scholarly journals SUN-MKL1 Crosstalk Regulates Nuclear Deformation and Fast Motility of Breast Carcinoma Cells in Fibrillar ECM Microenvironment

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1549
Author(s):  
Ved P. Sharma ◽  
James Williams ◽  
Edison Leung ◽  
Joe Sanders ◽  
Robert Eddy ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Motility ◽  
Tumor Cells ◽  
Carcinoma Cell ◽  
Nuclear Deformation ◽  
Linc Complex ◽  
Actomyosin Contractility ◽  
Tumor Cell Motility ◽  
Single Tumor

Aligned collagen fibers provide topography for the rapid migration of single tumor cells (streaming migration) to invade the surrounding stroma, move within tumor nests towards blood vessels to intravasate and form distant metastases. Mechanisms of tumor cell motility have been studied extensively in the 2D context, but the mechanistic understanding of rapid single tumor cell motility in the in vivo context is still lacking. Here, we show that streaming tumor cells in vivo use collagen fibers with diameters below 3 µm. Employing 1D migration assays with matching in vivo fiber dimensions, we found a dependence of tumor cell motility on 1D substrate width, with cells moving the fastest and the most persistently on the narrowest 1D fibers (700 nm–2.5 µm). Interestingly, we also observed nuclear deformation in the absence of restricting extracellular matrix pores during high speed carcinoma cell migration in 1D, similar to the nuclear deformation observed in tumor cells in vivo. Further, we found that actomyosin machinery is aligned along the 1D axis and actomyosin contractility synchronously regulates cell motility and nuclear deformation. To further investigate the link between cell speed and nuclear deformation, we focused on the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex proteins and SRF-MKL1 signaling, key regulators of mechanotransduction, actomyosin contractility and actin-based cell motility. Analysis of The Cancer Genome Atlas dataset showed a dramatic decrease in the LINC complex proteins SUN1 and SUN2 in primary tumor compared to the normal tissue. Disruption of LINC complex by SUN1 + 2 KD led to multi-lobular elongated nuclei, increased tumor cell motility and concomitant increase in F-actin, without affecting Lamin proteins. Mechanistically, we found that MKL1, an effector of changes in cellular G-actin to F-actin ratio, is required for increased 1D motility seen in SUN1 + 2 KD cells. Thus, we demonstrate a previously unrecognized crosstalk between SUN proteins and MKL1 transcription factor in modulating nuclear shape and carcinoma cell motility in an in vivo relevant 1D microenvironment.

scholarly journals SUN-MKL1 crosstalk regulates nuclear deformation and fast motility of breast carcinoma cells in fibrillar ECM micro-environment

2020 ◽  
Author(s):  
Ved P Sharma ◽  
James Williams ◽  
Edison Leung ◽  
Joe Sanders ◽  
Robert Eddy ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Motility ◽  
Tumor Cells ◽  
Carcinoma Cell ◽  
Nuclear Deformation ◽  
Linc Complex ◽  
Actomyosin Contractility ◽  
Tumor Cell Motility ◽  
Single Tumor

ABSTRACTAligned collagen fibers provide topography for the rapid migration of single tumor cells (streaming migration) to invade the surrounding stroma, move within tumor nests towards blood vessels to intravasate and form distant metastases. Mechanisms of tumor cell motility have been studied extensively in the 2D context, but the mechanistic understanding of rapid single tumor cell motility in the in vivo context is still lacking. Here, we show that streaming tumor cells in vivo use collagen fibers with diameters below 3 μm. Employing 1D migration assays with matching in vivo fiber dimensions, we found a dependence of tumor cell motility on 1D substrate width, with cells moving the fastest and the most persistently on the narrowest 1D fibers (700 nm – 2.5 μm). Interestingly, we also observed nuclear deformation in the absence of restricting extracellular matrix pores during high speed carcinoma cell migration in 1D, similar to the nuclear deformation observed in tumor cells in vivo. Further, we found that actomyosin machinery is aligned along the 1D axis and actomyosin contractility synchronously regulates cell motility and nuclear deformation. To further investigate the link between cell speed and nuclear deformation, we focused on the Linker of Nucleoskeleton and Cytoskeleton (LINC) complex proteins and SRF-MKL1 signaling, key regulators of mechanotransduction, actomyosin contractility and actin-based cell motility. Analysis of The Cancer Genome Atlas dataset showed a dramatic decrease in the LINC complex proteins SUN1 and SUN2 in primary tumor compared to the normal tissue. Disruption of LINC complex by SUN1+2 KD led to multi-lobular elongated nuclei, increased tumor cell motility and concomitant increase in F-actin, without affecting Lamin proteins. Mechanistically, we found that MKL1, an effector of changes in cellular G-actin to F-actin ratio, is required for increased 1D motility seen in SUN1+2 KD cells. Thus, we demonstrate a previously unrecognized crosstalk between SUN proteins and MKL1 transcription factor in modulating nuclear shape and carcinoma cell motility in an in vivo relevant 1D microenvironment.

scholarly journals Confinement hinders motility by inducing RhoA-mediated nuclear influx, volume expansion, and blebbing

2019 ◽  
Vol 218 (12) ◽  
pp. 4093-4111 ◽  
Author(s):  
Panagiotis Mistriotis ◽  
Emily O. Wisniewski ◽  
Kaustav Bera ◽  
Jeremy Keys ◽  
Yizeng Li ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Cell Motility ◽  
Volume Expansion ◽  
Myosin Ii ◽  
Nuclear Volume ◽  
Linc Complex ◽  
Actomyosin Contractility ◽  
Dependent Pathway ◽  
Passive Influx

