Loss of activating transcription factor 3 prevents KRAS-mediated pancreatic cancer

Abstract

The unfolded protein response (UPR) is activated in pancreatic pathologies and suggested as a target for therapeutic intervention. In this study, we examined Activating Transcription Factor 3 (ATF3), a mediator of the UPR which promotes acinar-to-ductal metaplasia (ADM) in response to pancreatic injury. Since ADM is an initial step in the progression to pancreatic ductal adenocarcinoma (PDAC), we hypothesized ATF3 is required for initiation and progression of PDAC. We generated mice carrying a germ line mutation of Atf3 (Atf3-/-) combined with acinarspecific induction of oncogenic KRAS (Ptf1acreERT/+KrasLSL-G12D). Atf3-/-mice with (termed APK) and without KRASG12D were exposed to cerulein-induced pancreatitis. In response to recurrent pancreatitis, Atf3-/-mice showed decreased ADM and enhanced regeneration based on morphological and biochemical analysis. Similarly, an absence of ATF3 reduced spontaneous pancreatic intraepithelial neoplasia formation and PDAC in Ptf1acreERT/+KrasLSL-G12D mice. In response to injury, KRASG12D bipassed the requirement for ATF3 with a dramatic loss in acinar tissue and PanIN formation observed regardless of ATF3 status. However, unlike Ptf1acreERT/+KrasLSL-G12D mice, APK mice exhibited a cachexia-like phenotype, did not progress through to PDAC, and showed altered pancreatic fibrosis and immune cell infiltration. These findings suggest a complex, multifaceted role for ATF3 in pancreatic cancer pathology..

Co-existing TP53 and ARID1A mutations promote aggressive endometrial tumorigenesis

“…Activation Transcription Factor 3 (ATF3) is a stress-inducible transcription factor and member of the Hallmark p53 pathway and apoptosis module of the core TP53 transcriptional program [47,60]. ATF3 has context-dependent roles in tumorigenesis, cell death, and cell cycle arrest or senescence [61][62][63][64][65][66][67][68][69][70][71]. ATF3 is known to both activate and repress transcriptional activity, and it co-regulates chromatin at p53 target genes [60,72,73].…”

KDM6A Regulates Cell Plasticity and Pancreatic Cancer Progression by Noncanonical Activin Pathway

“…We tested this hypothesis using our Kras wild-type, pancreas-specific Kdm6a -KO mice, namely Ptf1a Cre ; Kdm6a fl/fl , or Ptf1a Cre ; Kdm6a fl/Y (C- Kdm6a fl/fl or C-Kdm6a fl/Y ) ( Figure 12 A ), in a well-established, cerulein-induced, chronic pancreatitis model. 27 Mice were treated with cerulein for 2 weeks and then allowed to recover for 1 and 14 days ( Figure 12 B ). There was a significant and persistent weight loss in female C- Kdm6a fl/fl mice at both day 1 and day 14 of recovery compared with the wild-type Ptf1a Cre ; Kdm6a +/+ (C) mice ( Figure 12 C ).…”

Identification of an unfolded protein response-related signature for predicting the prognosis of pancreatic ductal adenocarcinoma

“…Besides, VEGFA upregulation affects tumor progression caused by the induction of ER stress ( 18 ). In addition, a recent study in ATF3-deficient mice showed that loss of ATF3 prevents the initiation and progression of KRAS-mediated PDAC ( 19 ). Several studies have shown that elevated SLC7A5 expression predicts a poor prognosis in PDAC and is regarded as a potential biomarker ( 20 – 22 ).…”