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, wxe 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 acinar-specific 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.

ATF3 induces RAB7 to govern autodegradation in paligenosis, a conserved cell plasticity program

“…In all those cases, Atf3 loss exacerbates the injury phenotype but is dispensable for homeostasis and embryonic development, just as we observed here in stomach and pancreas injury. A recent publication similarly showed that Atf3 loss leads to decreased ADM and that absence of Atf3 in a spontaneous cancer mouse model actually prevented KRAS G12D ‐driven pancreatic cancer (Azizi et al , 2021). That may be consistent with our results here, as mutant KRAS‐driven cancer depends on ADM, which depends on ATF3 and paligenosis.…”

“…Activating transcription factor 3 is a member of the ATF/CREB family of transcription factors and shares similar binding sites with AP‐1 (also from the ATF/CREB and c‐Fos/c‐Jun families), which regulates immediate early genes following stress/injury. Atf3 has been implicated in injury settings in many organs including cerebral ischemia (Wang et al , 2012), axon regeneration (Hunt et al , 2012; Gey et al , 2016), acute lung injury (Zhao et al , 2017), heart failure (Brooks et al , 2015), alcohol liver damage (Tsai et al , 2015), liver ischemia‐reperfusion injury (Zhu et al , 2018), stress‐induced β‐cell apoptosis (Hartman et al , 2004), ADM (Fazio et al , 2017; Azizi et al , 2021), and acute kidney injury (Li et al , 2010). ATF3 is also important for injury responses in Drosophila (Zhou et al , 2017) and Axolotl (Gerber et al , 2018).…”

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 12A), in a well-established, cerulein-induced, chronic pancreatitis model. 25 Mice were treated with cerulein for 2 weeks and then allowed to recover for 1 and 14 days (Figure 12B). 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 þ/þ (C) Q26 mice (Figure 12C).…”