Cell surface GRP78 promotes stemness in normal and neoplastic cells

Area of Science:

• Cellular Biology
• Cancer Research
• Stem Cell Biology

Background:

• Metastatic cancers exhibit embryonic signatures, suggesting stem cell mechanisms drive aggressive disease.
• Identifying and targeting cancer stem-like cells remains a significant challenge in oncology.
• GRP78, a chaperone protein, is normally intracellular but found on the cell surface of embryonic stem cells and various cancers.

Purpose of the Study:

• To investigate the role of cell surface GRP78 (sGRP78) in cellular reprogramming and cancer stemness.
• To determine if sGRP78 marks a population of tumor-initiating cells (TICs) with metastatic potential in breast cancer.

Main Methods:

• Utilized cellular reprogramming techniques to study GRP78.
• Analyzed GRP78 expression on induced pluripotent stem cells (iPSCs) and breast cancer cells.
• Investigated the functional role of sGRP78 in cellular functions and tumor initiation.
• Assessed the enrichment of stemness genes and metastatic potential in sGRP78-positive breast cancer cells in vivo.

Main Results:

• Cell surface GRP78 (sGRP78) is expressed on iPSCs and plays a role in reprogramming.
• sGRP78 enhances cellular functions in both pluripotent cells and breast cancer cells.
• Overexpression of GRP78 in breast cancer cells induces a CD24-/CD44+ tumor-initiating cell (TIC) population.
• sGRP78-positive breast cancer cells are enriched for stemness genes and represent a subset of TICs.
• sGRP78-positive breast cancer cells exhibit increased ability to form distant metastases in vivo.

Conclusions:

• GRP78 plays significant roles in regulating pluripotency and oncogenesis.
• sGRP78 serves as a marker for a stem-like population in breast cancer.
• This sGRP78-positive population possesses enhanced metastatic potential, offering a potential therapeutic target.