Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • Vascular Malformations (Apr 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Targeting collagen XVIII improves the efficiency of ErbB inhibitors in breast cancer models
Raman Devarajan, … , Taina Pihlajaniemi, Ritva Heljasvaara
Raman Devarajan, … , Taina Pihlajaniemi, Ritva Heljasvaara
Published July 27, 2023
Citation Information: J Clin Invest. 2023;133(18):e159181. https://doi.org/10.1172/JCI159181.
View: Text | PDF
Research Article Oncology Article has an altmetric score of 22

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

  • Text
  • PDF
Abstract

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.

Authors

Raman Devarajan, Valerio Izzi, Hellevi Peltoketo, Gunilla Rask, Saila Kauppila, Marja-Riitta Väisänen, Heli Ruotsalainen, Guillermo Martínez-Nieto, Sanna-Maria Karppinen, Timo Väisänen, Inderjeet Kaur, Jussi Koivunen, Takako Sasaki, Robert Winqvist, Aki Manninen, Fredrik Wärnberg, Malin Sund, Taina Pihlajaniemi, Ritva Heljasvaara

×

Figure 8

Depletion of ColXVIII improves the efficacy of ErbB-targeting drugs in preclinical BC models.

Options: View larger image (or click on image) Download as PowerPoint
Depletion of ColXVIII improves the efficacy of ErbB-targeting drugs in p...
(A–C) Cell proliferation, monitored as the cell confluence (percentage) for 5 days using the IncuCyte live-cell imaging platform, in BC cell lines with ColXVIII KD and lapatinib treatment (n = 3 biological replicates per cell line in triplicate). (D) Schematic figure of the lapatinib treatment regimen and follow up of the primary tumor growth (red) and lung metastasis (blue) in WT-PyMT and 18–/–-PyMT mice. (E) The total tumor burden in vehicle-treated (0.5% hydroxymethyl-cellulose) and lapatinib-treated WT-PyMT mice and 18–/–-PyMT mice at the age of 10 weeks. Two doses of lapatinib, 35 mg/kg and 70 mg/kg, were tested (n = 6 mice/group). (F and G) Quantification of the Ki67+ and the CK5+ cells (n = 6, n = 4 random fields/tumor at ×20). (H) Representative images of proliferating Ki67+ cells (red) and CK5+ mammary progenitor cells (green) in the vehicle- and lapatinib-treated WT-PyMT and 18–/–-PyMT tumors at week 10. Scale bars: 200 nm. (I) Mammary tumor burden in vehicle- and lapatinib-treated (70 mg/kg) WT-PyMT mice (14 weeks) and 18–/–-PyMT (17 weeks) mice (n = 4–5 mice/experimental group). (J) Quantification of lung metastasis area of vehicle and lapatinib (70 mg/kg) treated WT-PyMT mice (14 weeks) and 18–/–-PyMT (17 weeks) mice using ImageJ software (NIH) (n = 4–5). *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001, by 2-way ANOVA followed by Bonferroni’s post test (A–C) and Tukey’s multiple-comparison test (E–G, I, and J). Error bars indicate the SEM.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Picked up by 2 news outlets
Posted by 16 X users
32 readers on Mendeley
See more details