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. Epub 2021 Nov 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Pancreatic Ductal* / genetics
  • Cell Cycle Proteins / genetics
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Macrophages / metabolism
  • Nuclear Proteins / genetics
  • Pancreatic Neoplasms* / genetics
  • Prognosis
  • Transcription Factors / genetics
  • Tumor Microenvironment / genetics
  • Tumor Necrosis Factor-alpha / genetics


  • BRD4 protein, human
  • Cell Cycle Proteins
  • Nuclear Proteins
  • Transcription Factors
  • Tumor Necrosis Factor-alpha