TY - JOUR
T1 - LKB1 loss promotes endometrial cancer progression via CCL2-dependent macrophage recruitment
AU - Peña, Christopher G.
AU - Nakada, Yuji
AU - Saatcioglu, Hatice D.
AU - Aloisio, Gina M.
AU - Cuevas, Ileana
AU - Zhang, Song
AU - Miller, David S.
AU - Lea, Jayanthi S.
AU - Wong, Kwok Kin
AU - DeBerardinis, Ralph J.
AU - Amelio, Antonio L.
AU - Brekken, Rolf A.
AU - Castrillon, Diego H.
PY - 2015/11/2
Y1 - 2015/11/2
N2 - Endometrial cancer is the most common gynecologic malignancy and the fourth most common malignancy in women. For most patients in whom the disease is confined to the uterus, treatment results in successful remission; however, there are no curative treatments for tumors that have progressed beyond the uterus. The serine/threonine kinase LKB1 has been identified as a potent suppressor of uterine cancer, but the biological modes of action of LKB1 in this context remain incompletely understood. Here, we have shown that LKB1 suppresses tumor progression by altering gene expression in the tumor microenvironment. We determined that LKB1 inactivation results in abnormal, cell-autonomous production of the inflammatory cytokine chemokine (C-C motif) ligand 2 (CCL2) within tumors, which leads to increased recruitment of macrophages with prominent tumor-promoting activities. Inactivation of Ccl2 in an Lkb1-driven mouse model of endometrial cancer slowed tumor progression and increased survival. In human primary endometrial cancers, loss of LKB1 protein was strongly associated with increased CCL2 expression by tumor cells as well as increased macrophage density in the tumor microenvironment. These data demonstrate that CCL2 is a potent effector of LKB1 loss in endometrial cancer, creating potential avenues for therapeutic opportunities.
AB - Endometrial cancer is the most common gynecologic malignancy and the fourth most common malignancy in women. For most patients in whom the disease is confined to the uterus, treatment results in successful remission; however, there are no curative treatments for tumors that have progressed beyond the uterus. The serine/threonine kinase LKB1 has been identified as a potent suppressor of uterine cancer, but the biological modes of action of LKB1 in this context remain incompletely understood. Here, we have shown that LKB1 suppresses tumor progression by altering gene expression in the tumor microenvironment. We determined that LKB1 inactivation results in abnormal, cell-autonomous production of the inflammatory cytokine chemokine (C-C motif) ligand 2 (CCL2) within tumors, which leads to increased recruitment of macrophages with prominent tumor-promoting activities. Inactivation of Ccl2 in an Lkb1-driven mouse model of endometrial cancer slowed tumor progression and increased survival. In human primary endometrial cancers, loss of LKB1 protein was strongly associated with increased CCL2 expression by tumor cells as well as increased macrophage density in the tumor microenvironment. These data demonstrate that CCL2 is a potent effector of LKB1 loss in endometrial cancer, creating potential avenues for therapeutic opportunities.
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U2 - 10.1172/JCI82152
DO - 10.1172/JCI82152
M3 - Article
C2 - 26413869
AN - SCOPUS:84946762066
SN - 0021-9738
VL - 125
SP - 4063
EP - 4076
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
ER -