ArticleThe Journal of cell biology2014
LKB1 loss in melanoma disrupts directional migration toward extracellular matrix cues.
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Article in The Journal of cell biology, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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32citing papers in PubMed
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32 citing papers in PubMed, 46 citations in OpenAlex.
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Authors and funding
12 authors at 4 institutions in 2 countries.
Keefe T ChanUniversity of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599.
Sreeja B AsokanUniversity of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599.
Samantha J KingUniversity of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599.
Tao BoUniversity of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599.
Evan S DuboseUniversity of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599.
Wenjin LiuUniversity of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599.
Matthew E BerginskiUniversity of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599.
Jeremy M SimonUniversity of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599.
Ian J DavisUniversity of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599.
Shawn M GomezUniversity of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599.
Norman E SharplessUniversity of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599.
James E BearUniversity of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 University of North Carolina Lineberger Comprehensive Cancer Center, Department of Cell Biology and Physiology, Department of Genetics, Department of Biomedical Engineering, Carolina Center for Genome Science, Department of Pediatrics, and Howard Hughes Medical Institute, University of North Carolina-Chapel Hill, Chapel Hill, NC 27599 jbear@email.unc.edu.
UNC Lineberger Comprehensive Cancer CenterCentre for Biomedical Engineering and Physics · SEHoward Hughes Medical Institute · USUniversity of North Carolina at Chapel Hill · US
Funding
UNC-CH CENTER FOR ENVIRONMENTAL HEALTH &SUSCEPTIBILITYP30ES010126 · NIEHS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Melissa A. Troester · 2001 to 2026
$36.3MPREDOCTORAL TRAINING IN PHARMACOLOGICAL SCIST32GM007040 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI NICHOLAS, ROBERT A · 1985 to 2019
$6.0MIn vivo murine models of metastasis for therapeutic testingR01CA163896 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI SHARPLESS, NORMAN E, WONG, KWOK KIN · 2012 to 2016
$2.0MChromatin organization and transcription factor targeting in cancerR01CA166447 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI DAVIS, IAN J · 2012 to 2016
$1.6MThe Coordination of Cytoskeletal Dynamics by CoroninsR01GM083035 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI BEAR, JAMES E · 2007 to 2011
$1.2MHoward Hughes Medical InstituteNCI NIH HHS CA163896NCI NIH HHS CA166447NCI NIH HHS R01 CA163896NCI NIH HHS R01 CA166447NIEHS NIH HHS P30 ES010126NIGMS NIH HHS GM083035NIGMS NIH HHS R01 GM083035NIGMS NIH HHS T32 GM007040
Abstract
Somatic inactivation of the serine/threonine kinase gene STK11/LKB1/PAR-4 occurs in a variety of cancers, including ∼10% of melanoma. However, how the loss of LKB1 activity facilitates melanoma invasion and metastasis remains poorly understood. In LKB1-null cells derived from an autochthonous murine model of melanoma with activated Kras and Lkb1 loss and matched reconstituted controls, we have investigated the mechanism by which LKB1 loss increases melanoma invasive motility. Using a microfluidic gradient chamber system and time-lapse microscopy, in this paper, we uncover a new function for LKB1 as a directional migration sensor of gradients of extracellular matrix (haptotaxis) but not soluble growth factor cues (chemotaxis). Systematic perturbation of known LKB1 effectors demonstrated that this response does not require canonical adenosine monophosphate-activated protein kinase (AMPK) activity but instead requires the activity of the AMPK-related microtubule affinity-regulating kinase (MARK)/PAR-1 family kinases. Inhibition of the LKB1-MARK pathway facilitated invasive motility, suggesting that loss of the ability to sense inhibitory matrix cues may promote melanoma invasion.
Indexed as
Amino Acid SequenceAMP-Activated Protein Kinase KinasesCell MovementChemotaxisExtracellular MatrixHumansMelanomaMicrofluidicsMolecular Sequence DataNeoplasm InvasivenessProtein Serine-Threonine KinasesSequence AlignmentTime-Lapse ImagingAMP-Activated Protein Kinase KinasesProtein Serine-Threonine KinasesSTK11 protein, human
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.