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 Chen; E. Shelley Hwang; Morag Park; Lisa M. Coussens; Andrew C. Nelson; Kirk C. Hansen; Valerie M. Weaver

doi:10.1038/s41563-020-00849-5

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 Chen

E. Shelley Hwang, Morag Park, Lisa M. Coussens, Andrew C. Nelson, Kirk C. Hansen, Valerie M. Weaver

Research output: Contribution to journal › Article › peer-review

237 Scopus citations

Abstract

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 language	English (US)
Pages (from-to)	548-559
Number of pages	12
Journal	Nature Materials
Volume	20
Issue number	4
DOIs	https://doi.org/10.1038/s41563-020-00849-5
State	Published - 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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Maller, O., Drain, A. P., Barrett, A. S., Borgquist, S., Ruffell, B., Zakharevich, I., Pham, T. T., Gruosso, T., Kuasne, H., Lakins, J. N., Acerbi, I., Barnes, J. M., Nemkov, T., Chauhan, A., Gruenberg, J., Nasir, A., Bjarnadottir, O., Werb, Z., Kabos, P., ... Weaver, V. M. (2021). Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression. Nature Materials, 20(4), 548-559. https://doi.org/10.1038/s41563-020-00849-5

Maller, O, Drain, AP, Barrett, AS, Borgquist, S, Ruffell, B, Zakharevich, I, Pham, TT, Gruosso, T, Kuasne, H, Lakins, JN, Acerbi, I, Barnes, JM, Nemkov, T, Chauhan, A, Gruenberg, J, Nasir, A, Bjarnadottir, O, Werb, Z, Kabos, P, Chen, YY, Hwang, ES, Park, M, Coussens, LM, Nelson, AC, Hansen, KC & Weaver, VM 2021, 'Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression', Nature Materials, vol. 20, no. 4, pp. 548-559. https://doi.org/10.1038/s41563-020-00849-5

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

abstract = "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.",

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

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. L{\"o}vgren 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: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2021",

month = apr,

doi = "10.1038/s41563-020-00849-5",

language = "English (US)",

volume = "20",

pages = "548--559",

journal = "Nature Materials",

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T1 - Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression

AU - Maller, Ori

AU - Drain, Allison P.

AU - Barrett, Alexander S.

AU - Borgquist, Signe

AU - Ruffell, Brian

AU - Zakharevich, Igor

AU - Pham, Thanh T.

AU - Gruosso, Tina

AU - Kuasne, Hellen

AU - Lakins, Johnathon N.

AU - Acerbi, Irene

AU - Barnes, J. Matthew

AU - Nemkov, Travis

AU - Chauhan, Aastha

AU - Gruenberg, Jessica

AU - Nasir, Aqsa

AU - Bjarnadottir, Olof

AU - Werb, Zena

AU - Kabos, Peter

AU - Chen, Yunn Yi

AU - Hwang, E. Shelley

AU - Park, Morag

AU - Coussens, Lisa M.

AU - Nelson, Andrew C.

AU - Hansen, Kirk C.

AU - Weaver, Valerie M.

N1 - 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.

PY - 2021/4

Y1 - 2021/4

N2 - 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.

AB - 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.

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UR - https://www.scopus.com/pages/publications/85096939740#tab=citedBy

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DO - 10.1038/s41563-020-00849-5

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JO - Nature Materials

JF - Nature Materials

IS - 4

ER -

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

Abstract

Bibliographical note

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