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.
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Research Article Oncology

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

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

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Figure 4

The short ColXVIII isoform promotes mammary tumor growth in mice.

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The short ColXVIII isoform promotes mammary tumor growth in mice. (A) St...
(A) Structures of 3 α1(XVIII) collagen chains and Col18a1 mouse models. (B and C) ColXVIII expression (green) in MGs of WT and ColXVIII-KO (Col18a1–/–) females (n = 3) (B) and in WT MMTV-PyMT (WT-PyMT) and Col18a1–/– MMTV-PyMT (18–/–-PyMT) mammary tumors (n ≥10) (C). αSMA (red) in myoepithelial cells and vascular smooth muscle cells (B). Arrowheads, epithelial BM; arrows, vascular BM; a, adipocyte. (D) Expression of short, medium, and long Col18a1 transcripts normalized to Gapdh in WT MGs and WT-PyMT tumors (n = 3). (E) Tumor burden in WT-PyMT and 18–/–-PyMT mice at 9–18 weeks of age (n ≥3 per genotype at each time point). (F) Mammary tumor burden at week 13 in WT-PyMT (n = 10), 18–/–-PyMT (n = 9), P1-PyMT (n = 9), and P2-PyMT (n = 14) mice. (G) Kaplan-Meier plots for WT-PyMT (n = 38), 18–/–-PyMT (n = 31), P1-PyMT (n = 28), and P2-PyMT (n = 33) mice. (H) Tumors (circles) in MGs of WT-PyMT and 18–/–-PyMT mice at week 13. Arrows indicate macroscopically normal MGs. (I) Carmine Alum-stained MGs and H&E-stained WT-PyMT and 18–/–-PyMT tumor sections at week 13 (n ≥6). (J) Ki67 (red) and cleaved caspase-3 (green) in WT-PyMT and 18–/–-PyMT tumors. Arrowheads point to apoptotic cells in the 18–/–-PyMT specimen. (K) Ki67+ cells in WT-PyMT (n = 9) and 18–/–-PyMT tumors (n = 8) (4 fields/tumor at ×20). Scale bars: 200 μm (B, C, I, and J). **P < 0.01 and ***P < 0.001, by 2-tailed Student’s t test (D, E, and K), 1-way ANOVA with Bartlett’s post-correction test for equal variances (F), and Mantel-Cox test (G). Error bars indicate the SEM.