MEK activation modulates glycolysis and supports suppressive myeloid cells in TNBC.

Autor:	Franklin DA; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Sharick JT; Department of Biomedical Engineering, School of Engineering, Vanderbilt University, Nashville, Tennessee, USA.; Morgridge Institute for Research, University of Wisconsin-Madison, Wisconsin, USA., Ericsson-Gonzalez PI; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA., Sanchez V; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA., Dean PT; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Opalenik SR; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA., Cairo S; Xentech, Genopole Campus 3, Evry, France., Judde JG; Xentech, Genopole Campus 3, Evry, France., Lewis MT; Baylor College of Medicine, Houston, Texas, USA., Chang JC; Department of Radiation Oncology, Houston Methodist Research Institute, Houston, Texas, USA., Sanders ME; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.; Department of Pathology, Microbiology and Immunology and., Cook RS; Department of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville Tennessee, USA., Skala MC; Morgridge Institute for Research, University of Wisconsin-Madison, Wisconsin, USA.; Department of Biomedical Engineering, College of Engineering, University of Wisconsin-Madison, Wisconsin, USA., Bordeaux J; Navigate BioPharma Services, Inc., Carlsbad, California, USA., Orozco Bender J; Navigate BioPharma Services, Inc., Carlsbad, California, USA., Vaupel C; Navigate BioPharma Services, Inc., Carlsbad, California, USA., Geiss G; NanoString Technologies, Seattle, Washington, USA., Hinerfeld D; NanoString Technologies, Seattle, Washington, USA., Balko JM; Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.; Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2020 Aug 06; Vol. 5 (15). Date of Electronic Publication: 2020 Aug 06.
DOI:	10.1172/jci.insight.134290
Abstrakt:	Triple-negative breast cancers (TNBCs) are heterogeneous and aggressive, with high mortality rates. TNBCs frequently respond to chemotherapy, yet many patients develop chemoresistance. The molecular basis and roles for tumor cell-stromal crosstalk in establishing chemoresistance are complex and largely unclear. Here we report molecular studies of paired TNBC patient-derived xenografts (PDXs) established before and after the development of chemoresistance. Interestingly, the chemoresistant model acquired a distinct KRASQ61R mutation that activates K-Ras. The chemoresistant KRAS-mutant model showed gene expression and proteomic changes indicative of altered tumor cell metabolism. Specifically, KRAS-mutant PDXs exhibited increased redox ratios and decreased activation of AMPK, a protein involved in responding to metabolic homeostasis. Additionally, the chemoresistant model exhibited increased immunosuppression, including expression of CXCL1 and CXCL2, cytokines responsible for recruiting immunosuppressive leukocytes to tumors. Notably, chemoresistant KRAS-mutant tumors harbored increased numbers of granulocytic myeloid-derived suppressor cells (gMDSCs). Interestingly, previously established Ras/MAPK-associated gene expression signatures correlated with myeloid/neutrophil-recruiting CXCL1/2 expression and negatively with T cell-recruiting chemokines (CXCL9/10/11) across patients with TNBC, even in the absence of KRAS mutations. MEK inhibition induced tumor suppression in mice while reversing metabolic and immunosuppressive phenotypes, including chemokine production and gMDSC tumor recruitment in the chemoresistant KRAS-mutant tumors. These results suggest that Ras/MAPK pathway inhibitors may be effective in some breast cancer patients to reverse Ras/MAPK-driven tumor metabolism and immunosuppression, particularly in the setting of chemoresistance.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu