TNF-α-producing macrophages determine subtype identity and prognosis via AP1 enhancer reprogramming in pancreatic cancer
Menée à l'aide de lignées cellulaires, de modèles murins et de xénogreffes dérivées de tumeurs de patients atteints d'un cancer du pancréas, cette étude met en évidence un mécanisme par lequel les macrophages sécrétant le TNF alpha déterminent l'identité cellulaire des tumeurs du pancréas, le caractère agressif de ces dernières et le pronostic
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 Cancer , résumé, 2021