Scribble Deficiency Promotes Pancreatic Ductal Adenocarcinoma Development and Metastasis

Area of Science:

• Oncology
• Cell Biology
• Cancer Pathogenesis

Background:

• Cell polarity disruption is a key feature of pancreatic ductal adenocarcinoma (PDAC) progression.
• Scribble (SCRIB), a polarity regulator, has varied roles in neoplasm pathogenesis.

Purpose of the Study:

• To investigate the role of SCRIB deficiency in PDAC development and progression.
• To determine the impact of Scrib ablation on tumor initiation, invasion, and metastasis in mouse models.

Main Methods:

• Genetic ablation of Scrib expression in established mouse models of PDAC.
• Immunohistochemical and transcriptome analyses of Scrib-null tumors.
• In vitro studies using mouse PDAC organoids (mPDOs) and PDAC cell lines.

Main Results:

• Scrib deletion cooperated with KrasG12D and Trp53 heterozygous deletion to promote invasive PDAC and metastasis.
• Scrib-null tumors showed reduced collagen, increased cancer-associated fibroblasts (CAFs), and decreased IL1α levels.
• Scrib loss enhanced YAP activation, increasing cancer cell survival and impairing CAF activation.

Conclusions:

• SCRIB deficiency accelerates PDAC development and progression through both cell-autonomous and non-cell-autonomous mechanisms.
• Reduced SCRIB expression in human PDAC is linked to poorer patient outcomes.
• SCRIB functions as a tumor suppressor in advanced pancreatic cancer and may serve as a biomarker for recurrence prediction.