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

M Tu, L Klein, E Espinet, T Georgomanolis, F Wegwitz… - Nature cancer, 2021 - nature.com
M Tu, L Klein, E Espinet, T Georgomanolis, F Wegwitz, X Li, L Urbach, A Danieli-Mackay…
Nature cancer, 2021nature.com
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 …
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.
nature.com