TY - JOUR
T1 - Endometriosis-Associated Mesenchymal Stem Cells Support Ovarian Clear Cell Carcinoma through Iron Regulation
AU - Atiya, Huda I.
AU - Frisbie, Leonard
AU - Goldfeld, Ester
AU - Orellana, Taylor
AU - Donnellan, Nicole
AU - Modugno, Francesmary
AU - Calderon, Michael
AU - Watkins, Simon
AU - Zhang, Rugang
AU - Elishaev, Esther
AU - Soong, Thing Rinda
AU - Vlad, Anda
AU - Coffman, Lan
N1 - Publisher Copyright:
© 2022 The Authors; Published by the American Association for Cancer Research.
PY - 2022/12/1
Y1 - 2022/12/1
N2 - Ovarian clear cell carcinoma (OCCC) is a deadly and treatment-resistant cancer, which arises within the unique microenvironment of endometriosis. In this study, we identified a subset of endometriosis-derived mesenchymal stem cells (enMSC) characterized by loss of CD10 expression that specifically support OCCC growth. RNA sequencing identified alterations in iron export in CD10-negative enMSCs and reciprocal changes in metal transport in cocultured OCCC cells. CD10-negative enMSCs exhibited elevated expression of iron export proteins hephaestin and ferroportin and donate iron to associated OCCCs, functionally increasing the levels of labile intracellular iron. Iron is necessary for OCCC growth, and CD10-negative enMSCs prevented the growth inhibitory effects of iron chelation. In addition, enMSC-mediated increases in OCCC iron resulted in a unique sensitivity to ferroptosis. In vitro and in vivo, treatment with the ferroptosis inducer erastin resulted in significant death of cancer cells grown with CD10-negative enMSCs. Collectively, this work describes a novel mechanism of stromal-mediated tumor support via iron donation. This work also defines an important role of endometriosisassociated MSCs in supporting OCCC growth and identifies a critical therapeutic vulnerability of OCCC to ferroptosis based on stromal phenotype.
AB - Ovarian clear cell carcinoma (OCCC) is a deadly and treatment-resistant cancer, which arises within the unique microenvironment of endometriosis. In this study, we identified a subset of endometriosis-derived mesenchymal stem cells (enMSC) characterized by loss of CD10 expression that specifically support OCCC growth. RNA sequencing identified alterations in iron export in CD10-negative enMSCs and reciprocal changes in metal transport in cocultured OCCC cells. CD10-negative enMSCs exhibited elevated expression of iron export proteins hephaestin and ferroportin and donate iron to associated OCCCs, functionally increasing the levels of labile intracellular iron. Iron is necessary for OCCC growth, and CD10-negative enMSCs prevented the growth inhibitory effects of iron chelation. In addition, enMSC-mediated increases in OCCC iron resulted in a unique sensitivity to ferroptosis. In vitro and in vivo, treatment with the ferroptosis inducer erastin resulted in significant death of cancer cells grown with CD10-negative enMSCs. Collectively, this work describes a novel mechanism of stromal-mediated tumor support via iron donation. This work also defines an important role of endometriosisassociated MSCs in supporting OCCC growth and identifies a critical therapeutic vulnerability of OCCC to ferroptosis based on stromal phenotype.
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U2 - 10.1158/0008-5472.CAN-22-1294
DO - 10.1158/0008-5472.CAN-22-1294
M3 - Article
C2 - 36219681
AN - SCOPUS:85144588493
SN - 0008-5472
VL - 82
SP - 4680
EP - 4693
JO - Cancer Research
JF - Cancer Research
IS - 24
ER -