title: Aberrant glycosylation promotes lung cancer metastasis through adhesion to galectins in the metastatic niche.
abstract: Metastasis is the leading cause of cancer-associated deaths. Although dissemination of tumor cells likely occurs early in tumorigenesis, the constituents of the microenvironment play essential rate-limiting roles in determining whether these cells will form clinically relevant tumors. Recent studies have uncovered many molecular factors that contribute to the establishment of a protumorigenic metastatic niche. Here, we demonstrate that galectin-3, whose expression has clinical associations with advanced malignancy and poor outcome, contributes to metastatic niche formation by binding to carbohydrates on metastatic cells. We show that galectin-3 is expressed early during tumorigenesis by both CD11b(+)Gr-1(+) and CD11b(+)Ly-6C(hi) leukocytes. Tumors mobilize these myeloid populations through secretion of soluble factors, including IL6. We find that metastatic cancer cells exhibit elevated presentation of the oncofetal galectin-3 carbohydrate ligand, the Thomsen-Friedenreich antigen, on their surfaces as a result of altered C2GnT2 and St6GalNAc4 glycosyltransferase activity that inhibits further glycosylation of this carbohydrate motif and promotes metastasis.
  
  
  CONCLUSIONS
  Although clinical observations of elevated serum galectin-3 levels and altered glycosylation have been associated with malignancy, we identify novel roles for glycosyltransferases in promoting adhesion to galectins in the metastatic niche. This identification of a cytokine-leukocyte-glycosylation axis in metastasis provides mechanistic explanations for clinical associations between malignancy and aberrant glycosylation.
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts. Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Reticker-Flynn
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts. Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts. Howard Hughes Medical Institute, Cambridge, Massachusetts. Division of Medicine, Brigham and Women's Hospital, Boston, Massachusetts. Department of Electrical Engineering and Computer Science, Massachusetts Institute of Technology, Cambridge, Massachusetts. sbhatia@mit.edu.
authors.forename: Sangeeta N
authors.initials: SN
authors.lastname: Bhatia
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D037502:Galectin 3 / Q000378:metabolism*; D006031:Glycosylation; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D009362:Neoplasm Metastasis; D012799:Sialyltransferases / Q000378:metabolism*
chemical_list: D037502:Galectin 3; D017351:N-Acetylglucosaminyltransferases; C117361:beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase 3; D012799:Sialyltransferases; C485573:ST6GALNAC4 protein, human