Estrogen-related receptor ß activation and isoform shifting by cdc2-like kinase inhibition restricts migration and intracranial tumor growth in glioblastoma.

Glioblastoma (GBM; grade 4 glioma) is a highly aggressive and incurable tumor. GBM has recently been characterized as highly dependent on alternative splicing, a critical driver of tumor heterogeneity and plasticity. Estrogen-related receptor ß (ERR-ß) is an orphan nuclear receptor expressed in the brain, where alternative splicing of the 3' end of the pre-mRNA leads to the production of 3 validated ERR-ß protein products: ERR-ß short form (ERR-ßsf), ERR-ß2, and ERR-ß exon 10 deleted. Our prior studies have shown the ERR-ß2 isoform to play a role in G2/M cell cycle arrest and induction of apoptosis, in contrast to the function of the shorter ERR-ßsf isoform in senescence and G1 cell cycle arrest. In this study, we sought to better define the role of the proapoptotic ERR-ß2 isoform in GBM. We show that the ERR-ß2 isoform is located not only in the nucleus but also in the cytoplasm. ERR-ß2 suppresses GBM cell migration and interacts with the actin nucleation-promoting factor cortactin, and an ERR-ß agonist is able to remodel the actin cytoskeleton and similarly suppress GBM cell migration. We further show that inhibition of the splicing regulatory cdc2-like kinases in combination with an ERR-ß agonist shifts isoform expression in favor of ERR-ß2 and potentiates inhibition of growth and migration in GBM cells and intracranial tumors.-Tiek, D. M., Khatib, S. A., Trepicchio, C. J., Heckler, M. M., Divekar, S. D., Sarkaria, J. N., Glasgow, E., Riggins, R. B. Estrogen-related receptor ß activation and isoform shifting by cdc2-like kinase inhibition restricts migration and intracranial tumor growth in glioblastoma.

Advancements in Human Breast Organoid Culture: Modeling Complex Tissue Structures and Developmental Insights.

Organoids have been widely used for studying tissue growth and modeling diseases, but achieving physiologically relevant architecture, size, and function has remained a challenge. Here, we develop a next-generation organotypic culture method that enables the formation of a highly patterned, complex, branched tissue that is spatially organized to accurately recapitulate the morphology, scale, cellular, transcriptional, and tissue-level heterogeneity of human breast tissue. Hormone responsiveness of organoids is also a feature allowing for examination of androgen therapy or post-menopausal changes to breast tissue development and regeneration. Live imaging allows for studying stem cell dynamics during organoid formation and is adaptable to a high throughput setting. Real-time imaging of organoid formation reveals activation of latent epithelial organogenesis programs and inductive cellular dynamics that drive formation of a miniature breast tissue along with its mesenchyme akin to tissue stroma. By advancing human breast organoid technology, this model can elucidate cell- and tissue-level consequences to hormonal changes and therapy. In addition, this method can lead to new insights into the cellular, molecular, and tissue-level processes involved in organogenesis and regeneration, as well as disease.