RT Journal Article SR Electronic T1 Collagen XVIII promotes breast cancer through EGFR/ErbB signaling and its ablation improves the efficacy of ErbB-targeting inhibitors JF bioRxiv FD Cold Spring Harbor Laboratory SP 2022.01.10.474416 DO 10.1101/2022.01.10.474416 A1 Raman Devarajan A1 Hellevi Peltoketo A1 Valerio Izzi A1 Heli Ruotsalainen A1 Saila Kauppila A1 Marja-Riitta Väisänen A1 Gunilla Rask A1 Guillermo Martínez-Nieto A1 Sanna-Maria Karppinen A1 Timo Väisänen A1 Inderjeet Kaur A1 Jussi Koivunen A1 Takako Sasaki A1 Robert Winqvist A1 Fredrik Wärnberg A1 Malin Sund A1 Taina Pihlajaniemi A1 Ritva Heljasvaara YR 2022 UL http://biorxiv.org/content/early/2022/01/11/2022.01.10.474416.abstract AB The tumor extracellular matrix (ECM) is a critical regulator of cancer progression and metastasis, significantly affecting the treatment response. Expression of collagen XVIII (ColXVIII), a ubiquitous component of basement membranes, is induced in many solid tumors, but its involvement in tumorigenesis has remained elusive. We show here that ColXVIII is markedly upregulated in human breast cancer (BC) cells and is closely associated with a poor prognosis in high-grade BC, especially in human epidermal growth factor receptor 2 (HER2)-positive and basal/triple-negative cases. We identified a novel mechanism of action for ColXVIII as a modulator of epidermal growth factor receptor (EGFR/ErbB) signaling and show that it forms a complex with EGFR, 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. In vivo studies with Col18a1 mouse models crossed with the MMTV-PyMT mammary carcinogenesis model showed that the short ColXVIII isoform promotes BC growth and metastasis in a tumor cell-autonomous manner. Moreover, the number of mammary cancer stem cells was significantly reduced in both mouse and human cell models upon ColXVIII inhibition. Finally, ablation of ColXVIII in human BC cells and the MMTV-PyMT model substantially improved the efficacy of certain EGFR/ERbB-targeting therapies, even abolishing resistance to EGFR/ErbB inhibitors in some cell lines. In summary, a new function is revealed for ColXVIII in sustaining the stemness properties of BC cells, and tumor progression and metastasis through EGFR/ErbB signaling, suggesting that targeting ColXVIII in the tumor milieu may have significant therapeutic potential.One Sentence Summary Collagen XVIII is upregulated in breast cancer and promotes mammary carcinogenesis through EGFR/ErbB signaling and by sustaining cancer stem cells, so that its targeting improves the efficacy of ErbB-targeted therapies.Competing Interest StatementThe authors have declared no competing interest.