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

Maller, Ori (author)
University of California, San Francisco
Drain, Allison P. (author)
University of California, San Francisco
Barrett, Alexander S. (author)
University of Colorado
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Borgquist, Signe (author)
Lund University,Lunds universitet,Bröstcancer - prevention & intervention,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Breast cancer prevention & intervention,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments,Aarhus University,Aarhus University Hospital
Ruffell, Brian (author)
Oregon Health & Science University
Zakharevich, Igor (author)
University of Colorado
Pham, Thanh T. (author)
University of Colorado
Gruosso, Tina (author)
McGill University
Kuasne, Hellen (author)
McGill University
Lakins, Johnathon N. (author)
University of California, San Francisco
Acerbi, Irene (author)
University of California, San Francisco
Barnes, J. Matthew (author)
University of California, San Francisco
Nemkov, Travis (author)
University of Colorado
Chauhan, Aastha (author)
University of Minnesota
Gruenberg, Jessica (author)
University of Minnesota
Nasir, Aqsa (author)
University of Minnesota
Bjarnadottir, Olof (author)
Lund University,Lunds universitet,Bröstcancer - prevention & intervention,Forskargrupper vid Lunds universitet,LUCC: Lunds universitets cancercentrum,Övriga starka forskningsmiljöer,Breast cancer prevention & intervention,Lund University Research Groups,LUCC: Lund University Cancer Centre,Other Strong Research Environments
Werb, Zena (author)
University of California, San Francisco,UCSF Helen Diller Family Comprehensive Cancer Center
Kabos, Peter (author)
University of Colorado
Chen, Yunn Yi (author)
University of California, San Francisco
Hwang, E. Shelley (author)
Duke University Medical Center
Park, Morag (author)
McGill University
Coussens, Lisa M. (author)
Oregon Health & Science University
Nelson, Andrew C. (author)
University of Minnesota
Hansen, Kirk C. (author)
McGill University,University of Colorado
Weaver, Valerie M. (author)
UCSF Helen Diller Family Comprehensive Cancer Center,University of California, San Francisco
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 (creator_code:org_t)
2020-11-30
2020
English.
In: Nature Materials. - : Springer Science and Business Media LLC. - 1476-1122 .- 1476-4660.
Related links:
http://dx.doi.org/10...
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https://www.ncbi.nlm...
https://lup.lub.lu.s...
https://doi.org/10.1...
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  • Journal article (peer-reviewed)
Abstract Subject headings
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  • 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

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