Quantitative measures to reveal coordinated cytoskeleton-nucleus reorganization during in vitro invasion of cancer cells

• Published in: New journal of physics Vol. 17; no. 4; pp. 43010 - 43018
• Main Authors: Dvir, Liron, Nissim, Ronen, Alvarez-Elizondo, Martha B, Weihs, Daphne
• Format: Journal Article
• Language: English
• Published: Bristol IOP Publishing 08.04.2015
• Subjects: Breast cancer; cancer metastasis; cell force application; cytoskeleton reorganization; Dimpling; gel indentation; Gels; image analysis; Indentation; Metastasis; Myosin; Nuclei (cytology); Organs; Physics; Relocation; Substrates
• ISSN: 1367-2630; 1367-2630
• DOI: 10.1088/1367-2630/17/4/043010

Metastasis formation is a major cause of mortality in cancer patients and includes tumor cell relocation to distant organs. A metastatic cell invades through other cells and extracellular matrix by biochemical attachment and mechanical force application. Force is used to move on or through a 2- or 3-dimensional (3D) environment, respectively, or to penetrate a 2D substrate. We have previously shown that even when a gel substrate is impenetrable, metastatic breast cancer cells can still indent it by applying force. Cells typically apply force through the acto-myosin network, which is mechanically connected to the nucleus. We develop a 3D image-analysis to reveal relative locations of the cell elements, and show that as cells apply force to the gel, a coordinated process occurs that involves cytoskeletal remodeling and repositioning of the nucleus. Our approach shows that the actin and microtubules reorganize in the cell, bringing the actin to the leading edge of the cell. In parallel, the nucleus is transported behind the actin, likely by the cytoskeleton, into the indentation dimple formed in the gel. The nucleus volume below the gel surface correlates with indentation depth, when metastatic breast cancer cells indent gels deeply. However, the nucleus always remains above the gel in benign cells, even when small indentations are observed. Determining mechanical processes during metastatic cell invasion can reveal how cells disseminate in the body and can uncover targets for diagnosis and treatment.