Targeting cell surface GRP78-CD44v interaction suppresses cell migration in triple-negative breast cancer cells

Area of Science:

• Oncology
• Molecular Biology
• Cell Biology

Background:

• Triple-negative breast cancer (TNBC) lacks ER, PR, and HER2 targets, necessitating novel therapeutic strategies.
• Cell surface GRP78 (csGRP78), an ER chaperone, is upregulated in cancers and involved in non-canonical signaling.
• csGRP78 is a potential therapeutic target due to its preferential expression on malignant cells.

Purpose of the Study:

• To investigate the role and therapeutic potential of cell surface GRP78 (csGRP78) in triple-negative breast cancer (TNBC).
• To explore the relationship between csGRP78 and CD44 variant isoforms in TNBC cells.
• To evaluate the efficacy of targeting csGRP78 with the monoclonal antibody 76-E6.

Main Methods:

• Characterization of csGRP78 expression in MDA-MB-231 TNBC cells and xenografts.
• Immunofluorescence co-localization studies of csGRP78 and CD44v.
• Treatment of TNBC cells with anti-csGRP78 antibody 76-E6.
• Assessment of downstream signaling pathways (Src kinase) and cellular functions (morphology, motility).

Main Results:

• Over 70% of MDA-MB-231 TNBC cells express csGRP78, often co-localizing with CD44v at the cell's anterior.
• csGRP78 and CD44v co-localization was confirmed in vivo in tumor xenografts.
• Antibody 76-E6 targeting csGRP78 downregulated CD44v, inhibited Src kinase, altered cell morphology, and reduced cell motility.
• The epitope targeted by 76-E6 on GRP78 was mapped.

Conclusions:

• csGRP78 regulates TNBC cell morphology and migration, partly through a csGRP78-CD44v axis.
• csGRP78 represents a promising therapeutic target for triple-negative breast cancer.
• Targeting csGRP78 may offer a novel treatment strategy for TNBC patients.