Accession Number:

AD1159614

Title:

Targeting Ovarian Cancer Stem Cells Interactions with the Niche

Descriptive Note:

[Technical Report, Annual Report]

Corporate Author:

INDIANA UNIV AT INDIANAPOLIS

Personal Author(s):

Report Date:

2021-08-01

Pagination or Media Count:

26

Abstract:

Ovarian cancer OC recurrence and spread have been linked to a small population of cancer stem cells CSC, which are resistant to traditional chemotherapy. Tissue transglutaminase TG2, an enzyme found to be active in ovarian tumors, protects CSCs and stimulates their growth. We found that this enzyme is enriched at the membrane of OC cells forming a complex with several receptors, such as integrins and the Wnt receptors Frizzled 1, 7 and co-receptor LRP6. This interaction stimulates survival pathways linked with the integrin linked kinase ILK activation and CD166 expression in OC cells and maintains the CSC phenotype. We defined the amino acids residues involved in the TG2Fzd7 interaction and we are using this discovery to design a new treatment for OC by generating an antibody that could disrupt the complex. Our research has several important implications. First, we defined TG2 as novel Wnt pathway co-receptor. Second, the Wnt receptors in a complex with TG2 activate Wnt signals promoting the expression of several stemness-related genes ALDH1A1, Sox2, and Nanog and the novel proposed CSC marker CD166 involved in OCSCs proliferation as spheres. Third, we expanded our research identifying a new functional link between the TG2 regulated cell adhesion to the matrix, integrin linked kinase ILK phosphorylation and canonical Wnt signaling activation, proposing ILK as a central node of two combinatorial signals. These results point to TG2Wnt receptors as potential new therapeutic CSC targets. Ovarian cancer OC recurrence and spread have been linked to a small population of cancer stem cells CSC, which are resistant to traditional chemotherapy. Tissue transglutaminase TG2, an enzyme found to be active in ovarian tumors, protects CSCs and stimulates their growth. We found that this enzyme is enriched at the membrane of OC cells forming a complex with several receptors, such as integrins and the Wnt receptors Frizzled 1, 7 and co-receptor LRP6.

Descriptors:

Subject Categories:

  • Medicine and Medical Research

Distribution Statement:

[A, Approved For Public Release]