TY - JOUR
T1 - Tissue tranglutaminase regulates interactions between ovarian cancer stem cells and the tumor niche
AU - Condello, Salvatore
AU - Sima, Livia
AU - Ivan, Cristina
AU - Cardenas, Horacio
AU - Schiltz, Gary
AU - Mishra, Rama K.
AU - Matei, Daniela
N1 - Funding Information:
This work was made possible by funding from the U.S. Department of Veterans Affairs (I01 BX000792-06), the Diana Princess of Wales endowed Professorship from the Lurie Cancer Center (to D. Matei), and Friends of Prentice award (to S. Condello). We acknowledge the technical support provided by the Imaging Core Facility and Flow Cytometry Core supported by the Lurie Cancer Center and the NCI-P30 (CA 060553) award.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - Cancer progression and recurrence are linked to a rare population of cancer stem cells (CSC). Here, we hypothesized that interactions with the extracellular matrix drive CSC proliferation and tumor-initiating capacity and investigated the functions of scaffold protein tissue transglutaminase (TG2) in ovarian CSC. Complexes formed by TG2, fibronectin (FN), and integrin b1 were enriched in ovarian CSC and detectable in tumors. A function-inhibiting antibody against the TG2 FN-binding domain suppressed complex formation, CSC proliferation as spheroids, tumor-initiating capacity, and stemness-associated Wnt/b-catenin signaling. Disruption of the interaction between TG2 and FN also blocked spheroid formation and the response to Wnt ligands. TG2 and the Wnt receptor Frizzled 7 (Fzd7) form a complex in cancer cells and tumors, leading to Wnt pathway activation. Protein docking and peptide inhibition demonstrate that the interaction between TG2 and Fzd7 overlaps with the FN-binding domain of TG2. These results support a new function of TG2 in ovarian CSC, linked to spheroid proliferation and tumor-initiating capacity and mediated through direct interactions with Fzd7. We propose this complex as a new stem cell target. Significance: These findings reveal a new mechanism by which ovarian CSCs interact with the tumor microenvironment, promoting cell proliferation and tumor initiation.
AB - Cancer progression and recurrence are linked to a rare population of cancer stem cells (CSC). Here, we hypothesized that interactions with the extracellular matrix drive CSC proliferation and tumor-initiating capacity and investigated the functions of scaffold protein tissue transglutaminase (TG2) in ovarian CSC. Complexes formed by TG2, fibronectin (FN), and integrin b1 were enriched in ovarian CSC and detectable in tumors. A function-inhibiting antibody against the TG2 FN-binding domain suppressed complex formation, CSC proliferation as spheroids, tumor-initiating capacity, and stemness-associated Wnt/b-catenin signaling. Disruption of the interaction between TG2 and FN also blocked spheroid formation and the response to Wnt ligands. TG2 and the Wnt receptor Frizzled 7 (Fzd7) form a complex in cancer cells and tumors, leading to Wnt pathway activation. Protein docking and peptide inhibition demonstrate that the interaction between TG2 and Fzd7 overlaps with the FN-binding domain of TG2. These results support a new function of TG2 in ovarian CSC, linked to spheroid proliferation and tumor-initiating capacity and mediated through direct interactions with Fzd7. We propose this complex as a new stem cell target. Significance: These findings reveal a new mechanism by which ovarian CSCs interact with the tumor microenvironment, promoting cell proliferation and tumor initiation.
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U2 - 10.1158/0008-5472.CAN-17-2319
DO - 10.1158/0008-5472.CAN-17-2319
M3 - Article
C2 - 29510995
AN - SCOPUS:85048049463
VL - 78
SP - 2990
EP - 3001
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 11
ER -
