Biology subjects

Jungwirth, U.

Publications and source records attributed to Jungwirth, U..

4 recordsLinked to original sources

bioRxiv2026

ImmTACs overcome cytotoxic T cell suppression

Immune mobilizing monoclonal TCR against cancer (ImmTAC) are cancer therapeutics that activate T cells through recognition of a tumor-associated antigenic MHC/peptide complex. A first-in-class ImmTAC, Tebentafusp, is approved for the treatment of metastatic uveal melanoma. While clinical efficacy is thus established, the cellular mechanisms underpinning ImmTAC action are not fully resolved. Using a recently established experimental strategy to generate suppressed human primary cytotoxic T lymphocytes (CTL), we have investigated an ImmTAC that recognizes a peptide derived from the tumor associated antigen NY-ESO-1 in comparison to direct engagement of a TCR recognizing the same MHC/peptide complex. In response to endogenous antigen presentation, ImmTACs could elicit tumor cell cytolysis by suppressed CTL, but not IFN{gamma} secretion, in a manner dependent on the engager affinity for CD3{varepsilon}. ImmTACs enhanced the efficient execution of subcellular CTL polarization steps required for effective cytolysis and could trigger calcium signaling. These data establish that ImmTACs activate CTL similarly to direct engagement of a TCR by MHC/peptide and are likely to retain this capability under suppressive conditions such as in the tumor microenvironment.

immunology↗

bioRxiv2024

YAP engages RIF1 to dampen replication stress in squamous cell carcinoma.

Squamous cell carcinoma cells experience high levels of replication stress due to oncogene-induced cell cycle deregulation. How such cells sustain rapid proliferation despite replication stress is still not fully understood. Here, we discovered, using rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) analysis, that the squamous cell carcinoma oncoprotein YAP engages with RIF1, a key regulator of DNA replication and DNA damage repair under replication stress. RIF1 is highly expressed in human squamous cell carcinoma cell lines and tissues and upregulated during tumour progression. Depletion of RIF1 in squamous cell carcinoma cells exacerbates their endogenous replication stress. Mechanistically, we show that YAP interacts with RIF1 specifically at broken replication forks, and that YAP depletion impairs DNA damage repair under replication stress. Our results thus demonstrate that YAPs oncogenic functions in squamous cancers involve both transcriptional and non-transcriptional mechanisms, the latter through interaction with RIF1 to dampen replication stress.

cancer biology↗

bioRxiv2020

Impairment of a distinct cancer-associated fibroblast population limits tumour growth and metastasis

Profiling studies have revealed considerable phenotypic heterogeneity in cancer-associated fibroblasts (CAFs) present within the tumour microenvironment, however, functional characterisation of different CAF subsets is hampered by the lack of specific markers defining these populations. Here we show that genetic deletion of the Endo180 (MRC2) receptor, predominantly expressed by a population of matrix-remodelling CAFs, profoundly limits tumour growth and metastasis; effects that can be recapitulated in 3D co-culture assays. This impairment results from a CAF-intrinsic contractility defect and reduced CAF viability which, coupled with the lack of phenotype in the normal mouse, demonstrates that upregulated Endo180 expression by a specific, potentially targetable CAF subset is required to generate a supportive tumour microenvironment. Further, characterisation of a tumour subline selected via serial in vivo passage for its ability to overcome these stromal defects provides important insight into how tumour cells adapt to a non-activated stroma in the early stages of metastatic colonisation.

cancer biology↗

bioRxiv2018

Metabolic adaptability in metastatic breast cancer by AKR1B10-dependent balancing of glycolysis and fatty acid oxidation

The different stages of the metastatic cascade present distinct metabolic challenges to tumour cells and an altered tumour metabolism associated with successful metastatic colonisation provides a therapeutic vulnerability in disseminated disease. We identify the aldo-keto reductase AKR1B10 as a metastasis enhancer that has little impact on primary tumour growth or dissemination but promotes effective tumour growth in secondary sites and, in human disease, is associated with an increased risk of distant metastatic relapse. AKR1B10High tumour cells have reduced glycolytic capacity and dependency on glucose as fuel source but increased utilisation of fatty acid oxidation. Conversely, in both 3D tumour spheroid assays and in vivo metastasis assays, inhibition of fatty acid oxidation blocks AKR1B10High-enhanced metastatic colonisation with no impact on AKR1B10Low cells. Finally, mechanistic analysis supports a model in which AKR1B10 serves to limit the toxic side effects of oxidative stress thereby sustaining fatty acid oxidation in metabolically challenging metastatic environments.

cancer biology↗