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

Ori Maller, Allison P. Drain, Alexander S. Barrett, Signe Borgquist, Brian Ruffell, Igor Zakharevich, Thanh T. Pham, Tina Gruosso, Hellen Kuasne, Johnathon N. Lakins, Irene Acerbi, J. Matthew Barnes, Travis Nemkov, Aastha Chauhan, Jessica Gruenberg, Aqsa Nasir, Olof Bjarnadottir, Zena Werb, Peter Kabos, Yunn Yi ChenE. Shelley Hwang, Morag Park, Lisa M. Coussens, Andrew C. Nelson, Kirk C. Hansen, Valerie M. Weaver

Research output: Contribution to journalArticlepeer-review

126 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)548-559
Number of pages12
JournalNature Materials
Issue number4
StatePublished - Apr 2021

Bibliographical note

Funding Information:
We thank J. Northcott for writing the ImageJ Macro, L. Korets for mouse husbandry and N. Korets for histology support, as well as K. Lövgren and S. Baker for LH2 immunostaining on patient biopsies. We thank the UCSF Genomics core for their support with the RNA-seq analysis on mouse TAMs and C. Stashko for generating the gene expression heat map. The work was supported by investigator grants through the US National Cancer Institute R33 CA183685 (K.C.H. and V.M.W) and R01CA192914 and CA174929 to (V.M.W), and R01CA222508-01 to (V.M.W. and E.S.H.), as well as US DOD Breast Cancer Research Program (BCRP) grant BC122990 (V.M.W.). Trainee support was provided by US DOD BCRP grant BC130501 (O.M.), US NIH grants TL1 TR001081 and US NIH T32 HL007171 (A.S.B.), and US NIH T32 grant CA 108462 (O.M.). Funding from Eastern Star Scholar-Minnesota Masonic Cancer Center (A.C.N.), the Swedish Research Council (S.B.) and US NIH R01 CA057621 (Z.W.) also supported the work.

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.


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