Abstract
Pancreatic ductal adenocarcinoma (PDAC) will soon belong to the top three cancer killers. The only approved specific PDAC therapy targets the epidermal growth factor receptor (EGFR). Although EGFR is a crucial player in PDAC development, EGFR‐based therapy is disappointing. In this study, we evaluated the role of the EGFR ligand betacellulin (BTC) in PDAC. The expression of BTC was investigated in human pancreatic cancer specimen. Then, we generated a BTC knockout mouse model by CRISPR/Cas9 technology and a BTC overexpression model. Both models were crossed with the Ptf1aCre/+;KRASG12D/+ (KC) mouse model (B−/−KC or BKC, respectively). In addition, EGFR, ERBB2, and ERBB4 were investigated by the pancreas‐specific deletion of each receptor using the Cre‐loxP system. Tumor initiation and progression were analyzed in all mouse lines, and the underlying molecular biology of PDAC was investigated at different time points. BTC is expressed in human and murine PDAC. B−/−KC mice showed a decelerated PDAC progression, associated with decreased EGFR activation. BKC mice developed severe PDAC with a poor survival rate. The dramatically increased BTC‐mediated tumor burden was EGFR‐dependent, but also ERBB4 and ERBB2 were involved in PDAC development or progression, as depletion of EGFR, ERBB2, or ERBB4 significantly improved the survival rate of BTC‐mediated PDAC. BTC increases PDAC tumor burden dramatically by enhanced RAS activation. EGFR signaling, ERBB2 signaling, and ERBB4 signaling are involved in accelerated PDAC development mediated by BTC indicating that targeting the whole ERBB family, instead of a single receptor, is a promising strategy for the development of future PDAC therapies.
Highlights
With a 5-year survival rate of 8% pancreatic ductal adenocarcinoma (PDAC) is worldwide one of the deadliest cancers
To investigate BTC in pancreatic cancer, we generated a BTC knockout mouse model (BTCÀ/À) and overexpressed BTC in a transgenic mouse model (Btctg/+). Both models were crossed in a PDAC mouse model, and to assess the receptor dependency, BTC-transgenic mice were crossed with PDAC mouse lines with pancreas-specific epidermal growth factor receptor (EGFR), ERBB2, or ERBB4 deletions
Since EGFR is only one member of a family of four receptor tyrosine kinases, either working autonomously or as partner of ERBB2, ERBB3, or ERBB4, we assumed that the remaining ERBB receptors may have been underestimated in recent years and could play an important role in PDAC, because ERBB ligands specific for ERBB4 have been implicated in PDAC development or progression (Chaturvedi et al, 2007; Ito et al, 2001; Ray et al, 2014; Zhu et al, 2000)
Summary
With a 5-year survival rate of 8% pancreatic ductal adenocarcinoma (PDAC) is worldwide one of the deadliest cancers. The role of ERBB4 seems to be context-dependent, probably due to its—in contrast to its ERBB relatives—ability to signal in form of its soluble intracellular domain (ICD80) after undergoing regulated intramembrane proteolysis (RIP) (Carpenter, 2003), induced by tumor necrosis factor alpha converting enzyme (Kenny and Bissell, 2007) In another pancreatic disorder BTC transgenic mice were protected against acute pancreatitis mediated by ERBB4 signaling and independent of EGFR (Hedegger et al, 2019). To investigate BTC in pancreatic cancer, we generated a BTC knockout mouse model (BTCÀ/À) and overexpressed BTC in a transgenic mouse model (Btctg/+) Both models were crossed in a PDAC mouse model, and to assess the receptor dependency, BTC-transgenic mice were crossed with PDAC mouse lines with pancreas-specific EGFR, ERBB2, or ERBB4 deletions
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