Biology subjects

Koessinger, A. L.

Publications and source records attributed to Koessinger, A. L..

3 recordsLinked to original sources

bioRxiv2026

Fibroblast-derived Collagen VI shapes the structure and function of the tumor-immune microenvironment in clear cell renal cell carcinoma

The importance of the extracellular matrix (ECM) influencing tumor biology in stroma-rich tumors is well established. However, the relevance of individual ECM proteins in rather stroma-poor cancers such as clear cell renal cell carcinoma (ccRCC) is ill-defined. Using bulk proteomics, spatial imaging, and single-cell transcriptomics, we identify collagen VI (COL6) as a predominant ECM component of the ccRCC interstitial stroma, synthesized primarily by fibroblasts and pericytes. Using cell-derived matrix (CDM) models, we demonstrate that COL6 is essential for maintaining an isotropic ECM network architecture and governs the broader matrisomal composition, with direct pro-proliferative consequences for tumor cells both in vitro and in situ. Granular spatial analysis reveals that COL6-rich stromal septa constrain tumor-infiltrating T cells to boundary zones, where CD8+PD1+ phenotypes predominate. Importantly, tyrosine kinase inhibition (TKI) with cabozantinib suppresses COL6 expression in fibroblasts in vitro and in ex vivo tumor models, mirroring COL6-depleted CDM phenotypes. Our findings establish COL6 as a central stromal regulator of ccRCC tumor biology and immune contexture, revealing ECM remodeling as an underappreciated mechanism of TKI action, with implications for combination immunotherapy strategies.

cancer biology↗

bioRxiv2024

Versatile roles of Annexin A4 in ccRCC: impact on membrane repair, transcriptional signatures, and composition of the tumor microenvironment

Clear cell renal cell carcinoma (ccRCC) is the most prevalent type of renal malignant disease and is characterized by dismal prognosis in the metastasized setting. Invasive growth of cancer cells relates to high levels of compressive forces translating to relevant damage of the plasma membrane. However, functional implications of protein machineries required for plasma membrane repair in ccRCC are not yet completely elucidated. Given the membrane-associated localization of the large family of annexin proteins, we aimed for a global annotation of annexin proteins, which led to the identification of ANXA4 selectively expressed in cancer cells of ccRCC. Interestingly, ANXA4 showed context-dependent distinct localization patterns including the plasma membrane as well as the nuclear compartment/nuclear membrane. We investigated the functional role of ANXA4 in ccRCC employing genetic titration studies (knockdown, CRISPR/Cas9 knockout and overexpression) and identified impaired acute plasma membrane repair as well as invasive capability in conditions of reduced ANXA4 expression. Utilizing computational segmentation of the tumor microenvironment (TME) of ccRCC samples revealed that ANXA4 low tumors exhibited a distinct TME composition compared to ANXA4 high cases. ANXA4 low tumors showed higher levels of tumor infiltrating lymphocytes accompanied by increased deposition of acellular extracellular matrix. Further transcriptomic analysis demonstrated major alterations in transcriptional signatures related to epithelial-mesenchymal transition (EMT) and immune signaling. Transcription factor enrichment analysis and further functional validation identified ELF3 as one central regulator of invasive properties. Our integrative approach including molecular analyses with advanced histopathological segmentation uncovered novel roles for ANXA4 in modulating acute membrane repair, transcriptional regulation, and shaping cellular composition of the ccRCC tumor microenvironment.

cancer biology↗

bioRxiv2020

Quantitative in vivo bioluminescence imaging of orthotopic patient-derived glioblastoma xenografts

Despite extensive research, little progress has been made in glioblastoma therapy, owing in part to a lack of adequate preclinical in vivo models to study this disease. To mitigate this, primary patient-derived cell lines, which maintain their specific stem-like phenotypes, have replaced established glioblastoma cell lines. However, due to heterogenous tumour growth inherent in glioblastoma, the use of primary cells for orthotopic in vivo studies often requires large experimental group sizes. Therefore, when using intracranial patient-derived xenograft (PDX) approaches, it is advantageous to deploy imaging techniques to monitor tumour growth and allow stratification of mice. Here we show that stable expression of near-infrared fluorescent protein (iRFP) in patient-derived glioblastoma cells enables rapid direct non-invasive monitoring of tumour development without compromising tumour stemness or tumorigenicity. Moreover, as this approach does not depend on the use of agents like luciferin, which can cause variability due to changing bioavailability, it can be used for quantitative longitudinal monitoring of tumour growth. Notably, we show that this technique also allows quantitative assessment of tumour burden in highly invasive models spreading throughout the brain. Thus, iRFP transduction of primary patient-derived glioblastoma cells is a reliable, cost- and time-effective way to monitor heterogenous orthotopic PDX growth.

cancer biology↗