SPRY2 loss enhances ErbB trafficking and PI3K/AKT signalling to drive human and mouse prostate carcinogenesis

Area of Science:

• Oncology
• Molecular Biology
• Cell Signaling

Background:

• Loss of SPRY2 and activation of receptor tyrosine kinases (RTKs) are frequent in prostate cancer (PC).
• The molecular mechanisms linking SPRY2 loss to aberrant signaling and treatment resistance in PC require further investigation.

Purpose of the Study:

• To elucidate the molecular interplay between SPRY2 loss and RTK signaling in prostate cancer.
• To investigate the functional consequences of SPRY2 loss on cellular signaling pathways and disease progression.
• To evaluate the therapeutic potential of targeting the identified signaling cascade in PC.

Main Methods:

• Utilized in vitro and pre-clinical in vivo models of prostate cancer.
• Investigated the regulation of the ErbB-PI3K/AKT signaling cascade.
• Assessed the role of SPRY2 expression, PTEN status, and ErbB receptor signaling in PC cell proliferation and invasion.
• Evaluated the efficacy of PI3K inhibition in preclinical models.

Main Results:

• SPRY2 loss leads to hyper-activation of the PI3K/AKT pathway in PC.
• Reduced SPRY2 enhances EGFR/HER2 internalization and sustained signaling via early endosomes in a PTEN-dependent manner.
• PI3K activation of p38 MAPK facilitates clathrin-mediated ErbB receptor endocytosis.
• Inhibition of PI3K suppressed proliferation and invasion in preclinical models.

Conclusions:

• SPRY2 acts as a tumor suppressor in prostate cancer by negatively regulating the PI3K/AKT pathway.
• SPRY2 loss drives PC progression and treatment resistance through functional interaction with the ErbB signaling system.
• Targeting the PI3K/AKT pathway is a promising therapeutic strategy for patients with PTEN-haploinsufficient, low SPRY2, and ErbB-expressing tumors.