Project description:This project aimed to identify a specific target for chromosome 8p deletions. Using large-scale functional-genomic screening data of over 527 well-characterized cancer cell lines. We were able to identify the dependency of SLC25A28 (Mitoferrin-2, MFRN2), a mitochondrial iron transporter, in chromosome 8p deleted cancer cell lines. Interestingly, we found that SLC25A37 (Mitoferrin-1, MFRN1), the paralog of MFRN2, resides on chromosome 8p and is frequently deleted in liver cancer. We found a strong correlation between the cellular dependency on MFRN2 and the MFRN1 expression levels, possibly explaining why MFRN2 is a synthetic lethal target for 8p deletions. Our study discovered MFRN2 as a target for a therapeutic strategy in chromosome 8p deleted cancer specimens. Further, it revealed MFRN1 as a biomarker that predicts the response to MFRN2-directed therapy.
Project description:Osteosarcoma (OS), a malignant bone tumor with limited treatment options, exhibits low sensitivity to immune checkpoint therapy (ICT). Through genomics and transcriptomics analyses, we have identified a subgroup of OS with methylthioadenosine phosphorylase (MTAP) deletion, which contributes to ICT resistance, leading to a 'cold' tumor microenvironment. MTAP-deleted OS relies on methionine metabolism, and is sensitive to methionine intervention, achieved either through dietary restriction or inhibition of methionine adenosyltransferase 2a (MAT2A), a key enzyme in methionine metabolism. We have further demonstrated that methionine intervention triggers PD-L1 transcription factor IKAROS family zinc finger 1 (IKZF1) and enhances PD-L1 expression in MTAP-deleted OS cells. Methionine intervention also activates the immune-related signaling pathways in MTAP-deleted OS cells and attracts CD8+ T cells, thereby enhancing the efficacy of ICT. Combining methionine intervention with ICT provides a significant survival benefit in MTAP-deleted OS murine models, suggesting a rationale for combination regimens in OS ICT.
Project description:ChIP Seq revealed presence of unique CEN-proximal neocentromere peaks in CEN deleted clones. Using 10 million reads generated from ChIP-seq for each sample, chromosome wide maps for CENP-A enrichment were generated . Examination of CENP-A enrichment in Input/IP samples of various CEN deleted C. albicans clones
Project description:PTPN2 was deleted from a selection of murine and human cancer cells using CRISPR/Cas9. The loss-of-function phenotype was assessed in vitro with cytokine stimulation or vehicle control.