In this study, loss of expression of the fragile site encoded Wwox protein, was found to contribute to radiation and cisplatin resistance of cells, responses that could be associated with cancer recurrence and poor outcome. WWOX gene deletions occur in a variety of human cancer types and reduced Wwox protein expression can be detected early during cancer development. We find that Wwox loss is followed by mild chromosome instability in genomes of mouse embryo fibroblast cells from Wwox knockout mice. Human and mouse cells deficient for Wwox also exhibit significantly enhanced survival of ionizing radiation and bleomycin treatment, agents that induce double-strand breaks (DSBs). Cancer cells that survive radiation recur more rapidly in a xenograft model of irradiated breast cancer cells; Wwox-deficient cells exhibited significantly shorter tumor latencies vs Wwox-expressing cells. This Wwox effect has important consequences in human disease: in a cohort of cancer patients treated with radiation, Wwox-deficiency significantly correlated with shorter overall survival times. In examining mechanisms underlying Wwox-dependent survival differences, we found that Wwox-deficient cells exhibit enhanced homology directed repair (HDR), and decreased non-homologous end-joining repair, suggesting that Wwox contributes to DNA DSB repair pathway choice. Upon silencing of Rad51, a protein critical for HDR, Wwox-deficient cells were resensitized to radiation. We also demonstrated interaction of Wwox with Brca1, a driver of HDR, and show via immunofluorescent detection of repair proteins at ionizing radiation-induced DNA damage foci that Wwox expression suppresses DSB repair at the end-resection step of HDR. We propose a genome caretaker function for Wwox, in which Brca1-Wwox interaction supports non-homologous end-joining as the dominant DSB repair pathway in Wwox-sufficient cells. Together, the experimental results suggest that reduced Wwox expression, a common occurrence in cancers, dysregulates DSB repair, enhancing efficiency of likely mutagenic repair, and enabling radiation and cisplatin treatment resistance.

We have developed a new deep learning based algorithm for breast density segmentation and estimation. We showed that the proposed algorithm correlated well with BI-RADS density assessments by radiologists and outperformed an existing state of the art algorithm.

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Immune checkpoint inhibitors (ICIs) have substantially improved the survival of cancer patients over the past several years. However, only a minority of patients respond to ICI treatment (~30% in solid tumors), and current ICI-response-associated biomarkers often fail to predict the ICI treatment response. Here, we present a machine learning (ML) framework that leverages network-based analyses to identify ICI treatment biomarkers (NetBio) that can make robust predictions. We curate more than 700 ICI-treated patient samples with clinical outcomes and transcriptomic data, and observe that NetBio-based predictions accurately predict ICI treatment responses in three different cancer types—melanoma, gastric cancer, and bladder cancer. Moreover, the NetBio-based prediction is superior to predictions based on other conventional ICI treatment biomarkers, such as ICI targets or tumor microenvironment-associated markers. This work presents a network-based method to effectively select immunotherapy-response-associated biomarkers that can make robust ML-based predictions for precision oncology.

The phytohormone abscisic acid (ABA) plays crucial roles in various physiological processes, including responses to abiotic stresses, in plants. Recently, multiple ABA transporters were identified. The loss-of-function and gain-of-function mutants of these transporters show altered ABA sensitivity and stomata regulation, highlighting the importance of ABA transporters in ABA-mediated processes. However, how the activity of these transporters is regulated remains elusive. Here, we show that spatial regulation of ATP BINDING CASETTE G25 (ABCG25), an ABA exporter, is an important mechanism controlling its activity. ABCG25, as a soluble green fluorescent protein (sGFP) fusion, was subject to posttranslational regulation via clathrin-dependent and adaptor protein complex-2-dependent endocytosis followed by trafficking to the vacuole. The levels of sGFP:ABCG25 at the plasma membrane (PM) were regulated by abiotic stresses and exogenously applied ABA; PM-localized sGFP:ABCG25 decreased under abiotic stress conditions via activation of endocytosis in an ABA-independent manner, but increased upon application of exogenous ABA via activation of recycling from early endosomes in an ABA-dependent manner. Based on these findings, we propose that the spatial regulation of ABCG25 is an important component of the mechanism by which plants fine-tune cellular ABA levels according to cellular and environmental conditions.