Philpott¹, Yanbo Fan³, Guo-Chang Fan⁴, Qi Liu⁵, Jun Qi⁵, Cheng Wang⁶, Wanzi Hong⁷, Hannah Morgan⁸, Mingyang Wang⁹, Sakthivel Sadayappan⁸, Anil G Jegga¹⁰, Udo Oppermann¹¹, Yigang Wang¹², Wei Huang¹³, Lei Jiang¹⁴, Siim Pauklin¹⁵

Affiliations

¹ Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.
² Department of Pharmacology, School of Medicine, Southern University of Science and Technology, Guangdong, China.
³ Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati College of Medicine, Cincinnati, Ohio.
⁴ Departments of Pharmacology and Systems Physiology, University of Cincinnati College of Medicine, Cincinnati, Ohio.
⁵ Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
⁶ Smurfit Institute of Genetics, Trinity College Dublin, Dublin, Ireland.
⁷ Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, China.
⁸ Heart, Lung and Vascular Institute, Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, Cincinnati, Ohio.
⁹ College of Engineering and Applied Science, University of Cincinnati, Cincinnati, Ohio.
¹⁰ Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio; Department of Computer Science, University of Cincinnati College of Engineering, Cincinnati, Ohio.
¹¹ Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom; Oxford Translational Myeloma Centre, Botnar Research Centre, Oxford, United Kingdom.
¹² Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address: [email protected].
¹³ Heart, Lung and Vascular Institute, Department of Internal Medicine, Division of Cardiovascular Health and Disease, University of Cincinnati, Cincinnati, Ohio. Electronic address: [email protected].
¹⁴ Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, China. Electronic address: [email protected].
¹⁵ Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom. Electronic address: [email protected].

Abstract

Background & aims: The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. The epigenetic mechanisms regulating CSCs are currently insufficiently understood, which hampers the development of novel strategies for eliminating CSCs.

Methods: By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodeling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFβ/Activin-SMAD2/3 signaling pathway.

Results: Inhibition and genetic ablation of BRD9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumors from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs.

Conclusions: Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.

Keywords: Cancer Stem Cells; Cancer Therapy; Epigenetics; Pancreatic Cancer; TGFβ/Activin-SMAD2/3.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Bromodomain Containing Proteins
Carcinoma, Pancreatic Ductal* / drug therapy
Carcinoma, Pancreatic Ductal* / genetics
Carcinoma, Pancreatic Ductal* / metabolism
Cell Line, Tumor
Cell Transformation, Neoplastic / pathology
Gemcitabine
Humans
Mice
Neoplastic Stem Cells / pathology
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / genetics
Pancreatic Neoplasms* / metabolism
Smad2 Protein / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

BRD9 protein, human
Bromodomain Containing Proteins
Gemcitabine
Smad2 Protein
SMAD2 protein, human
Transcription Factors
SMAD3 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding