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The following is a summary of “myCAF-derived exosomal PWAR6 accelerates CRC liver metastasis via altering glutamine availability and NK cell function in the tumor microenvironment,” published in the December 2024 issue of Hematology by Fang et al.
Liver metastasis from colorectal cancer (CRC) significantly impacts survival. Myofibroblastic cancer-associated fibroblasts (myCAFs) drive tumor progression and metastasis through exosomal signaling.
Researchers conducted a retrospective study to explore the role of myCAF-derived exosomes in CRC liver metastases (CRLM).
They performed single-cell analysis to identify an increase in myCAFs in CRLM. Exosomal sequencing revealed PWAR6 as the most elevated lncRNA. In vivo and in vitro assays assessed PWAR6’s impact on CRC cell stemness, migration, and glutamine uptake. RNA pulldown, RNA immunoprecipitation (RIP), and Co-immunoprecipitation (co-IP) assays explored the PWAR6/NRF2/SLC38A2 signaling axis, while flow cytometry evaluated NK cell activity and cytotoxicity.
They analyzed PWAR6 expression levels in patients with CRLM and correlated them with 68Ga FAPI-PET/CT SUVmax values, finding significantly higher expression in CRLM compared to non-LM cases and normal tissues. Regression analysis and survival data identified PWAR6 as a negative prognostic marker. Mechanistically, they examined how PWAR6 inhibits NRF2 degradation by binding to Keap1, leading to increased SLC38A2 expression and enhanced glutamine uptake in CRC cells, which limits glutamine availability for NK cells.
Investigators found that myCAF-derived exosomal PWAR6 served as a critical marker for CRLM. Targeted inhibition with ASO-PWAR6, combined with FAPI treatment, effectively reduced metastasis in preclinical models, suggesting promising therapeutic potential.
Source: jhoonline.biomedcentral.com/articles/10.1186/s13045-024-01643-5#Abs1
