Biology subjects

Tsai, K. K.

Publications and source records attributed to Tsai, K. K..

4 recordsLinked to original sources

bioRxiv2026

WRN deficiency generates oncogenic rearrangements at TA-rich tandem repeats

Werner syndrome, a premature-aging disorder caused by inherited loss of the WRN helicase, predisposes to a narrow set of cancers, including melanoma and sarcoma, through mechanisms that have been unclear. WRN resolves the secondary structures that TA-dinucleotide repeats form, a role established for the expanded repeats of mismatch-repair-deficient cancers. We show that WRN loss also destabilizes native, unexpanded TA-rich tandem repeats, which become fragile sites where chromosomes break and rearrange. In melanoma these rearrangements recurrently produce an identical 15.7Mb-long deletion that transcriptionally activates TERT, the earliest driver of these tumors, and separately disrupt tumor suppressors such as CDKN2A/B and NF1. The same class of rearrangement occurs in WRN-deficient cancers of other types. WRN deficiency is thus a source of instability at TA-rich tandem repeats that generates oncogenic rearrangements.

cancer biology↗

bioRxiv2025

NCOR2 represses MHC class I molecule expression to drive metastatic progression of breast cancer

Metastatic progression depends upon the ability of disseminated tumor cells to evade immune surveillance. MHC molecule expression facilitates T cell recognition and activation to permit the eradication of metastatic tumor cells. We identified nuclear corepressor 2 (NCOR2) as a key epigenetic regulator of MHC class I molecule expression on breast tumor cells. Patients with triple negative breast cancers (TNBC) that expressed high levels of NCOR2 also exhibited reduced metastasis free survival and decreased MHC class I expression, and the metastatic lesions in patients with TNBC had high nuclear NCOR2 and reduced CD8 T cell levels and activity. Genetically and experimentally reducing NCOR2 expression in tumor cells permitted interferon gamma upregulation of MHC class I, and potentiated CD8 T cell activity and induction of apoptosis to repress metastatic progression of disseminated breast cancer cells. These studies provide evidence to support NCOR2 as a targetable epigenetic regulator of metastasis towards which therapies could be developed to reduce patient mortality.

cancer biology↗

bioRxiv2024

Targeted DNA Sequencing of Cutaneous Melanoma Identifies Prognostic and Predictive Alterations

ImportanceCutaneous melanoma (CM) can be molecularly classified into four groups: BRAF mutant, NRAS mutant, NF1 loss, and triple wild type (TWT) tumors lacking any of these three alterations. In the era of immune checkpoint inhibition (ICI) and targeted molecular therapy, the clinical significance of these groups remains unclear. Here, we integrate targeted DNA sequencing with comprehensive clinical follow-up in CM patients. ObjectiveTo explore how molecular features and tumor mutational burden (TMB) impact outcomes in patients with cutaneous melanoma. DesignThis was a retrospective cohort study that assessed clinical and molecular features from patients with localized or metastatic CM who underwent targeted next-generation sequencing as part of routine clinical care. SettingTertiary referral, comprehensive NCI cancer center from 2013 - 2023. ParticipantsA total of 254 patients with CM who had a CLIA certified targeted sequencing assay performed on their tumor tissue were included ExposureA CLIA certified targeted sequencing assay was performed as standard of care on 254 patients with CM treated at a single institution. Main OutcomeNRAS mutation correlated with significantly worse overall survival compared to other TCGA driver groups. Elevated TMB correlated with improved progression-free survival on combination checkpoint inhibition (anti-PD1 plus anti-CTLA4). ResultsOf 254 patients with cutaneous melanoma, 77 were BRAF mutant (30.3%), 77 were NRAS mutant (30.3%), 47 were NF1 mutant (18.5%), 33 were TWT (13.0%) and the remaining 20 (7.9%) carried mutations in multiple driver genes (BRAF/NRAS/NF1 co-mutated). The majority of this co-mutation group carried mutations in NF1 (n=19 or 90%) with co-occurring mutations in BRAF or NRAS, often with a weaker oncogenic variant. Consistently, NF1 mutant tumors harbored numerous significantly co-altered genes compared to BRAF or NRAS mutant tumors. The majority of TWT tumors (n=29, 87.9%) harbored a pathogenic mutation within a known Ras/MAPK signaling pathway component. Of the 154 cases with available TMB data, the median TMB was 20 (range 0.7 - 266 mutations/Mb). A total of 14 cases (9.1%) were classified as TMB low (<5 mutations/Mb), 64 of 154 (41.6%) were TMB intermediate (>5 and <20 mutations/Mb), 40 of 154 (26.0%) were TMB high (>20 and <50 mutations/Mb) and 36 of 154 (23.4%) were classified as TMB very high (>50 mutations/Mb). NRAS mutant melanoma demonstrated significantly decreased overall survival on multivariable analysis (HR for death 2.95, 95% CI 1.13 - 7.69, p = 0.027, log rank test) compared with other TCGA molecular subgroups. Other factors correlated with decreased overall survival included age and ECOG score. Of the 116 patients in our cohort with available treatment data, 36 received combination dual ICI with anti-CTLA4 and anti-PD1 inhibition as first line therapy. Elevated TMB was associated with significantly longer progression-free survival following dual agent ICI (HR 0.26, 95% CI 0.07 - 0.90, p =0.033, log rank test). Conclusions and RelevanceNRAS mutation in CMs correlated with significantly worse overall survival. Elevated TMB was associated with increased progression-free survival for patients treated with combination dual ICI, supporting the potential utility of TMB as a predictive biomarker for ICI response in melanoma.

cancer biology↗

bioRxiv2020

Single-cell analyses identify circulating anti-tumor CD8 T cells and markers for their enrichment

The ability to monitor anti-tumor CD8+ T cell responses in the blood has tremendous therapeutic potential. Here, we used paired single-cell RNA sequencing and T cell receptor (TCR) sequencing to detect and characterize "tumor matching" (TM) CD8+ T cells in the blood of mice with MC38 tumors and melanoma patients using the TCR as a molecular barcode. TM cells showed increased activation compared to non-matching T cells in blood, and appeared less exhausted than matching counterparts in tumor. Importantly, PD-1, which has been used to identify putative circulating anti-tumor CD8+ T cells, showed poor sensitivity for identifying TM cells. By leveraging the transcriptome we identified candidate cell surface marker panels for TM cells in mice and melanoma patients, and validated NKG2D, CD39, and CX3CR1 in mice. These data demonstrate that the TCR can be used to identify tumor-relevant populations for comprehensive characterization, reveal unique transcriptional properties of TM cells, and develop marker panels for tracking and analysis of these cells. SummaryUsing single-cell RNA-sequencing coupled with TCR sequencing, we detected CD8+ T cell clones shared between blood and tumor in mice and melanoma patients, characterized these matching clones in blood and tumor, and identified potential biomarkers for their isolation in blood.

immunology↗