Suppression of the Ubiquitin Ligase Function of FBXW7 Accelerates Metastatic Progression of Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the most lethal common malignancy because it is usually diagnosed at an advanced/metastatic stage. Dysregulation of protein stability and degradation has been associated with uncontrolled proliferation and genomic instability, promoting cancer progression to metastasis. One of the major regulators of protein degradation is the tumor suppressor FBXW7, a substrate recognition domain of the SCF E3 ubiquitin ligase, frequently dysregulated in many cancers.

The function and clinical significance of FBXW7 in pancreatic cancer has been studied in some detail. Pancreatic cancer patients with low FBXW7 expression levels have poor probability of survival compared to patients with high FBXW7 expression levels. Furthermore, Fbxw7 mutations and loss cooperate with KrasG12D to accelerate PDAC formation with a high frequency, showing that Fbxw7 is an important tumor suppressor in Kras-driven pancreatic cancer. However, studies on the impact of Fbxw7 expression and its substrates in pancreatic cancer progression to metastasis remains poorly understood.

Here, we demonstrate that Fbxw7 loss accelerates progression and metastatic potential of pancreatic cancer in KrasG12D/+; Trp53-/- PDAC models, in immunocompromised and immunocompetent hosts. We explore the impact of different Fbxw7 mutants in tumorigenesis, where the hotspot mutant R465 recapitulates the phenotype seen in complete loss-of-function of Fbxw7. Finally, we looked at global proteomic changes when Fbxw7 is lost to better understand mechanistically the role of Fbxw7 in PDAC progression to metastasis. This study addresses novel facets of PDAC metastasis which has the potential to identify novel therapeutic strategies for advanced and metastatic disease.