PT  - JOURNAL ARTICLE
AU  - Ori Maller
AU  - Allison P. Drain
AU  - Alexander S. Barrett
AU  - Signe Borgquist
AU  - Brian Ruffell
AU  - Pham T Thanh
AU  - Tina Gruosso
AU  - Hellen Kuasne
AU  - Johnathon N. Lakins
AU  - Irene Acerbi
AU  - J. Matthew Barnes
AU  - Travis Nemkov
AU  - Aastha Chauhan
AU  - Jessica Gruenberg
AU  - Aqsa Nasir
AU  - Olof Bjarnadottir
AU  - Zena Werb
AU  - Peter Kabos
AU  - E. Shelley Hwang
AU  - Morag Park
AU  - Lisa M. Coussens
AU  - Andrew C. Nelson
AU  - Kirk C. Hansen
AU  - Valerie M. Weaver
TI  - Inflammation promotes tumor aggression by stimulating stromal cell-dependent collagen crosslinking and stromal stiffening
AID  - 10.1101/2020.02.13.948141
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.02.13.948141
4099  - http://biorxiv.org/content/early/2020/02/13/2020.02.13.948141.short
4100  - http://biorxiv.org/content/early/2020/02/13/2020.02.13.948141.full
AB  - Collagen deposition and stromal stiffening accompany malignancy, compromise treatment, and promote tumor aggression. Clarifying the molecular nature of and the factors that regulate extracellular matrix stiffening in tumors should identify biomarkers to stratify patients for therapy and therapeutic interventions to improve outcome. We profiled lysyl hydroxylase- and lysyl oxidase-mediated collagen crosslinks and quantified the greatest abundance of total and complex collagen crosslinks in more aggressive human breast cancer subtypes with the stiffest stroma. These tissues also harbored the highest number of tumor-associated macrophages (TAM), whose therapeutic ablation not only reduced metastasis, but also concomitantly decreased accumulation of collagen crosslinks and stromal stiffening. Epithelial-targeted expression of the crosslinking enzyme lysyl oxidase had no impact on collagen crosslinking in PyMT mammary tumors, whereas stromal cell targeting did. Consistently, stromal cells in microdissected human tumors expressed the highest level of collagen crosslinking enzymes. Immunohistochemical analysis of a cohort of breast cancer patient biopsies revealed that stromal expression of lysyl hydroxylase two, an enzyme that induces hydroxylysine aldehyde-derived collagen crosslinks and stromal stiffening correlated significantly disease specific mortality. The findings link tissue inflammation, stromal cell-mediated collagen crosslinking and stiffening to tumor aggression and identify lysyl hydroxylase two as a novel stromal biomarker.Significance We show infiltrating macrophages induce stromal fibroblast, and not epithelial, expression of collagen crosslinking enzymes that drive tumor stiffening. Stromal enzyme LH2 is significantly upregulated in breast cancer patients with the stiffest stroma, the most trivalent HLCCs and the worst prognosis, underscoring its potential as a biomarker and therapeutic target.