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

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 l...

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Published in	Nature materials Vol. 20; no. 4; pp. 548 - 559
Main Authors	Maller, Ori, Drain, Allison P., Barrett, Alexander S., Borgquist, Signe, Ruffell, Brian, Zakharevich, Igor, Pham, Thanh T., Gruosso, Tina, Kuasne, Hellen, Lakins, Johnathon N., Acerbi, Irene, Barnes, J. Matthew, Nemkov, Travis, Chauhan, Aastha, Gruenberg, Jessica, Nasir, Aqsa, Bjarnadottir, Olof, Werb, Zena, Kabos, Peter, Chen, Yunn-Yi, Hwang, E. Shelley, Park, Morag, Coussens, Lisa M., Nelson, Andrew C., Hansen, Kirk C., Weaver, Valerie M.
Format	Journal Article
Language	English
Published	London Nature Publishing Group UK 01.04.2021 Nature Publishing Group
Subjects	631/1647/296 631/67 631/67/1857 631/67/327 639/638/45 Ablation Adult Aggression Aldehydes Biomarkers Biomaterials Biopsy Breast cancer Breast Neoplasms - immunology Breast Neoplasms - metabolism Breast Neoplasms - pathology Cancer and Oncology Cancer och onkologi Cell Line, Tumor Chemistry and Materials Science Clinical Medicine Collagen Collagen - metabolism Condensed Matter Physics Crosslinking Enzymes Female Fibroblasts Humans Klinisk medicin Macrophages Materials Science Medical and Health Sciences Medicin och hälsovetenskap Middle Aged Nanotechnology Optical and Electronic Materials Oxidase Protein-Lysine 6-Oxidase - metabolism Stiffening Stromal Cells - metabolism Stromal Cells - pathology Tumor-Associated Macrophages - metabolism Tumors
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Summary:	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. It is now shown that tumour-associated macrophages recruited early during tumour evolution stimulate stromal fibroblasts to express collagen crosslinking enzymes and that the stromal expression, particularly of lysyl hydroxylase 2, can predict survival in a patient cohort.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 These authors contributed equally to this work V.M.W., K.C.H., O.M., A.S.B., and A.P.D. conceived the project, prepared figures and wrote the manuscript. A.S.B, T.P., T.N., and K.C.H. developed the xAAA method, and A.S.B and I.Z. performed all LC-MS and LC-PRM experiments. J.N.L generated the TetO_mLOX mouse model. O.M. designed and conducted in vivo experiments using inducible LOX overexpression models. B.R. and L.C. designed and conducted CSF1 blocking antibody mouse experiment. O.M. and A.P.D. performed and quantified immunofluorescence, H&E, PS and SHG imaging and analyses on mouse tissue samples. I.A., A.P.D., and J.M.B performed AFM on human or mouse tissue specimens. I.A. performed SHG imaging on human tissue. E.S.H, and P.K. provided human breast tumor biopsies for xAAA. B.R. and L.C. designed and conducted immunoprofiling on human breast tumor via flow cytometry. O.M. and A.P.D. performed all gene expression analyses with the exception of Fig. 5g-j. T.G, H.K. and M.P. performed gene expression analyses gene expression in microdissected epithelial and stromal compartments of human invasive breast carcinomas. S.B. established and managed MDCS cohort used for LH2 IHC. Z.W. and S.B. performed LH2 IHC. A.C.N. designed scoring schemes for stromal and neoplastic epithelial LH2 IHC, and A.C.N, A.N., J.G., and A.C. scored all human biopsies. S.B., O.B., A.C.N., O.M., and V.M.W analyzed and interpreted clinical data from LH2 scores. These authors jointly supervised this work Author Contributions
ISSN:	1476-1122 1476-4660 1476-4660
DOI:	10.1038/s41563-020-00849-5