Ovarian cancer (OC) is the most lethal gynecological neoplasm, characterized by high rates of tumor recurrence associated to a small population (less than 1% of the total population) of cancer stem cells (CSC) or tumor initiating cells resistant to the conventional chemotherapies. Ascites represents a unique type of tumor microenvironment (TME) characterized by an abundance of growth factors, cytokines and extracellular matrix (ECM) essential to promote CSC survival and their proliferation as highly aggressive multicellular spheroids. In our laboratory we identified tissue transglutaminase or TG2, an enzyme involved in Ca2+-dependent protein post-translational modifications and cross-linking, as a protein highly expressed in OC and enriched in the tumor milieu. Mechanistic studies demonstrated that TG2 correlates with the highly aggressive CSC phenotype (ALDH+/CD133+), and by interacting with components of the TME, such as fibronectin (FN) and integrins, activates the oncogenic Wnt/β-catenin pathway in OC cells. OC spheroid cells, treated with function-inhibiting mAbs directed against TG2/FN complexes, showed a significant decrease in Wnt-frizzled receptors and by co-immunoprecipitation analysis, I was able to detect a direct TG2/Frizzled7 complex formation. This is the first and unpublished demonstration of the interaction between the two proteins, and defines TG2 as a putative newly discovered co-receptor for the Wnt/β-catenin canonical pathway.
|Effective start/end date||9/1/17 → 8/31/20|
- Northwestern Memorial Hospital (NMH Contract #11 Signed 10/04/17)