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.

• MeSH
• lidé MeSH
• metastázy nádorů patologie   patofyziologie   MeSH
• myši inbrední C57BL MeSH
• nádorové buněčné linie MeSH
• nádorové cirkulující buňky patologie   MeSH
• nádory patologie   patofyziologie   MeSH
• pohyb buněk MeSH
• polarita buněk * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Microfluidic devices are becoming mainstream tools to recapitulate in vitro the behavior of cells and tissues. In this study, we use microfluidic devices filled with hydrogels of mixed collagen-Matrigel composition to study the migration of lung cancer cells under different cancer invasion microenvironments. We present the design of the microfluidic device, characterize the hydrogels morphologically and mechanically and use quantitative image analysis to measure the migration of H1299 lung adenocarcinoma cancer cells in different experimental conditions. Our results show the plasticity of lung cancer cell migration, which turns from mesenchymal in collagen only matrices, to lobopodial in collagen-Matrigel matrices that approximate the interface between a disrupted basement membrane and the underlying connective tissue. Our quantification of migration speed confirms a biphasic role of Matrigel. At low concentration, Matrigel facilitates migration, most probably by providing a supportive and growth factor retaining environment. At high concentration, Matrigel slows down migration, possibly due excessive attachment. Finally, we show that antibody-based integrin blockade promotes a change in migration phenotype from mesenchymal or lobopodial to amoeboid and analyze the effect of this change in migration dynamics, in regards to the structure of the matrix. In summary, we describe and characterize a robust microfluidic platform and a set of software tools that can be used to study lung cancer cell migration under different microenvironments and experimental conditions. This platform could be used in future studies, thus benefitting from the advantages introduced by microfluidic devices: precise control of the environment, excellent optical properties, parallelization for high throughput studies and efficient use of therapeutic drugs.

• MeSH
• buněčné sféroidy MeSH
• difuze MeSH
• extracelulární matrix MeSH
• fenotyp MeSH
• fixní kombinace léků MeSH
• hydrogely MeSH
• kolagen * chemie   ultrastruktura   MeSH
• konfokální mikroskopie MeSH
• laminin * chemie   ultrastruktura   MeSH
• lidé MeSH
• mechanické jevy MeSH
• metastázy nádorů MeSH
• mikrofluidika * metody   MeSH
• nádorové buněčné linie MeSH
• nádorové buňky kultivované MeSH
• nádorové mikroprostředí MeSH
• pohyb buněk * MeSH
• proteoglykany * chemie   ultrastruktura   MeSH
• tkáňové podpůrné struktury * chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• fixní kombinace léků MeSH
• hydrogely MeSH
• kolagen * MeSH
• laminin * MeSH
• matrigel MeSH Prohlížeč
• proteoglykany * MeSH

Tumor growth and cancer development are considered clear examples of Darwinian selection, whereby random mutational events in heterogeneous cancer cell populations that best fit the selective microenvironment are preferred.(1) As a result, cancer cells evolve resistance to apoptosis, hide from immune surveillance and acquire the ability to invade other organs. Cancer cells, however, are not necessarily passive subjects of selection; they can actively subvert the host tissue to provide a favorable habitat for their growth. Recent findings by Calon et al. convincingly demonstrate that transforming growth factor-β-induced secretion of interleukin 11 by tumor stromal fibroblasts is a necessary prerequisite for the development of distant metastases in colorectal carcinoma. Thus, understanding the complex molecular feedback loops between cancer cells and the surrounding microenvironment (i.e., the tumor-associated stroma or invaded host tissue) should aid the identification of useful molecular targets for improving clinical management of advanced metastatic cancers.

• Klíčová slova
• dissemination, interleukin 11, metastasis, metastatic niche, microenvironment, transforming growth factor-β, tumor stroma,
• Publikační typ
• časopisecké články MeSH