title: Tumor Cell-Driven Extracellular Matrix Remodeling Drives Haptotaxis during Metastatic Progression.
abstract: Fibronectin (FN) is a major component of the tumor microenvironment, but its role in promoting metastasis is incompletely understood. Here, we show that FN gradients elicit directional movement of breast cancer cells, in vitro and in vivo Haptotaxis on FN gradients requires direct interaction between α5β1 integrin and MENA, an actin regulator, and involves increases in focal complex signaling and tumor cell-mediated extracellular matrix (ECM) remodeling. Compared with MENA, higher levels of the prometastatic MENA(INV) isoform associate with α5, which enables 3-D haptotaxis of tumor cells toward the high FN concentrations typically present in perivascular space and in the periphery of breast tumor tissue. MENA(INV) and FN levels were correlated in two breast cancer cohorts, and high levels of MENA(INV) were significantly associated with increased tumor recurrence as well as decreased patient survival. Our results identify a novel tumor cell-intrinsic mechanism that promotes metastasis through ECM remodeling and ECM-guided directional migration.
  
  
  
  Here, we provide new insight into how tumor cell:ECM interactions generate signals and structures that promote directed tumor cell migration, a critical component of metastasis. Our results identify a tumor cell-intrinsic mechanism driven by the actin regulatory protein MENA that promotes ECM remodeling and haptotaxis along FN gradients. Cancer Discov; 6(5); 516-31. ©2016 AACR.See related commentary by Santiago-Medina and Yang, p. 474This article is highlighted in the In This Issue feature, p. 461.
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Madeleine J
authors.initials: MJ
authors.lastname: Oudin
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Oliver
authors.initials: O
authors.lastname: Jonas
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Tatsiana
authors.initials: T
authors.lastname: Kosciuk
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Liliane C
authors.initials: LC
authors.lastname: Broye
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Bruna C
authors.initials: BC
authors.lastname: Guido
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Jeff
authors.initials: J
authors.lastname: Wyckoff
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Daisy
authors.initials: D
authors.lastname: Riquelme
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: John M
authors.initials: JM
authors.lastname: Lamar
authors.affiliation: Lineberger Comprehensive Cancer Center, UNC Chapel Hill, Chapel Hill, North Carolina.
authors.forename: Sreeja B
authors.initials: SB
authors.lastname: Asokan
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Charlie
authors.initials: C
authors.lastname: Whittaker
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Duanduan
authors.initials: D
authors.lastname: Ma
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Robert
authors.initials: R
authors.lastname: Langer
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cima
authors.affiliation: Department of Medicine, University of Wisconsin Carbone Cancer Center, Madison, Wisconsin.
authors.forename: Kari B
authors.initials: KB
authors.lastname: Wisinski
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. Department of Biology, MIT, Cambridge, Massachusetts. Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: Richard O
authors.initials: RO
authors.lastname: Hynes
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. Department of Biological Engineering, MIT, Cambridge, Massachusetts.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Lauffenburger
authors.affiliation: Department of Cell and Regenerative Biology, University of Wisconsin Madison, Madison, Wisconsin.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Keely
authors.affiliation: Lineberger Comprehensive Cancer Center, UNC Chapel Hill, Chapel Hill, North Carolina. Howard Hughes Medical Institute, Chevy Chase, Maryland.
authors.forename: James E
authors.initials: JE
authors.lastname: Bear
authors.affiliation: David H. Koch Institute for Integrative Cancer Research, MIT, Cambridge, Massachusetts. Department of Biology, MIT, Cambridge, Massachusetts. fgertler@mit.edu.
authors.forename: Frank B
authors.initials: FB
authors.lastname: Gertler
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D005109:Extracellular Matrix / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D064593:Heterografts; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D011485:Protein Binding; D015398:Signal Transduction; D059016:Tumor Microenvironment
chemical_list: D000199:Actins; C511939:Enah protein, human; D005353:Fibronectins; D039081:Integrin alpha5beta1; D008840:Microfilament Proteins; D003094:Collagen
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