Ward, A. S. | bioRxiv Science

bioRxiv2023

Spheroid architecture strongly induces miR-221/222 expression and promotes oxidative phosphorylation and survival of mobile tumor cells through a mechanism that includes restriction of miR-9 expression

Tumor cell spheroids are three dimensional multicellular structures that form during the expansive growth of carcinoma cells. Spheroids support tumor metastasis as vehicles of dissemination, promoting growth and survival of bulk tumor and cancer stem cells within the mobile tumor cell population. Deciphering how spheroid architecture affects tumor cell phenotype will be essential for the development of therapeutics to inhibit transperitoneal metastasis and the development of peritoneal carcinomatosis by ovarian cancers. We investigated how spheroid formation directly affects OXPHOS activity and microRNA expression in a cultured ovarian carcinoma cell system. The rate of oxidative phosphorylation/respiration per cell in spheroids was nearly double that of the same cell type growing in suspension as single cells. Cells growing as spheroids showed greatly enhanced expression of miR-221/222, an oncomiR that targets multiple tumor suppressor genes, promotes invasion, as well as reduced expression of miR-9, which targets mitochondrial tRNA-modification enzymes and inhibits OXPHOS. Consistent with the greater efficiency of ATP generation afforded by OXPHOS phosphorylation, tumor cells growing as spheroids injected into the nutrient-poor environment of the murine peritoneum survived longer than the cells growing in suspension as loosely associated aggregates. The data suggest that in addition to the reported effects of spheroid formation on cancer cell growth and phenotype, including promotion of stem cell generation, spheroid architecture increases the OXPHOS activity of constituent tumor cells. During the mobile phase of metastasis, when ovarian tumor cells disperse through nutrient-poor environments such as the peritoneum, enhanced OXPHOS activity afforded by spheroid architecture would enhance survival and thereby contribute to metastatic potential.

cancer biology↗

bioRxiv2020

Ecological theory applied to environmental metabolomes reveals compositional divergence despite conserved molecular properties

Stream and river systems transport and process substantial amounts of dissolved organic matter (DOM) from terrestrial and aquatic sources to the ocean, with global biogeochemical implications. However, the underlying mechanisms affecting the spatiotemporal organization of DOM composition are under-investigated. To understand the principles governing DOM composition, we leverage the recently proposed synthesis of metacommunity ecology and metabolomics, termed meta-metabolome ecology. Applying this novel approach to a freshwater ecosystem, we demonstrated that despite similar molecular properties across metabolomes, metabolite identity significantly diverged due to environmental filtering. We refer to this phenomenon as thermodynamic redundancy, which is analogous to the ecological concept of functional redundancy. We suggest that under thermodynamic redundancy, divergent metabolomes can support equivalent biogeochemical function just as divergent ecological communities can support equivalent ecosystem function. As these analyses are performed in additional ecosystems, potentially generalizable principles, like thermodynamic redundancy, can be revealed and provide insight into DOM dynamics.

ecology↗