Biology subjects

Sinnberg, T.

Publications and source records attributed to Sinnberg, T..

4 recordsLinked to original sources

bioRxiv2026

Genomic correlates of metastatic competence and progression in human melanoma

Genomic events and their timing that grant a primary tumour the competence to disseminate remain poorly defined. We performed sequencing of 247 stage I/II primary cutaneous melanomas (CMs) and 60 matched metastases without intervening therapy from a prospectively followed registry cohort with a median followup of 92 months, integrating copy-number, mutational, protein and spatial-transcriptomic analyses. Relapse was not distinguished by oncogenic point mutations, which were largely shared between primaries and metastases, but by somatic copy-number alterations (SCNAs) and global chromosomal instability. We defined OncoCycle, a six-gene copy-number signature (amplification of CDK4, MCL1 and CD276; biallelic loss of CDKN2A, CDKN2B and TP53BP1) that predicted relapse independently of established clinicopathological features in melanoma, and a pan-cancer analysis. In matched pairs, metastatic progression was driven by continued copy-number evolution and reduction in intra-tumoural heterogeneity, rather than by acquired point mutations, and OncoCycle alterations from primary tumours were preserved in metastasis seeding clones. Clonal reconstruction revealed both monoclonal and polyclonal metastasis seeding, and spatial transcriptomics resolved copy-number-defined metastatic subclones occupying and programming distinct immune and stromal niches. Thus, metastatic competence was primed early by focal SCNAs on a background of chromosomal instability, elaborated by continued copy-number evolution during dissemination and spatio-temporal interactions with the tumour-microenvironment.

genomics↗

bioRxiv2026

High immune receptor clonality in melanoma-draining lymph nodes associates with immune dysfunction and poor survival

Tumor-draining lymph nodes (tdLNs) are critical hubs of anti-tumor immunity but are also vulnerable to tumor-mediated immunosuppression. We analyzed T cell and B cell receptor (TCR/BCR) repertoires and transcriptomes from sentinel and non-sentinel lymph nodes of patients with melanoma from a historical pre-immune checkpoint inhibitor cohort (1994-2002) and an independent contemporary validation cohort (2022-2024). Melanoma-positive lymph nodes exhibited increased immune receptor clonality compared with tumor-free nodes. While average clonality showed no consistent association with outcome, the presence of extreme high-clonality outliers in individual lymph nodes was strongly associated with poor melanoma-specific survival. These outliers were characterized by a loss of lymphocyte-related genes and activation markers, an enrichment of melanocytic transcripts, and the suppression of immune signaling pathways, consistent with local immune dysfunction. Increased clonality was confined to lymph nodes and not observed in the peripheral blood. T cell responses to melanocyte differentiation antigens were infre-quently shared between lymph nodes and peripheral blood, highlighting immune compartmentalization.

immunology↗

bioRxiv2024

Constitutive expression of IκBζ promotes tumor growth and immunotherapy resistance in melanoma

BackgroundI{kappa}B{zeta}, a rather unknown co-regulator of NF-{kappa}B, is mostly inducibly expressed and can either activate or repress a specific subset of NF-{kappa}B target genes. While its role as a transcriptional regulator of various cytokines and chemokines in immune cells has been revealed, I{kappa}B{zeta}s function in solid cancer remains unclear. MethodsWe investigated I{kappa}B{zeta} expression in melanoma, and assessed its impact on target gene expression, tumor growth, and response to immunotherapy in melanoma cell lines, mouse models, and patient samples. ResultsUnlike in other cell types, I{kappa}B{zeta} protein was found to be constitutively expressed in a subfraction of melanoma cell lines, and around 35% of melanoma cases. This atypical expression pattern of I{kappa}B{zeta} did not correlate with its mRNA levels or known driver mutations, but instead seemed to result from changes in its post-transcriptional or post-translational regulation. Deleting constitutively expressed I{kappa}B{zeta} abrogated the activity and chromatin association of STAT3 and p65, leading to reduced expression of the pro-proliferative cytokines IL-1{beta} and IL-6 in melanoma cells. Consequently, loss of tumor-derived I{kappa}B{zeta} suppressed self-sustained melanoma cell growth both in vitro and in vivo. Additionally, constitutive I{kappa}B{zeta} expression suppressed the induction of the chemokines CXCL9, CXCL10, and CCL5, which impaired the recruitment of NK and CD8+ T-cells to the tumor, causing resistance to -PD-1 immunotherapy in mice. Furthermore, the expression of tumor-derived I{kappa}B{zeta} also correlated with the absence of CD8+ T-cells in human melanoma samples and progressive disease during immunotherapy. ConclusionWe propose that tumor-derived I{kappa}B{zeta} could serve as a new therapeutic target and prognostic marker that characterizes melanoma with high tumor cell proliferation, cytotoxic T- and NK-cell exclusion, and unfavorable immunotherapy responses. Targeting I{kappa}B{zeta} expression might open up a new therapy option to re-establish the recruitment of cytotoxic cells, thereby resensitizing for immunotherapy. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=126 SRC="FIGDIR/small/613946v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@76389aorg.highwire.dtl.DTLVardef@17e3f1eorg.highwire.dtl.DTLVardef@161d491org.highwire.dtl.DTLVardef@1ca9f2d_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2020

Individualised Proteogenomics Applied to Analysis of Amino Acid Variants in Malignant Melanoma

Analysis of patient-specific nucleotide variants is a cornerstone of personalised medicine. Although only 2% of the genomic sequence is protein-coding, mutations occurring in these regions have the potential to influence protein structure and may have severe impact on disease aetiology. Of special importance are variants that affect modifiable amino acid residues, as protein modifications involved in signal transduction networks cannot be analysed by genomics. Proteogenomics enables analysis of proteomes in context of patient- or tissue-specific non-synonymous nucleotide variants. Here, we developed a proteogenomics workflow and applied it to study resistance to serine/threonine-protein kinase B-raf (BRAF) inhibitor (BRAFi) vemurafenib in malignant melanoma cell line A375. This approach resulted in high identification and quantification of non-synonymous nucleotide variants and (phospho)proteins. We integrated multi-omic datasets to reconstruct the perturbed signalling networks associated with BRAFi resistance and to predict drug therapies with the potential to disrupt BRAFi resistance mechanism in A375 cells. Notably, we showed that aurora kinase A (AURKA) inhibition is effective and specific against BRAFi resistant A375 cells. Furthermore, we investigated nucleotide variants that interfere with protein post-translational modification (PTM) status and potentially influence cell signalling. Mass spectrometry (MS) measurements confirmed variant-driven PTM changes in 12 proteins; among them was the runt-related transcription factor 1 (RUNX1) displaying a variant on a known phosphorylation site S(Ph)276L. We confirmed the loss of phosphorylation site by MS and demonstrated the impact of this variant on RUNX1 interactome.

cancer biology↗