Batavia, A. | Search bioRxiv

bioRxiv2024

The Notch1/Delta-like-4 axis is crucial for the initiation and progression of oral squamous cell carcinoma

The Notch signaling pathway is frequently altered in Oral Squamous Cell Carcinoma (OSCC), the most common malignant neoplasm of the oral mucosa. In this study, we aimed to elucidate the functional role of this pathway in OSCC initiation and progression. Using transgenic animal models, advanced imaging, and next-generation-sequencing techniques, we analyzed Notch-dependent changes driving OSCC. We found specific expression patterns of Notch1 and Delta-like-4 confined to the malignant tissue, while Jagged1 was downregulated in OSCC. This mutually exclusive expression of Delta-like-4 and Jagged1 occurs at the early hyperplastic stage and persists until more advanced stages of the tumor. Transcriptomic analyses confirmed the dysregulation of the Notch pathway circuitry associated with a genetic signature for undifferentiation in OSCC. Furthermore, pharmacological Notch inhibition significantly impaired cancer cell motility. Taken together, these results reveal the pivotal importance of the Notch1/Delta-like-4 signaling axis as a central oncogenic driver in OSCC.

cancer biology↗

bioRxiv2022

The vascular gene Apold1 is dispensable for normal development but controls angiogenesis under pathological conditions

The molecular mechanisms of angiogenesis have been intensely studied, but many genes that control endothelial behavior and fate still need to be described. Here, we characterize the role of Apold1 (Apolipoprotein L domain containing 1) in angiogenesis in vivo and in vitro. Single-cell analyses reveal that - across tissues - the expression of Apold1 is restricted to the vasculature, and that Apold1 expression in endothelial cells (ECs) is highly sensitive to environmental factors. Using Apold1-/- mice, we find that Apold1 is dispensable for development and does not affect postnatal retinal angiogenesis nor alters the vascular network in adult brain and muscle. However, when exposed to ischemic conditions following photothrombotic stroke as well as femoral artery ligation, Apold1-/- mice display dramatic impairments in recovery and revascularization. We also find that human tumor endothelial cells express strikingly higher levels of Apold1, and that Apold1 deletion in mice stunts the growth of subcutaneous B16 melanoma tumors, which have smaller and poorly perfused vessels. Mechanistically, Apold1 is activated in ECs upon growth factor stimulation as well as in hypoxia, and Apold1 intrinsically controls EC proliferation but not migration. Our data demonstrate that Apold1 is a key regulator of angiogenesis in pathological settings, whereas it does not affect developmental angiogenesis, thus making it a promising candidate for clinical investigation.

cell biology↗