TNFα-mediated subtype switch and tumor progression in pancreatic cancer
von Mengyu Tu
Datum der mündl. Prüfung:2021-09-08
Betreuer:Dr. Shiv K. Singh
Gutachter:Dr. Shiv K. Singh
Gutachter:Prof. Dr. Holger Reichardt
EnglischPancreatic cancer (PDAC) represents an extremely poor clinical outcome with a 5-year survival rate of <9%. It is anticipated to become the second leading cause of cancer-related deaths in the industrialized countries by 2030. A vast majority of PDAC patients exhibit locally advanced or distant metastases at the time of diagnosis, which makes surgical resection challenging. The complex molecular heterogeneity within neoplastic-epithelium and stromal cells profoundly attributes to this poor prognosis, and makes therapy challenging. Extensive whole genome sequencing and transcriptional profiling of PDAC biopsies identified the two most clinically relevant and molecularly distinct subtypes: the basal-like (BL) subtype displays highly aggressive phenotype, metastatic disease and chemoresistance profile in PDAC patients, whereas classical (CLA) subtype often responds to therapy and exhibits better prognosis. However, the coexisting stromal components (e.g. inflammatory macrophages and cancer-associated fibroblasts) within CLA or BL subtypes underlie distinct prognosis. Whether and how CLA or BL neoplastic cells shape the stromal microenvironment, and hence, determine PDAC aggressiveness and therapeutic vulnerabilities remain largely unresolved. Herein, we show that BL neoplastic cells recruit inflammatory macrophages, which foster highly inflamed and aggressive tumor phenotype in PDAC. We identified a mutually exclusive AP1-driven transcriptional program, which determines PDAC subtype identity and prognosis. CLA-restricted JUNB/AP1 is associated with less aggressive and chemoresponsive CLA tumors; conversely, BL-restricted cJUN/AP1 largely controls tumor invasiveness, chemoresistance and proinflammatory program. Mechanistically, cJUN controls CCL2 expression via enhancer-promoter regulation, which, in turn, facilitate recruitment of TNFα-producing macrophages in the PDAC microenvironment. Subsequently, TNFα switches PDAC subtype identity through converting CLA tumors into a highly aggressive BL phenotypic state by activating cJUN-CCL2 signaling axis, thus, forming a positive feed forward loop. Finally, we show that BRD4 regulates cJUN-transcription via enhancer-promoter interactions; hence, pharmacological inhibition of the BRD4-cJUN axis induces a favorable subtype switch and improves overall survival in preclinical models. This study provides compelling evidence that subtype-specific transcriptional program shapes the subtype identity, tumor aggressiveness and prognosis in PDAC. Thus, cJUNhigh/TNFαhigh subtype-specific precision therapy has the potential to overcome the highly aggressive and chemoresistant PDAC.
Keywords: pancreatic cancer; subtype identity; JUN/AP1; macrophages; BRD4