Biology subjects

Szasz, A. M.

Publications and source records attributed to Szasz, A. M..

4 recordsLinked to original sources

bioRxiv2024

Predicting immune checkpoint therapy response in three independent metastatic melanoma cohorts

While Immune checkpoint inhibition (ICI) therapy shows significant efficacy in metastatic melanoma, only about 50% respond, lacking reliable predictive methods. We introduce a panel of six proteins aimed at predicting response to ICI therapy. Evaluating previously reported proteins in two untreated melanoma cohorts, we used a published predictive model (EaSIeR score) to identify potential proteins distinguishing responders and non-responders. Six proteins initially identified in the ICI cohort correlated with predicted response in the untreated cohort. Additionally, three proteins correlated with patient survival, both at the protein, and at the transcript levels, in an independent immunotherapy treated cohort. Our study identifies predictive biomarkers across three melanoma cohorts, suggesting their use in therapeutic decision-making. O_FIG O_LINKSMALLFIG WIDTH=164 HEIGHT=200 SRC="FIGDIR/small/592032v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@754668org.highwire.dtl.DTLVardef@1616263org.highwire.dtl.DTLVardef@827009org.highwire.dtl.DTLVardef@1899ba7_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2023

Histopathology-assisted proteogenomics provides foundations for stratification of melanoma metastases

Here we describe the histopathology-driven proteogenomic landscape of 142 treatment-naive metastatic melanoma samples. We identified five proteomic subtypes that integrate the immune and stroma microenvironment components, and associate with clinical and histopathological parameters, providing foundations for an in-depth molecular classification of melanoma. Our study shows that BRAF V600 mutated melanomas display heterogeneous biology, where the presence of an oncogene-induced senescence-like phenotype improves patient survival. Therefore, we propose a mortality-risk-based stratification, which may contribute to a more personalized approach to patient treatment. We also found a strong association between tumor microenvironment composition, disease progression, and patient outcome supported by single-cell omic signatures that point to straightforward histopathological connective tissue-to-tumor ratio assessment for better informed medical decisions. A melanoma-associated signature of single amino acid variants (SAAV) responsible for remodeling the extracellular matrix was uncovered together with SAAV-derived neoantigen candidates as targets of anti-tumor immune responses. Overall, this study offers comprehensive stratifications of melanoma metastases that may help develop tailored strategies for diagnosing and treating the disease.

cancer biology↗

bioRxiv2022

Proteogenomic Characterization Reveals Therapeutic Opportunities Related to Mitochondrial Function in Melanoma

The dynamics of more than 1900 mitochondrial proteins was explored through quantitative proteomics in 151 melanoma-related tissue samples of both surgical and autopsy origin. Dysregulation of mitochondrial pathways in primary tumors, metastases, and peritumoral tissues was correlated with age and survival of patients, as well as with tumor cell proliferation and the BRAF mutation status of the tumors. The outlined proteomic landscape confirmed the central role of a pathologically upregulated mitochondrial translation machinery and oxidative phosphorylation (OXPHOS) in the development, proliferation, and progression of melanomas. Our results from different melanoma cell lines confirmed our findings and we could document that treatments with selected OXPHOS inhibitors and antibiotics successfully impaired tumor cell proliferation. In addition, we provided proteomic evidence on the mechanism-of-action of the different treatments. These observations could contribute to the development of therapeutic approaches targeting the mitochondrial pathology in melanoma. TOC figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=134 SRC="FIGDIR/small/513481v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@11f21e2org.highwire.dtl.DTLVardef@e98c64org.highwire.dtl.DTLVardef@100145forg.highwire.dtl.DTLVardef@399284_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIMitochondrial proteome landscape outlined in 151 melanoma-related samples C_LIO_LIMitochondrial Translation and OXPHOS impact disease severity and survival C_LIO_LIBRAF V600E mutation correlates with upregulation of mitochondrial energy production C_LIO_LITargeting the mitochondrial OXPHOS and ribosomes impairs tumor cell proliferation C_LIO_LITherapeutic opportunities complementary to the standard of care are proposed C_LI In briefMitochondrial proteome profiling of melanomas reveals dysregulation in major metabolic pathways, suggesting a central role of the mitochondria within the development and progression of melanoma. Targeting mitochondrial pathways has the potential to impact the course of the disease, which provides opportunities for complementary drug interventions.

cancer biology↗

bioRxiv2021

Proteogenomics Reveals how Metastatic Melanoma Modulates the Immune System to Allow Immune Evasion

Malignant melanoma (MM) develops from the melanocytes and in its advanced stage is the most aggressive type of skin cancer. Here we report a comprehensive analysis on a prospective cohort study, including non-tumor, primary and metastasis tissues (n=77) with the corresponding plasma samples (n=56) from patients with malignant melanoma. The tumors and surrounding tissues were characterized with a combination of high-throughput analyses including quantitative proteomics, phosphoproteomics, acetylomics, and whole exome sequencing (WES) combined with in-depth histopathology analysis. Melanoma cell proliferation highly correlates with dysregulation at the proteome, at the posttranslational- and at the transcriptome level. Some of the changes were also verified in the plasma proteome. The metabolic reprogramming in melanoma includes upregulation of the glycolysis and the oxidative phosphorylation, and an increase in glutamine consumption, while downregulated proteins involved in the degradation of amino acids, fatty acids, and the extracellular matrix (ECM) receptor interaction. The pathways most dysregulated in MM including the MAP kinases-, the PI3K-AKT signaling, and the calcium homeostasis, are among the most affected by mutations, thus, dysregulation in these pathways can be manifested as drivers in melanoma development and progression. The phosphoproteome analysis combined with target-based prediction mapped 75% of the human kinome. Melanoma cell proliferation was driven by two key factors: i) metabolic reprogramming leading to upregulation of the glycolysis and oxidative phosphorylation, supported by HIF-1 signaling pathway and mitochondrial translation; and ii) a dysregulation of the immune system response, which was mirrored by immune system processes in the plasma proteome. Regulation of the melanoma acetylome and expression of deacetylase enzymes discriminated between groups based on tissue origin and proliferation, indicating a way to guide the successful use of HDAC inhibitors in melanoma. The disease progression toward metastasis is driven by the downregulation of the immune system response, including MHC class I and II, which allows tumors to evade immune surveillance. Altogether, new evidence is provided at different molecular levels to allow improved understanding of the melanoma progression, ultimately contributing to better treatment strategies. TOC figure O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/439245v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@937db9org.highwire.dtl.DTLVardef@1230b57org.highwire.dtl.DTLVardef@1bd889eorg.highwire.dtl.DTLVardef@547d90_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