Project description:Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with 5-year survival of ~50%. Genomic profiling studies have identified important somatic mutations in this disease which presents an opportunity for precision medicine. We demonstrate that KMT2D, a histone methyltransferase harbors somatic mutations in ~17% of HNSCC and is associated with 2-year recurrence in TCGA data. Consistent with algorithmic prediction of bring a driver tumor-suppressor event, its loss results in larger oral tumors in immune-proficient orthotopic models. Mechanistically, we find that KMT2D knockdown or KMT2D mutation causes loss of H3K4me1-marked enhancers harboring IRF7/9 binding sites, which is known to regulate interferon signaling. Indeed, KMT2D loss in human and murine cell lines deregulated transcriptional levels of cytokine expression and impacted numerous immune signaling pathways, including interferon signaling. Consistently, Kmt2d knockdown in murine tumors exhibited decrease in IFN-producing effector T cells and an increase in T-cells with an exhausted phenotype. Epistasis experiments showed that exogenous treatment with IFN abrogated the increased tumor growth in Kmt2d-deficient oral tumors. Together, these results support the role of KMT2D as a tumor suppressor in HNSCC that regulates the tumor microenvironment by modulating H3K4me1-marked enhancers controlling interferon signaling.
Project description:We used scRNA-seq to assess the differential effect of Smyd3 ASOs on the transcriptomic profile of different cell types in the TME of MOC1 tumors.
Project description:We used scRNA-seq to assess the transcriptomic differences in the different cell types of the TME of MOC1 tumors that responded or not to Smyd3 ASOs and anti-PD-1 combination therapy.
Project description:This study compared the transcriptomes of control MOC1 murine oral squamous cell carcinoma cells and MOC1 cells subjected to repeated fractionated irradiation. Three biologically independent samples from each group were analyzed by paired-end RNA sequencing. The study aimed to characterize transcriptional alterations and to provide a mechanistic basis for the subsequent evaluation of COF-Tpy-Se-Cu.
Project description:Patient-derived colorectal cancer organoids were injected into mice to grow into subcutaneous tumors. Tumors were profiled through multiplexed single-cell RNA-sequencing.