Sund, M. | bioRxiv Science

bioRxiv2022

Identification of unique α4 chain structure and conserved anti-angiogenic activity of α3NC1 type IV collagen in zebrafish

Type IV collagen is an abundant component of basement membranes in all multicellular species and is essential for the extracellular scaffold supporting tissue architecture and function. Lower organisms typically have two type IV collagen genes, encoding 1 and 2 chains, in contrast with the six genes in humans, encoding 1 to 6 chains. The chains assemble into trimeric protomers, the building blocks of the type IV collagen network. The detailed evolutionary conservation of type IV collagen network remains to be studied. We report on the molecular evolution of type IV collagen genes. The zebrafish 4 non-collagenous (NC1) domain, in contrast with its human ortholog, contains an additional cysteine residue and lacks the M93 and K211 residues involved in sulfilimine bond formation between adjacent protomers. This may alter 4 chain interactions with other chains, as supported by temporal and anatomic expression patterns of collagen IV chains during zebrafish development. Despite the divergence between zebrafish and human 3 NC1 domain (endogenous angiogenesis inhibitor, Tumstatin), the zebrafish 3 NC1 domain exhibits conserved anti-angiogenic activity in human endothelial cells. Our work supports type IV collagen is largely conserved between zebrafish and humans, with a possible difference involving the 4 chain.

developmental biology↗

bioRxiv2022

Collagen XVIII promotes breast cancer through EGFR/ErbB signaling and its ablation improves the efficacy of ErbB-targeting inhibitors

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 6 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 SummaryCollagen 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.

cancer biology↗