Abstract

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.

Original languageEnglish (US)
Pages (from-to)4063-4076
Number of pages14
JournalJournal of Clinical Investigation
Volume125
Issue number11
DOIs
StatePublished - Nov 2 2015

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Endometrial Neoplasms
Macrophages
Ligands
Neoplasms
Tumor Microenvironment
Uterus
Uterine Neoplasms
Chemokine CCL2
Protein-Serine-Threonine Kinases
Therapeutics
Cytokines
Gene Expression
Survival

ASJC Scopus subject areas

  • Medicine(all)

Cite this

LKB1 loss promotes endometrial cancer progression via CCL2-dependent macrophage recruitment. / Peña, Christopher G.; Nakada, Yuji; Saatcioglu, Hatice D.; Aloisio, Gina M.; Cuevas, Ileana; Zhang, Song; Miller, David S.; Lea, Jayanthi S.; Wong, Kwok Kin; DeBerardinis, Ralph J.; Amelio, Antonio L.; Brekken, Rolf A.; Castrillon, Diego H.

In: Journal of Clinical Investigation, Vol. 125, No. 11, 02.11.2015, p. 4063-4076.

Research output: Contribution to journalArticle

Peña, Christopher G. ; Nakada, Yuji ; Saatcioglu, Hatice D. ; Aloisio, Gina M. ; Cuevas, Ileana ; Zhang, Song ; Miller, David S. ; Lea, Jayanthi S. ; Wong, Kwok Kin ; DeBerardinis, Ralph J. ; Amelio, Antonio L. ; Brekken, Rolf A. ; Castrillon, Diego H. / LKB1 loss promotes endometrial cancer progression via CCL2-dependent macrophage recruitment. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 11. pp. 4063-4076.
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AU - Castrillon, Diego H.

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