Publications Bernd Bodenmiller

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    Analysis of the Human Kinome and Phosphatome by Mass Cytometry Reveals Overexpression-Induced Effects on Cancer-Related Signaling.

    Mol Cell. 2019 Jun 06;74(5):1086-1102.e5

    Authors: Lun XK, Szklarczyk D, Gábor A, Dobberstein N, Zanotelli VRT, Saez-Rodriguez J, von Mering C, Bodenmiller B

    Kinase and phosphatase overexpression drives tumorigenesis and drug resistance. We previously developed a mass-cytometry-based single-cell proteomics approach that enables quantitative assessment of overexpression effects on cell signaling. Here, we applied this approach in a human kinome- and phosphatome-wide study to assess how 649 individually overexpressed proteins modulated cancer-related signaling in HEK293T cells in an abundance-dependent manner. Based on these data, we expanded the functional classification of human kinases and phosphatases and showed that the overexpression effects include non-catalytic roles. We detected 208 previously unreported signaling relationships. The signaling dynamics analysis indicated that the overexpression of ERK-specific phosphatases sustains proliferative signaling. This suggests a phosphatase-driven mechanism of cancer progression. Moreover, our analysis revealed a drug-resistant mechanism through which overexpression of tyrosine kinases, including SRC, FES, YES1, and BLK, induced MEK-independent ERK activation in melanoma A375 cells. These proteins could predict drug sensitivity to BRAF-MEK concurrent inhibition in cells carrying BRAF mutations.

    PMID: 31101498 [PubMed - in process]

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    A Single-Cell Atlas of the Tumor and Immune Ecosystem of Human Breast Cancer.

    Cell. 2019 May 16;177(5):1330-1345.e18

    Authors: Wagner J, Rapsomaniki MA, Chevrier S, Anzeneder T, Langwieder C, Dykgers A, Rees M, Ramaswamy A, Muenst S, Soysal SD, Jacobs A, Windhager J, Silina K, van den Broek M, Dedes KJ, Rodríguez Martínez M, Weber WP, Bodenmiller B

    Breast cancer is a heterogeneous disease. Tumor cells and associated healthy cells form ecosystems that determine disease progression and response to therapy. To characterize features of breast cancer ecosystems and their associations with clinical data, we analyzed 144 human breast tumor and 50 non-tumor tissue samples using mass cytometry. The expression of 73 proteins in 26 million cells was evaluated using tumor and immune cell-centric antibody panels. Tumors displayed individuality in tumor cell composition, including phenotypic abnormalities and phenotype dominance. Relationship analyses between tumor and immune cells revealed characteristics of ecosystems related to immunosuppression and poor prognosis. High frequencies of PD-L1+ tumor-associated macrophages and exhausted T cells were found in high-grade ER+ and ER- tumors. This large-scale, single-cell atlas deepens our understanding of breast tumor ecosystems and suggests that ecosystem-based patient classification will facilitate identification of individuals for precision medicine approaches targeting the tumor and its immunoenvironment.

    PMID: 30982598 [PubMed - in process]

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    IL-8 and CXCR1 expression is associated with cancer stem cell-like properties of clear cell renal cancer.

    J Pathol. 2019 Jul;248(3):377-389

    Authors: Corrò C, Healy ME, Engler S, Bodenmiller B, Li Z, Schraml P, Weber A, Frew IJ, Rechsteiner M, Moch H

    Recent studies suggest that clear cell renal cell carcinoma (ccRCC) possesses a rare population of cancer stem cells (CSCs) that might contribute to tumor heterogeneity, metastasis and therapeutic resistance. Nevertheless, their relevance for renal cancer is still unclear. In this study, we successfully isolated CSCs from established human ccRCC cell lines. CSCs displayed high expression of the chemokine IL-8 and its receptor CXCR1. While recombinant IL-8 significantly increased CSC number and properties in vitro, CXCR1 inhibition using an anti-CXCR1 antibody or repertaxin significantly reduced these features. After injection into immune-deficient mice, CSCs formed primary tumors that metastasized to the lung and liver. All xenografted tumors in mice expressed high levels of IL-8 and CXCR1. Furthermore, IL-8/CXCR1 expression significantly correlated with decreased overall survival in ccRCC patients. These results suggest that the IL-8/CXCR1 phenotype is associated with CSC-like properties in renal cancer. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

    PMID: 30883740 [PubMed - in process]

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