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Murine Model of Metastatic Liver Tumors in the Setting of Ischemia Reperfusion Injury
Published on: August 30, 2019
Reprogramming liver metastasis-associated macrophages toward an anti-tumoral phenotype through enforced miR-342
Chiara Bresesti1, Eleonora Carito1, Marco Notaro2
1Vector Engineering and In vivo Tumor Targeting Unit, San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Vita-Salute San Raffaele University, 20132 Milan, Italy.
Abstract:
Upon metastatic seeding in the liver, liver macrophages, including Kupffer cells, acquire a transcriptional profile typical of tumor-associated macrophages (TAMs), which support tumor progression. MicroRNAs (miRNAs) fine-tune TAM pro-tumoral functions, making their modulation a promising strategy for macrophage reprogramming into an anti-tumoral phenotype. Here, we analyze the transcriptomic profiles of liver and splenic macrophages, identifying miR-342-3p as a key regulator of liver macrophage function. miR-342-3p is highly active in healthy liver macrophages but significantly downregulated in colorectal cancer liver metastases (CRLMs). Lentiviral vector-engineered liver macrophages enforcing miR-342-3p expression acquire a pro-inflammatory phenotype and reduce CRLM growth. We identify Slc7a11, a cysteine-glutamate antiporter linked to pro-tumoral activity, as a direct miR-342-3p target, which may be at least partially responsible for TAM phenotypic reprogramming. Our findings highlight the potential of in vivo miRNA modulation as a therapeutic strategy for TAM reprogramming, offering an approach to enhance cancer immunotherapy.
Insights
MicroRNAs (miRNAs) can reprogram liver macrophages to fight cancer. Enhancing miR-342-3p in liver macrophages reduces colorectal cancer liver metastasis growth by targeting Slc7a11.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Liver macrophages, including Kupffer cells, adopt tumor-associated macrophage (TAM) phenotypes upon metastatic seeding.
- MicroRNAs (miRNAs) regulate TAM functions, offering therapeutic targets for reprogramming macrophages to an anti-tumoral state.
Purpose of the Study:
- To identify key microRNAs regulating liver macrophage function in colorectal cancer liver metastases (CRLMs).
- To investigate the therapeutic potential of modulating miR-342-3p for cancer immunotherapy.
Main Methods:
- Transcriptomic profiling of liver and splenic macrophages.
- Lentiviral vector-mediated enhancement of miR-342-3p expression in liver macrophages.
- Identification of direct microRNA targets using bioinformatic and experimental approaches.
Main Results:
- miR-342-3p is highly expressed in healthy liver macrophages but downregulated in CRLMs.
- Enforced miR-342-3p expression in liver macrophages induced a pro-inflammatory phenotype and suppressed CRLM growth.
- Slc7a11, a cysteine-glutamate antiporter, was identified as a direct miR-342-3p target involved in TAM reprogramming.
Conclusions:
- miR-342-3p is a critical regulator of liver macrophage function and a potential therapeutic target in CRLMs.
- In vivo miRNA modulation represents a promising strategy for TAM reprogramming and enhancing cancer immunotherapy.
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