Werner Syndrome (WS) is characterized by premature aging, genomic instability, and cancer. The combined impact of WRN helicase deficiency and limiting telomere reserves is central to disease pathogenesis. Here, we report that cells doubly deficient for telomerase and WRN helicase show chromosomal aberrations and elevated recombination rates between telomeres of sister chromatids. Somatic reconstitution of WRN function, but not a WRN helicase-deficient mutant, abolished telomere sister chromatid exchange (T-SCE), indicating that WRN normally represses T-SCEs. Elevated T-SCE was associated with greater immortalization potential and resultant tumors maintained telomeres via the alternative lengthening of telomere (ALT) pathway. We propose that the increased incidence of chromosomal instability and cancer in WS relates in part to aberrant recombinations between sister chromatids at telomeres, which facilitates the activation of ALT and engenders cancer-relevant chromosomal aberrations and tumor formation.[Keywords: Werner; alternative lengthening of telomeres; cancer; escape from senescence; telomeres] Supplemental material is available at http://genesdev.org.

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Cognitive impairments are a common side effect of chemotherapy that often persists long after treatment completion. There are no FDA-approved interventions to treat these cognitive deficits also called ‘chemobrain’. We hypothesized that nasal administration of mesenchymal stem cells (MSC) reverses chemobrain. To test this hypothesis, we used a mouse model of cognitive deficits induced by cisplatin that we recently developed. Mice were treated with two cycles of cisplatin followed by nasal administration of MSC. Cisplatin treatment induced deficits in the puzzle box, novel object/place recognition and Y-maze tests, indicating cognitive impairment. Nasal MSC treatment fully reversed these cognitive deficits in males and females. MSC also reversed the cisplatin-induced damage to cortical myelin. Resting state functional MRI and connectome analysis revealed a decrease in characteristic path length after cisplatin, while MSC treatment increased path length in cisplatin-treated mice. MSCs enter the brain but did not survive longer than 12-72 hrs, indicating that they do not replace damaged tissue. RNA-sequencing analysis identified mitochondrial oxidative phosphorylation as a top pathway activated by MSC administration to cisplatin-treated mice. Consistently, MSC treatment restored the cisplatin-induced mitochondrial dysfunction and structural abnormalities in brain synaptosomes. Nasal administration of MSC did not interfere with the peripheral anti-tumor effect of cisplatin. In conclusion, nasal administration of MSC may represent a powerful, non-invasive, and safe regenerative treatment for resolution of chemobrain.

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Summary Extensive reprogramming of cellular energy metabolism is a hallmark of cancer. Despite its importance, the molecular mechanism controlling this tumour metabolic shift remains not fully understood. Here we show that 14-3-3σ regulates cancer metabolic reprogramming and protects cells from tumourigenic transformation. 14-3-3σ opposes tumour-promoting metabolic programs by enhancing c-Myc poly-ubiquitination and subsequent degradation. 14-3-3σ demonstrates the suppressive impact on cancer glycolysis, glutaminolysis, mitochondrial biogenesis and other major metabolic processes of tumours. Importantly, 14-3-3σ expression levels predict overall and recurrence-free survival rates, tumour glucose uptake and metabolic gene expression in breast cancer patients. Thus, these results highlight that 14-3-3σ is an important regulator of tumour metabolism, and loss of 14-3-3σ expression is critical for cancer metabolic reprogramming. We anticipate that pharmacologically elevating the function of 14-3-3σ in tumours could be a promising direction for targeted anti-cancer metabolism therapy development in future.