University of Oulu

Devarajan, R., Izzi, V., Peltoketo, H., Rask, G., Kauppila, S., Väisänen, M.-R., Ruotsalainen, H., Martínez-Nieto, G., Karppinen, S.-M., Väisänen, T., Kaur, I., Koivunen, J., Sasaki, T., Winqvist, R., Manninen, A., Wärnberg, F., Sund, M., Pihlajaniemi, T., & Heljasvaara, R. (2023). Targeting collagen XVIII improves the efficiency of ErbB inhibitors in breast cancer models. Journal of Clinical Investigation, 133(18), e159181.

Targeting collagen XVIII improves the efficiency of ErbB inhibitors in breast cancer models

Saved in:
Author: Devarajan, Raman1,2,3; Izzi, Valerio1,4,5; Peltoketo, Hellevi2,3;
Organizations: 1Oulu Center for Cell-Matrix Research, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
2Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland
3Biocenter Oulu,University of Oulu, Oulu, Finland
4Research Unit of Biomedicine, University of Oulu, Oulu, Finland
5Finnish Cancer Research Institute, Helsinki, Finland
6Department of Medical Biosciences/Pathology, Umeå University, Umeå, Sweden
7Department of Pathology, Oulu University Hospital and University of Oulu, Oulu, Finland
8Northern Finland Laboratory Centre, NordLab, Oulu, Finland
9Department of Pathology, Kainuu Central Hospital, Kajaani, Finland
10Department of Medical Oncology and Radiotherapy and Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
11Department of Pharmacology, Faculty of Medicine, Oita University, Oita, Japan
12Disease Networks Research Unit, Faculty of Biochemistry and Molecular Medicine, University of Oulu, Oulu, Finland
13Department of Surgery, Institute of Clinical Sciences, Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
14Department of Surgery and Perioperative Sciences/Surgery, Umeå University, Umeå, Sweden
15Department of Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 9 MB)
Persistent link:
Language: English
Published: American Society for Clinical Investigation, 2023
Publish Date: 2023-10-13


The tumor extracellular matrix (ECM) critically regulates cancer progression and treatment response. Expression of the basement membrane component collagen XVIII (ColXVIII) is induced in solid tumors, but its involvement in tumorigenesis has remained elusive. We show here that ColXVIII was markedly upregulated in human breast cancer (BC) and was closely associated with a poor prognosis in high-grade BCs. We discovered a role for ColXVIII as a modulator of epidermal growth factor receptor tyrosine kinase (ErbB) signaling and show that it forms a complex with ErbB1 and -2 (also known as EGFR and human epidermal growth factor receptor 2 [HER2]) and α6-integrin to promote cancer cell proliferation in a pathway involving its N-terminal portion and the MAPK/ERK1/2 and PI3K/AKT cascades. Studies using Col18a1 mouse models crossed with the mouse mammary tumor virus–polyoma virus middle T antigen (MMTV-PyMT) mammary carcinogenesis model showed that ColXVIII promoted BC growth and metastasis in a tumor cell–autonomous manner. Moreover, the number of mammary cancer stem cells was significantly reduced in the MMTV-PyMT and human cell models upon ColXVIII inhibition. Finally, ablation of ColXVIII substantially improved the efficacy of ErbB-targeting therapies in both preclinical models. In summary, ColXVIII was found to sustain the stemness properties of BC cells and tumor progression and metastasis through ErbB signaling, suggesting that targeting ColXVIII in the tumor milieu may have important therapeutic potential.

see all

Series: Journal of clinical investigation
ISSN: 0021-9738
ISSN-E: 1558-8238
ISSN-L: 0021-9738
Volume: 133
Issue: 18
Article number: e159181
DOI: 10.1172/JCI159181
Type of Publication: A1 Journal article – refereed
Field of Science: 1182 Biochemistry, cell and molecular biology
3122 Cancers
Funding: The research was funded by the Academy of Finland (grants 308867, 251314, 284065, and 311934); the Jane and Aatos Erkko Foundation; the Sigrid Jusélius Foundation; the Cancer Foundation Finland (grants 190147 and 170138); the Finnish Cultural Foundation; and the Västerbotten Region (ALF RV-866131 and RV-932421).
Academy of Finland Grant Number: 308867
Detailed Information: 308867 (Academy of Finland Funding decision)
251314 (Academy of Finland Funding decision)
Copyright information: © 2023, Devarajan et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.