CYRI-B-mediated macropinocytosis drives metastasis via lysophosphatidic acid receptor uptake

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and limited treatments.
• KRAS hyperactivation drives tumor cell migration, proliferation, and macropinocytosis.
• The role of macropinocytosis in signaling receptor trafficking remains unclear.

Purpose of the Study:

• To investigate the role of CYRI-B in KRAS-driven pancreatic cancer.
• To understand CYRI-B's function in tumor growth and metastasis.
• To explore CYRI-B's impact on RAC1 activation and signaling pathways.

Main Methods:

• Utilized a mouse model of KRAS and p53-driven pancreatic cancer.
• Assessed tumor growth and metastasis in wild-type and Cyrib-deficient mice.
• Analyzed cell proliferation, migration, and macropinocytosis.
• Quantified lysophosphatidic acid receptor 1 (LPA1) uptake in CYRI-B depleted cells.

Main Results:

• CYRI-B is highly expressed in pancreatic tumors.
• Deletion of Cyrib accelerated early tumorigenesis by enhancing ERK and JNK signaling.
• Loss of CYRI-B inhibited metastasis in later stages of the disease.
• CYRI-B depletion reduced chemotaxis to lysophosphatidic acid due to impaired macropinocytic uptake of LPA1.

Conclusions:

• CYRI-B acts as a buffer for RAC1 hyperactivation in early pancreatic cancer.
• CYRI-B mediates tumor cell growth and signaling.
• CYRI-B plays a dual role in pancreatic cancer, promoting early growth but inhibiting later-stage metastasis.
• Targeting CYRI-B-mediated macropinocytosis offers potential therapeutic strategies for pancreatic cancer.