CUX1 Enhances Pancreatic Cancer Formation by Synergizing with KRAS and Inducing MEK/ERK-Dependent Proliferation.

Abstract

Simple SummaryIn pancreatic cancer, CUX1 acts as an important mediator of tumor cell proliferation and resistance to apoptosis. Using two different mouse models for the prevalent CUX1 isoforms p200 and p110, we identified p110 CUX1 as the major isoform promoting pancreatic cancer formation in the context of mutant KRAS. We could show an enhanced proliferation by activating and potentiating MEK-ERK signaling via an increased upstream activation of the ADAM17-EGFR axis. This strengthened activation in a KRAS-dependent manner, leading to a dramatically more accelerated formation of invasive PDAC in p110 CUX1 mice within 4 weeks. These results provide the first in vivo evidence for the importance of CUX1 in the development of pancreatic cancer, and highlight CUX1-dependent signaling pathways as potential therapeutic targets.The transcription factor CUX1 has been implicated in either tumor suppression or progression, depending on the cancer entity and the prevalent CUX1 isoform. Previously, we could show that CUX1 acts as an important mediator of tumor cell proliferation and resistance to apoptosis in pancreatic cancer cell lines. However, in vivo evidence for its impact on pancreatic carcinogenesis, isoform-specific effects and downstream signaling cascades are missing. We crossbred two different CUX1 isoform mouse models (p200 CUX1 and p110 CUX1) with KC (KrasLSL-G12D/+; Ptf1aCre/+) mice, a genetic model for pancreatic precursor lesions (PanIN). In the context of oncogenic KRASs, both mice KCCux1p200 and KCCux1p110 led to increased PanIN formation and development of invasive pancreatic ductal adenocarcinomata (PDAC). In KCCux1p110 mice, tumor development was dramatically more accelerated, leading to formation of invasive PDAC within 4 weeks. In vitro and in vivo, we could show that CUX1 enhanced proliferation by activating MEK-ERK signaling via an upstream increase of ADAM17 protein, which in turn led to an activation of EGFR. Additionally, CUX1 further enhanced MEK-ERK activation through upregulation of the serine/threonine kinase MOS, phosphorylating MEK in a KRAS-independent manner. We identified p110 CUX1 as major driver of pancreatic cancer formation in the context of mutant KRAS. These results provide the first in vivo evidence for the importance of CUX1 in the development of pancreatic cancer, and highlight the importance of CUX1-dependent signaling pathways as potential therapeutic targets.