The DOI matches its Crossref record; 71 of the 71 references it cites were found in a registry or an index.
Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression
Open accessAbstract
Abstract 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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
3 retracted
Lysyl oxidase is essential for hypoxia-induced metastasis
Erler, J. T., Bennewith, K. L., Nicolau, M., Dornhöfer, N., Kong, C., Le, Q.-T., Chi, J.-T. A., Jeffrey, S. S., & Giaccia, A. J. (2006) · Nature · doi:10.1038/nature04695 · Cited by 1,309
RetractedGilkes, D. M., Bajpai, S., Chaturvedi, P., Wirtz, D., & Semenza, G. L. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.442939 · Cited by 467
RetractedProcollagen lysyl hydroxylase 2 is essential for hypoxia-induced breast cancer metastasis
Gilkes, D. M., Bajpai, S., Wong, C. C., Chaturvedi, P., Hubbi, M. E., Wirtz, D., & Semenza, G. L. (2013) · Molecular Cancer Research · doi:10.1158/1541-7786.mcr-12-0629 · Cited by 252
RetractedCerami, E., Gao, J., Dogrusoz, U., Gross, B. E., Sumer, S. O., Aksoy, B. A., Jacobsen, A., Byrne, C. J., Heuer, M. L., Larsson, E., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0095 · Cited by 17,455
Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal
Gao, J., Aksoy, B. A., Dogrusoz, U., Dresdner, G., Gross, B., Sumer, S. O., Sun, Y., Jacobsen, A., Sinha, R., Larsson, E., et al. (2013) · Science Signaling · doi:10.1126/scisignal.2004088 · Cited by 15,160
Immunity, Inflammation, and Cancer
Grivennikov, S. I., Greten, F. R., & Karin, M. (2010) · Cell · doi:10.1016/j.cell.2010.01.025 · Cited by 10,755
The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups
METABRIC Group, Curtis, C., Shah, S. P., Chin, S.-F., Turashvili, G., Rueda, O. M., Dunning, M. J., Speed, D., Lynch, A. G., Samarajiwa, S., et al. (2012) · Nature · doi:10.1038/nature10983 · Cited by 6,097
Tumors: Wounds That Do Not Heal
Flier, J. S., Underhill, L. H., & Dvorak, H. F. (1986) · New England Journal of Medicine · doi:10.1056/nejm198612253152606 · Cited by 4,391
Györffy, B., Lanczky, A., Eklund, A. C., Denkert, C., Budczies, J., Li, Q., & Szallasi, Z. (2010) · Breast Cancer Research and Treatment · doi:10.1007/s10549-009-0674-9 · Cited by 4,169
Matrix Crosslinking Forces Tumor Progression by Enhancing Integrin Signaling
Levental, K. R., Yu, H., Kass, L., Lakins, J. N., Egeblad, M., Erler, J. T., Fong, S. F. T., Csiszar, K., Giaccia, A., Weninger, W., et al. (2009) · Cell · doi:10.1016/j.cell.2009.10.027 · Cited by 4,101
Self-citation
Cited by
The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth
de Visser, K. E., & Joyce, J. A. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.02.016 · Cited by 4,059
Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer
Buechler, M. B., Fu, W., & Turley, S. J. (2021) · Immunity · doi:10.1016/j.immuni.2021.04.021 · Cited by 494
Metastasis-Initiating Cells and Ecosystems
Massagué, J., & Ganesh, K. (2021) · Cancer Discovery · doi:10.1158/2159-8290.cd-21-0010 · Cited by 372
Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets
Guan, F., Wang, R., Yi, Z., Luo, P., Liu, W., Xie, Y., Liu, Z., Xia, Z., Zhang, H., & Cheng, Q. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02124-y · Cited by 371
Targeting the tumor stroma for cancer therapy
Xu, M., Zhang, T., Xia, R., Wei, Y., & Wei, X. (2022) · Molecular Cancer · doi:10.1186/s12943-022-01670-1 · Cited by 319
Metadata
- Authors
- 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., Chen, Y.-Y., Hwang, E. S., Park, M., Coussens, L. M., Nelson, A. C., Hansen, K. C., & Weaver, V. M.
- Venue
- Nature Materials
- Published
- 2020-11-30
- Volume
- 20
- Issue
- 4
- Pages
- 548-559
- ISSN
- 1476-1122 (ISSN-L)
- 1476-4660
- OpenAlex
- W3106839863
- Cited by
- 298
- References
- 71
- FWCI
- 14.35
- Type
- journal article
- Language
- en
- Open access
- green
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
How to cite
Cite CoChat for the checks on this page, and the paper for its own findings.
- This page
- CoChat. (2026). Citation check: Tumour-associated macrophages drive stromal cell-dependent collagen crosslinking and stiffening to promote breast cancer aggression. https://app.cochat.ai/papers/10.1038/s41563-020-00849-5
- The paper
- 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. https://doi.org/10.1038/s41563-020-00849-5
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
