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MEK activation modulates glycolysis and supports suppressive myeloid cells in TNBC
- Source :
- JCI Insight
- Publication Year :
- 2020
- Publisher :
- American Society for Clinical Investigation, 2020.
-
Abstract
- 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.<br />Longitudinally-derived TNBC xenografts identify acquired KRAS mutation/MEK activation as a driving feature of CXCL1/2-mediated MDSC recruitment.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Chemokine
Myeloid
medicine.medical_treatment
Immunology
MAP Kinase Kinase 1
Mice, Nude
Antineoplastic Agents
Apoptosis
Triple Negative Breast Neoplasms
Biology
medicine.disease_cause
03 medical and health sciences
Mice
0302 clinical medicine
Breast cancer
medicine
Biomarkers, Tumor
Tumor Cells, Cultured
Animals
Humans
Cell Proliferation
Myeloid-Derived Suppressor Cells
Immunosuppression
General Medicine
Xenograft Model Antitumor Assays
CXCL1
Gene Expression Regulation, Neoplastic
CXCL2
030104 developmental biology
medicine.anatomical_structure
Oncology
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
biology.protein
Cancer research
ras Proteins
CXCL9
Female
KRAS
Glycolysis
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 23793708
- Volume :
- 5
- Issue :
- 15
- Database :
- OpenAIRE
- Journal :
- JCI Insight
- Accession number :
- edsair.doi.dedup.....90361bcbac237996e5a9597354a3a9a4