New Method Enables Development of Customized Vasculature in Organoids

Organoids and tumoroids have an invaluable place in cancer research; however, using them to study interactions between parenchymal cells and the vasculature that would grow around and within organs and tumors in vivo has been challenging because cultured adult endothelial cells are not efficient in forming new tissue-specific vessels. To address this, Palikuqi and colleagues developed “reset” vascular endothelial cells (R-VEC), which were produced via lentiviral transient transduction of ETV2, encoding a pioneer transcription factor that promotes vascular adaptation and lumen formation during early development. In serum-free medium, these R-VECs grew into three-dimensional vessels with continuous open lumens and apicobasal polarity, and R-VECs implanted into mice formed durable, non-leaky, branching vessels capable of transporting blood. RNA-sequencing experiments revealed that early-stage R-VECs exhibited upregulation of genes in pathways that regulate vasculogenesis, angiogenesis, GTPase activity, extracellular matrix remodeling, response to mechanical stimuli, and activation of the small GTPase RAP1, which is required for lumen formation. Chromatin immunoprecipitation–sequencing experiments showed that ETV2 transduction promoted epigenetic changes that resulted in activation and priming of tubulogenic and vasculogenic genes and demonstrated that this was due to direct binding between ETV2 and promoters of upregulated genes, where ETV2 binding led to an altered histone-modification profile. Importantly, R-VECs were able to vascularize and conform to normal colon organoids and maladapt to colorectal cancer organoids. In colon organoids, R-VECs adjusted to normal organoids and expressed organotypic marker genes, including PLVAP and TFF3, whereas R-VECs in colorectal cancer organoids exhibited the aberrant gene expression characteristic of tumor endothelial cells, expressing genes such as ID1, JUNB, and ADAMTS4. In summary, this work lays the foundation for a new approach for investigating the cross-talk between vasculature and parenchymal cells that, in the cancer field, may be of particular use in uncovering how tumor vasculature acquires corrupted features and identifying druggable targets to block tumor growth and metastasis.

Palikuqi B, Nguyen DHT, Li G, Schreiner R, Pellegata AF, Liu Y, et al. Adaptable haemodynamic endothelial cells for organogenesis and tumorigenesis. Nature 2020;585:426–32.

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