Alvarez, J. — Page 2 | bioRxiv Science

bioRxiv2019

RIPK3 upregulation confers robust proliferation and collateral cystine-dependence on breast cancer recurrence

The molecular and genetic basis of tumor recurrence is complex and poorly understood. RIPK3 is a key effector in programmed necrotic cell death and, therefore, its expression is frequently suppressed in primary tumors. In a transcriptome profiling between primary and recurrent breast tumor cells from a murine model of breast cancer recurrence, we found that RIPK3, while absent in primary tumor cells, is dramatically re-expressed in recurrent breast tumor cells by an epigenetic mechanism. Unexpectedly, we found that RIPK3 knockdown in recurrent tumor cells reduced clonogenic growth, causing cytokinesis failure, p53 stabilization, and repressed the activities of YAP/TAZ. These data uncover a surprising role of the pro-necroptotic RIPK3 kinase in enabling productive cell cycle during tumor recurrence. Remarkably, high RIPK3 expression also rendered recurrent tumor cells exquisitely dependent on extracellular cystine and undergo programmed necrosis upon cystine deprivation. The induction of RIPK3 in recurrent tumors unravels an unexpected mechanism that paradoxically confers on tumors both growth advantage and necrotic vulnerability, providing potential strategies to eradicate recurrent tumors.

cancer biology↗

bioRxiv2019

Mapping changes in the spatiotemporal distribution of lumpy skin disease virus

Lumpy skin disease virus (LSDV) is an infectious disease of cattle transmitted by arthropod vectors which results in substantial economic losses due to impact on production efficiency and profitability, and represents an emerging threat to international trade of livestock products and live animals. Since 2015, the disease has spread across many Eastern European countries as well as Russia and Kazakhstan. This rapid expansion highlights the emergent nature of the virus in more temperate regions than those in which LSDV traditionally occurred. The goal of this study was to assess the risk for further LSDV spread in Eurasia through a) analysis of environmental factors conducive for LSDV and b) estimate of the underlying LSDV risk using a fine spatiotemporally explicit Bayesian hierarchical model on LSDV outbreak occurrence information. We used ecological niche modeling to estimate the potential distribution of LSDV outbreaks for 2014-2016. This analysis resulted in a spatial representation of environmental limits where, if introduced, LSDV is expected to efficiently spread. The Bayesian space-time model incorporated both environmental factors and the changing spatiotemporal distribution of the disease to capture the dynamics of disease spread and predict areas in which there is an increased risk of LSDV occurrence. Variables related to the average temperature, precipitation, wind speed, as well as land cover and host densities were found to be important drivers explaining the observed distribution of LSDV in both modeling approaches. Areas of elevated LSDV risks were identified mainly in Russia, Turkey, Serbia, and Bulgaria. Results suggest that prevailing ecological conditions may be compatible with further spread of LSDV in Eurasia, though models should be continually updated to reflect the current epidemiologic conditions. The results presented here advance our understanding of the ecological requirements of LSDV in temperate regions and may help in the design and implementation of prevention and surveillance strategies in the region.

epidemiology↗