title: LKB1 loss in melanoma disrupts directional migration toward extracellular matrix cues.
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.
authors.affiliation: 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.
authors.forename: Keefe T
authors.initials: KT
authors.lastname: Chan
authors.affiliation: 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.
authors.forename: Sreeja B
authors.initials: SB
authors.lastname: Asokan
authors.affiliation: 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.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: King
authors.affiliation: 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.
authors.forename: Tao
authors.initials: T
authors.lastname: Bo
authors.affiliation: 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.
authors.forename: Evan S
authors.initials: ES
authors.lastname: Dubose
authors.affiliation: 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.
authors.forename: Wenjin
authors.initials: W
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Berginski
authors.affiliation: 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 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.
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Simon
authors.affiliation: 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.
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Davis
authors.affiliation: 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.
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Gomez
authors.affiliation: 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.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Sharpless
authors.affiliation: 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 jbear@email.unc.edu.
authors.forename: James E
authors.initials: JE
authors.lastname: Bear
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000595:Amino Acid Sequence; D002465:Cell Movement; D002633:Chemotaxis / Q000235:genetics; D005109:Extracellular Matrix / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D044085:Microfluidics; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D016415:Sequence Alignment; D059008:Time-Lapse Imaging
chemical_list: D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases