Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression

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  • Ori Maller, Univ Calif San Francisco, University of California System, University of California San Francisco, Dept Surg, Ctr Bioengn & Tissue Regenerat
  • ,
  • Allison P. Drain, Univ Calif San Francisco, University of California System, University of California San Francisco, Dept Surg, Ctr Bioengn & Tissue Regenerat
  • ,
  • Alexander S. Barrett, Univ Colorado Denver, Children's Hospital Colorado, University of Colorado System, University of Colorado Anschutz Medical Campus, Dept Biochem & Mol Genet
  • ,
  • Signe Borgquist
  • Brian Ruffell, Oregon Hlth & Sci Univ, Oregon Health & Science University, Knight Canc Inst
  • ,
  • Igor Zakharevich, Univ Colorado Denver, Children's Hospital Colorado, University of Colorado System, University of Colorado Anschutz Medical Campus, Dept Biochem & Mol Genet
  • ,
  • Thanh T. Pham, Univ Colorado Denver, Children's Hospital Colorado, University of Colorado System, University of Colorado Anschutz Medical Campus, Dept Biochem & Mol Genet
  • ,
  • Tina Gruosso, McGill Univ, McGill University, Dept Oncol, Program Canc Genet
  • ,
  • Hellen Kuasne, McGill Univ, McGill University, Dept Oncol, Program Canc Genet
  • ,
  • Johnathon N. Lakins, Univ Calif San Francisco, University of California System, University of California San Francisco, Dept Surg, Ctr Bioengn & Tissue Regenerat
  • ,
  • Irene Acerbi, Univ Calif San Francisco, University of California System, University of California San Francisco, Dept Surg, Ctr Bioengn & Tissue Regenerat
  • ,
  • J. Matthew Barnes, Univ Calif San Francisco, University of California System, University of California San Francisco, Dept Surg, Ctr Bioengn & Tissue Regenerat
  • ,
  • Travis Nemkov, Univ Colorado Denver, Children's Hospital Colorado, University of Colorado System, University of Colorado Anschutz Medical Campus, Dept Biochem & Mol Genet
  • ,
  • Aastha Chauhan, Univ Minnesota, University of Minnesota System, University of Minnesota Twin Cities, Dept Lab Med & Pathol
  • ,
  • Jessica Gruenberg, Univ Minnesota, University of Minnesota System, University of Minnesota Twin Cities, Dept Lab Med & Pathol
  • ,
  • Aqsa Nasir, Univ Minnesota, University of Minnesota System, University of Minnesota Twin Cities, Dept Lab Med & Pathol
  • ,
  • Olof Bjarnadottir, Lund Univ, Lund University, Skane University Hospital, Skane Univ Hosp, Dept Clin Sci, Div Oncol & Pathol
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  • Zena Werb, Univ Calif San Francisco, University of California System, University of California San Francisco, UCSF Medical Center, UCSF Helen Diller Family Comprehensive Cancer Center, UCSF Helen Diller Comprehens Canc Ctr
  • ,
  • Peter Kabos, Univ Colorado Denver, Children's Hospital Colorado, University of Colorado System, University of Colorado Anschutz Medical Campus, Dept Med, Div Med Oncol
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  • Yunn-Yi Chen, Univ Calif San Francisco, University of California System, University of California San Francisco, Dept Pathol
  • ,
  • E. Shelley Hwang, Duke Univ, Duke University, Med Ctr, Dept Surg
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  • Morag Park, McGill Univ, McGill University, Dept Oncol, Program Canc Genet
  • ,
  • Lisa M. Coussens, Oregon Hlth & Sci Univ, Oregon Health & Science University, Knight Canc Inst
  • ,
  • Andrew C. Nelson, Univ Minnesota, University of Minnesota System, University of Minnesota Twin Cities, Dept Lab Med & Pathol
  • ,
  • Kirk C. Hansen, McGill Univ, McGill University, Dept Biochem
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  • Valerie M. Weaver, Univ Calif San Francisco, University of California System, University of California San Francisco, Eli & Edythe Broad Ctr Regenerat Med & Stem Cell

Stromal stiffening accompanies malignancy, compromises treatment and promotes tumour aggression. Clarifying the molecular nature and the factors that regulate stromal stiffening in tumours should identify biomarkers to stratify patients for therapy and interventions to improve outcome. We profiled lysyl hydroxylase-mediated and lysyl oxidase-mediated collagen crosslinks and quantified the greatest abundance of total and complex collagen crosslinks in aggressive human breast cancer subtypes with the stiffest stroma. These tissues harbour the highest number of tumour-associated macrophages, whose therapeutic ablation in experimental models reduced metastasis, and decreased collagen crosslinks and stromal stiffening. Epithelial-targeted expression of the crosslinking enzyme, lysyl oxidase, had no impact on collagen crosslinking in PyMT mammary tumours, whereas stromal cell targeting did. Stromal cells in microdissected human tumours expressed the highest level of collagen crosslinking enzymes. Immunohistochemical analysis of biopsies from a cohort of patients with breast cancer revealed that stromal expression of lysyl hydroxylase 2, an enzyme that induces hydroxylysine aldehyde-derived collagen crosslinks and stromal stiffening, correlated significantly with disease specific mortality. The findings link tissue inflammation, stromal cell-mediated collagen crosslinking and stiffening to tumour aggression and identify lysyl hydroxylase 2 as a stromal biomarker.

OriginalsprogEngelsk
TidsskriftNature Materials
Vol/bind20
Nummer4
Sider (fra-til)548-+
Antal sider30
ISSN1476-1122
DOI
StatusUdgivet - apr. 2021

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