Tu, Mengyu, Klein, Lukas, Espinet, Elisa, Georgomanolis, Theodoros, Wegwitz, Florian ORCID: 0000-0003-0750-6998, Li, Xiaojuan, Urbach, Laura, Danieli-Mackay, Adi, Kueffer, Stefan, Bojarczuk, Kamil ORCID: 0000-0002-6110-4060, Mizi, Athanasia, Guenesdogan, Ufuk, Chapuy, Bjoern, Gu, Zuguang, Neesse, Albrecht, Kishore, Uday, Stroebel, Philipp, Hessmann, Elisabeth, Hahn, Stephan A., Trumpp, Andreas, Papantonis, Argyris, Ellenrieder, Volker and Singh, Shiv K. ORCID: 0000-0002-5725-4058 (2021). TNF-alpha-producing macrophages determine subtype identity and prognosis via AP1 enhancer reprogramming in pancreatic cancer. Nat. Cancer, 2 (11). S. 1185 - 1220. BERLIN: NATURE PORTFOLIO. ISSN 2662-1347

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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)-alpha-secreting macrophages. TNF-alpha(+) 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-alpha axis, restoration of classical subtype identity and a favorable prognosis. Hence, patient-tailored therapy for a cJUN(high)/TNF-alpha(high) subtype is paramount in overcoming highly inflamed and aggressive PDAC states. Singh and colleagues show that PDAC phenotypic plasticity is regulated via AP1 enhancer remodeling and modulated by TNF-alpha(+) macrophages and pharmacological inhibition of the BRD4-cJUN-CCL2-TNF-alpha axis restores favorable PDAC subtypes and prognosis.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Tu, MengyuUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klein, LukasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Espinet, ElisaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Georgomanolis, TheodorosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wegwitz, FlorianUNSPECIFIEDorcid.org/0000-0003-0750-6998UNSPECIFIED
Li, XiaojuanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Urbach, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Danieli-Mackay, AdiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kueffer, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bojarczuk, KamilUNSPECIFIEDorcid.org/0000-0002-6110-4060UNSPECIFIED
Mizi, AthanasiaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guenesdogan, UfukUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Chapuy, BjoernUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gu, ZuguangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Neesse, AlbrechtUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kishore, UdayUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stroebel, PhilippUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hessmann, ElisabethUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hahn, Stephan A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Trumpp, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Papantonis, ArgyrisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ellenrieder, VolkerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Singh, Shiv K.UNSPECIFIEDorcid.org/0000-0002-5725-4058UNSPECIFIED
URN: urn:nbn:de:hbz:38-594881
DOI: 10.1038/s43018-021-00258-w
Journal or Publication Title: Nat. Cancer
Volume: 2
Number: 11
Page Range: S. 1185 - 1220
Date: 2021
Publisher: NATURE PORTFOLIO
Place of Publication: BERLIN
ISSN: 2662-1347
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SET ENRICHMENT ANALYSIS; DUCTAL ADENOCARCINOMA; READ ALIGNMENT; DNA-BINDING; WEB SERVER; C-JUN; CELL; INHIBITION; TUMOR; DIFFERENTIATIONMultiple languages
OncologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/59488

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