Cells migrate in vivo through complex confining microenvironments, which induce significant nuclear deformation that may lead to nuclear blebbing and nuclear envelope rupture. While actomyosin contractility has been implicated in regulating nuclear envelope integrity, the exact mechanism remains unknown. Here, we argue that confinement-induced activation of RhoA/myosin-II contractility, coupled with LINC complex-dependent nuclear anchoring at the cell posterior, locally increases cytoplasmic pressure and promotes passive influx of cytoplasmic constituents into the nucleus without altering nuclear efflux. Elevated nuclear influx is accompanied by nuclear volume expansion, blebbing, and rupture, ultimately resulting in reduced cell motility. Moreover, inhibition of nuclear efflux is sufficient to increase nuclear volume and blebbing on two-dimensional surfaces, and acts synergistically with RhoA/myosin-II contractility to further augment blebbing in confinement. Cumulatively, confinement regulates nuclear size, nuclear integrity, and cell motility by perturbing nuclear flux homeostasis via a RhoA-dependent pathway.

scholarly journals The role of brevican in glioma: promoting tumor cell motility in vitro and in vivo

BMC Cancer ◽  
2012 ◽  
Vol 12 (1) ◽  
Author(s):  
Renquan Lu ◽  
Chengsheng Wu ◽  
Lin Guo ◽  
Yingchao Liu ◽  
Wei Mo ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Cell Motility ◽  
Tumor Cell Motility

scholarly journals A naturally occurring truncated β3 integrin in tumor cells: Native anti-integrin involved in tumor cell motility

2007 ◽  
Vol 6 (10) ◽  
pp. 1559-1568 ◽  
Author(s):  
Rongxian Jin ◽  
Mohit Trikha ◽  
Yinlong Cai ◽  
David Grignon ◽  
Kenneth V. Honn
Keyword(s):  
Tumor Cell ◽  
Cell Motility ◽  
Tumor Cells ◽  
Naturally Occurring ◽  
Tumor Cell Motility ◽  
Β3 Integrin

scholarly journals The Inhibition of Tumor Cell Intravasation and Subsequent Metastasis via Regulation of In Vivo Tumor Cell Motility by the Tetraspanin CD151

Cancer Cell ◽  
2008 ◽  
Vol 13 (3) ◽  
pp. 221-234 ◽  
Author(s):  
Andries Zijlstra ◽  
John Lewis ◽  
Bernard DeGryse ◽  
Heidi Stuhlmann ◽  
James P. Quigley
Keyword(s):  
Tumor Cell ◽  
Cell Motility ◽  
Tumor Cell Motility

scholarly journals Actomyosin, vimentin and LINC complex pull on osteosarcoma nuclei to deform on micropillar topography

2019 ◽  
Author(s):  
Nayana Tusamda Wakhloo ◽  
Sebastian Anders ◽  
Florent Badique ◽  
Melanie Eichhorn ◽  
Isabelle Brigaud ◽  
...  
Keyword(s):  
Cancer Metastasis ◽  
Cell Model ◽  
Cell Deformation ◽  
Nuclear Deformation ◽  
Biological Processes ◽  
Linc Complex ◽  
Actomyosin Contractility ◽  
Pulling Forces ◽  
Underlying Mechanisms

ABSTRACTCell deformation occurs in many critical biological processes, including cell extravasation during immune response and cancer metastasis. These cells deform the nucleus, its largest and stiffest organelle, while passing through narrow constrictions in vivo and the underlying mechanisms still remain elusive. It is unclear which biochemical actors are responsible and whether the nucleus is pushed or pulled (or both) during deformation. Herein we use an easily-tunable poly-L-lactic acid micropillar topography, mimicking in vivo constrictions to determine the mechanisms responsible for nucleus deformation. Using biochemical tools, we determine that actomyosin contractility, vimentin and nucleo-cytoskeletal connections play essential roles in nuclear deformation, but not A-type lamins. We chemically tune the adhesiveness of the micropillars to show that pulling forces are predominantly responsible for the deformation of the nucleus. We confirm these results using an in silico cell model and propose a comprehensive mechanism for cellular and nuclear deformation during confinement. These results indicate that microstructured biomaterials are extremely versatile tools to understand how forces are exerted in biological systems and can be useful to dissect and mimic complex in vivo behaviour.

scholarly journals Smurf1 regulates tumor cell plasticity and motility through degradation of RhoA leading to localized inhibition of contractility

2006 ◽  
Vol 176 (1) ◽  
pp. 35-42 ◽  
Author(s):  
Erik Sahai ◽  
Raquel Garcia-Medina ◽  
Jacques Pouysségur ◽  
Emmanuel Vial
Keyword(s):  
Cell Migration ◽  
Tumor Cell ◽  
Rho Gtpases ◽  
Rho Kinase ◽  
Cell Movement ◽  
Leading Edge ◽  
Cell Periphery ◽  
Tumor Cell Migration ◽  
Tumor Cell Motility

Rho GTPases participate in various cellular processes, including normal and tumor cell migration. It has been reported that RhoA is targeted for degradation at the leading edge of migrating cells by the E3 ubiquitin ligase Smurf1, and that this is required for the formation of protrusions. We report that Smurf1-dependent RhoA degradation in tumor cells results in the down-regulation of Rho kinase (ROCK) activity and myosin light chain 2 (MLC2) phosphorylation at the cell periphery. The localized inhibition of contractile forces is necessary for the formation of lamellipodia and for tumor cell motility in 2D tissue culture assays. In 3D invasion assays, and in in vivo tumor cell migration, the inhibition of Smurf1 induces a mesenchymal–amoeboid–like transition that is associated with a more invasive phenotype. Our results suggest that Smurf1 is a pivotal regulator of tumor cell movement through its regulation of RhoA signaling.

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