2. Academic Validation
  3. TNF-α-producing macrophages determine subtype identity and prognosis via AP1 enhancer reprogramming in pancreatic cancer

TNF-α-producing macrophages determine subtype identity and prognosis via AP1 enhancer reprogramming in pancreatic cancer

  • Nat Cancer. 2021 Nov;2(11):1185-1203. doi: 10.1038/s43018-021-00258-w.
Mengyu Tu # 1,  Lukas Klein # 1,  Elisa Espinet 2 3,  Theodoros Georgomanolis 4,  Florian Wegwitz 5,  Xiaojuan Li 6,  Laura Urbach 1,  Adi Danieli-Mackay 7,  Stefan Küffer 7,  Kamil Bojarczuk 8,  Athanasia Mizi 7,  Ufuk Günesdogan 6,  Björn Chapuy 8,  Zuguang Gu 9 10,  Albrecht Neesse 1,  Uday Kishore 11,  Philipp Ströbel 7,  Elisabeth Hessmann 1,  Stephan A Hahn 12,  Andreas Trumpp 2 3,  Argyris Papantonis 7,  Volker Ellenrieder 1,  Shiv K Singh 13
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Germany.
  • 2 Division of Stem Cells and Cancer, DKFZ, Heidelberg, Germany.
  • 3 Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbh), Heidelberg, Germany.
  • 4 Cologne Center for Genomics, University of Cologne, Cologne, Germany.
  • 5 Department of Gynecology and Obstetrics, University Medical Center Göttingen, Göttingen, Germany.
  • 6 Department of Developmental Biology, Göttingen Center for Molecular Biosciences, Göttingen, Germany.
  • 7 Institute of Pathology, University Medical Center Göttingen, Göttingen, Germany.
  • 8 Department of Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany.
  • 9 Bioinformatics and Omics Data Analytics, DKFZ, Heidelberg, Germany.
  • 10 Division of Cancer Epigenomics, DKFZ, Heidelberg, Germany.
  • 11 Biosciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK.
  • 12 Faculty of Medicine, Department of Molecular GI Oncology, Ruhr University Bochum, Bochum, Germany.
  • 13 Department of Gastroenterology, Gastrointestinal Oncology and Endocrinology, University Medical Center Göttingen, Göttingen, Germany. [email protected].
  • # Contributed equally.
PMID: 35122059 DOI: 10.1038/s43018-021-00258-w
Abstract

Large-scale genomic profiling of pancreatic Cancer (PDAC) has revealed two distinct subtypes: 'classical' and 'basal-like'. Their variable coexistence within the stromal immune microenvironment is linked to differential prognosis; however, the extent to which these neoplastic subtypes shape the stromal immune landscape and impact clinical outcome remains unclear. By combining preclinical models, patient-derived xenografts, as well as FACS-sorted PDAC patient biopsies, we show that the basal-like neoplastic state is sustained via BRD4-mediated cJUN/AP1 expression, which induces CCL2 to recruit tumor necrosis factor (TNF)-α-secreting macrophages. TNF-α+ macrophages force classical neoplastic cells into an aggressive phenotypic state via lineage reprogramming. Integration of ATAC-, ChIP- and RNA-seq data revealed distinct JUNB/AP1 (classical) and cJUN/AP1 (basal-like)-driven regulation of PDAC subtype identity. Pharmacological inhibition of BRD4 led to suppression of the BRD4-cJUN-CCL2-TNF-α axis, restoration of classical subtype identity and a favorable prognosis. Hence, patient-tailored therapy for a cJUNhigh/TNF-αhigh subtype is paramount in overcoming highly inflamed and aggressive PDAC states.

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