Kathrin Weidele

Fraunhofer Institute for Toxicology and Experimental Medicine

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Christoph A. Klein

Deutsches Herzzentrum der Charité

Christian Werno

Fraunhofer Institute for Toxicology and Experimental Medicine

Bernhard Polzer

Fraunhofer Institute for Toxicology and Experimental Medicine

Steffi Treitschke

Fraunhofer Institute for Toxicology and Experimental Medicine

Petra Rümmele

Universitätsklinikum Erlangen

Sebastian Haferkamp

University Hospital Regensburg

Zbigniew T. Czyż

University of Regensburg

Stefan Kirsch

Fraunhofer Institute for Toxicology and Experimental Medicine

Martin Hoffmann

Krankenhaus der Augustinerinnen

Melanie Werner‐Klein

University of Regensburg

Cooperative Institutions

University of Regensburg

Technical University of Munich

Heidelberg University

Fraunhofer Institute for Toxicology and Experimental Medicine

German Cancer Research Center

Helmholtz Zentrum München

University Hospital Regensburg

Klinikum rechts der Isar

Ludwig-Maximilians-Universität München

DKFZ-ZMBH Alliance

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Single cell polarity in liquid phase facilitates tumour metastasis

Nature Communications (2018)

Anna Lorentzen Paul F. Becker Jan Kosla Massimo Saini Kathrin Weidele

Abstract Dynamic polarisation of tumour cells is essential for metastasis. While the role of polarisation during dedifferentiation and migration is well established, polarisation of metastasising tumour cells during phases of detachment has not been investigated. Here we identify and characterise a type of polarisation maintained by single cells in liquid phase termed single-cell (sc) polarity and investigate its role during metastasis. We demonstrate that sc polarity is an inherent feature of cells from different tumour entities that is observed in circulating tumour cells in patients. Functionally, we propose that the sc pole is directly involved in early attachment, thereby affecting adhesion, transmigration and metastasis. In vivo, the metastatic capacity of cell lines correlates with the extent of sc polarisation. By manipulating sc polarity regulators and by generic depolarisation, we show that sc polarity prior to migration affects transmigration and metastasis in vitro and in vivo.

Cell polarity

Polarity (international relations)

10.1038/s41467-018-03139-6

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Citations (53)

Genetic alterations driving metastatic colony formation are acquired outside of the primary tumour in melanoma

Nature Communications (2018)

Melanie Werner‐Klein Sebastian Scheitler Martin Hoffmann Isabelle Hodak Klaus Dietz

Abstract Mouse models indicate that metastatic dissemination occurs extremely early; however, the timing in human cancers is unknown. We therefore determined the time point of metastatic seeding relative to tumour thickness and genomic alterations in melanoma. Here, we find that lymphatic dissemination occurs shortly after dermal invasion of the primary lesion at a median thickness of ~0.5 mm and that typical driver changes, including BRAF mutation and gained or lost regions comprising genes like MET or CDKNA2 , are acquired within the lymph node at the time of colony formation. These changes define a colonisation signature that was linked to xenograft formation in immunodeficient mice and death from melanoma. Thus, melanoma cells leave primary tumours early and evolve at different sites in parallel. We propose a model of metastatic melanoma dormancy, evolution and colonisation that will inform direct monitoring of adjuvant therapy targets.

Primary tumor

Colonisation

10.1038/s41467-017-02674-y

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Interleukin-6 trans-signaling is a candidate mechanism to drive progression of human DCCs during clinical latency

Nature Communications (2020)

Melanie Werner‐Klein Ana Grujovic Christoph Irlbeck Milan M. S. Obradović Martin Hoffmann

Although thousands of breast cancer cells disseminate and home to bone marrow until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. To identify signals that support survival or outgrowth in patients, we profile rare bone marrow-derived disseminated cancer cells (DCCs) long before manifestation of metastasis and identify IL6/PI3K-signaling as candidate pathway for DCC activation. Surprisingly, and similar to mammary epithelial cells, DCCs lack membranous IL6 receptor expression and mechanistic dissection reveals IL6 trans-signaling to regulate a stem-like state of mammary epithelial cells via gp130. Responsiveness to IL6 trans-signals is found to be niche-dependent as bone marrow stromal and endosteal cells down-regulate gp130 in premalignant mammary epithelial cells as opposed to vascular niche cells. PIK3CA activation renders cells independent from IL6 trans-signaling. Consistent with a bottleneck function of microenvironmental DCC control, we find PIK3CA mutations highly associated with late-stage metastatic cells while being extremely rare in early DCCs. Our data suggest that the initial steps of metastasis formation are often not cancer cell-autonomous, but also depend on microenvironmental signals.

10.1038/s41467-020-18701-4

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Citations (45)

Single-cell microRNA sequencing method comparison and application to cell lines and circulating lung tumor cells

Nature Communications (2021)

Sarah M. Hücker Tobias Fehlmann Christian Werno Kathrin Weidele Florian Lüke

Abstract Molecular single cell analyses provide insights into physiological and pathological processes. Here, in a stepwise approach, we first evaluate 19 protocols for single cell small RNA sequencing on MCF7 cells spiked with 1 pg of 1,006 miRNAs. Second, we analyze MCF7 single cell equivalents of the eight best protocols. Third, we sequence single cells from eight different cell lines and 67 circulating tumor cells (CTCs) from seven SCLC patients. Altogether, we analyze 244 different samples. We observe high reproducibility within protocols and reads covered a broad spectrum of RNAs. For the 67 CTCs, we detect a median of 68 miRNAs, with 10 miRNAs being expressed in 90% of tested cells. Enrichment analysis suggested the lung as the most likely organ of origin and enrichment of cancer-related categories. Even the identification of non-annotated candidate miRNAs was feasible, underlining the potential of single cell small RNA sequencing.

10.1038/s41467-021-24611-w

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Citations (64)