Chromosomal instability (CIN) is a hallmark of cancer and it results from ongoing errors in chromosome segregation during mitosis. While CIN is a major driver of tumor evolution, its role in metastasis has not been established. Here we show that CIN promotes metastasis by sustaining a tumor-cell autonomous response to cytosolic DNA. Errors in chromosome segregation create a preponderance of micronuclei whose rupture spills genomic DNA into the cytosol. This leads to the activation of the cGAS-STING cytosolic DNA-sensing pathway and downstream noncanonical NF-κB signaling. Genetic suppression of CIN significantly delays metastasis even in highly aneuploid tumor models, whereas inducing continuous chromosome segregation errors promotes cellular invasion and metastasis in a STING-dependent manner. By subverting lethal epithelial responses to cytosolic DNA, chromosomally unstable tumor cells co-opt chronic activation of innate immune pathways to spread to distant organs.

Over the past century, the notion that vitamin C can be used to treat cancer has generated much controversy. However, new knowledge regarding the pharmacokinetic properties of vitamin C and recent high-profile preclinical studies have revived interest in the utilization of high-dose vitamin C for cancer treatment. Studies have shown that pharmacological vitamin C targets many of the mechanisms that cancer cells utilize for their survival and growth. In this Opinion article, we discuss how vitamin C can target three vulnerabilities many cancer cells share: redox imbalance, epigenetic reprogramming and oxygen-sensing regulation. Although the mechanisms and predictive biomarkers that we discuss need to be validated in well-controlled clinical trials, these new discoveries regarding the anticancer properties of vitamin C are promising to help identify patient populations that may benefit the most from high-dose vitamin C therapy, developing effective combination strategies and improving the overall design of future vitamin C clinical trials for various types of cancer. The 'magic bullet' theory serves as a paradigm for modern cancer research and has inspired numerous groundbreaking targeted therapies such as imatinib and vemurafenib 1. However, despite remarkable initial responses, the eventual acquisition of resistance and therapyassociated toxic effects continues to impede progress towards achieving meaningful patient survival. Thus, a new strategy for treating and managing cancer is needed. In this Opinion article, we propose that vitamin C, a natural compound with an unusually high safety profile, can be used to target multiple critical pathways in cancer.

A hallmark of metastasis is the adaptation of tumor cells to new environments. Metabolic constraints imposed by the serine and glycine-limited brain environment restrict metastatic tumor growth. How brain metastases overcome these growth-prohibitive conditions is poorly understood. Here, we demonstrate that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is a major determinant of brain metastasis in multiple human cancer types and preclinical models. Enhanced serine synthesis proved important for nucleotide production and cell proliferation in highly aggressive brain metastatic cells. In vivo , genetic suppression and pharmacologic inhibition of PHGDH attenuated brain metastasis, but not extracranial tumor growth, and improved overall survival in mice. These results reveal that extracellular amino acid availability determines serine synthesis pathway dependence, and suggest that PHGDH inhibitors may be useful in the treatment of brain metastasis. SIGNIFICANCE:Using proteomics, metabolomics, and multiple brain metastasis models, we demonstrate that the nutrient-limited environment of the brain potentiates brain metastasis susceptibility to serine synthesis inhibition. These fi ndings underscore the importance of studying cancer metabolism in physiologically relevant contexts, and provide a rationale for using PHGDH inhibitors to treat brain metastasis.

genetic diversity. This variation in LUAD has led to the development of genetic markers that have successfully guided drug therapies. Despite impressive initial clinical responses, there is variability in the extent of response even within homogeneous baskets and resistance to targeted and genotoxic therapies ultimately ensues. The extent of these failures is attributed to the topographic differences in genomes within tumors, or intratumoral heterogeneity, remains poorly studied which represents a major obstacle to tumor eradication. Tumors can have genetically distinct subclones that compete for space and resources and differentially resist therapy. Herein, we seek to elucidate subclone architecture in the most common type of lung cancer for the purpose of guiding radiotherapeutic strategies. Materials/Methods: We identified 405 candidate BRAF variants by analyzing targeted and genome-wide screen data from a collection of 48,397 tumors representing 35 cancers deposited in COSMIC. We selected 28 BRAF variants by random sampling and 7 variants considering local mutational density, evolutionary conservation and prior knowledge. We used site-directed mutagenesis to generate mutant clones and transferred alleles into lentiviral vectors. We generated 74 expression constructs adding wild-type and vector controls and representing biological replicates then stably-expressed each variant in bronchial epithelial cells (BEAS-2B). Total mRNA gene expression was assayed using RNAseq. Gene level copy number and mutational data were combined with estimates of the sample purity to infer the cancer cell fraction, or the proportion of cancer cells with the single nucleotide variant (CCFSNV) as follows: CCFSNV Z (VAF*(2+(ploidyCNV-2)*CCFCNV))/purity. Results: We identified BRAF driver mutations as predominately clonal in some cancers (melanoma) and subclonal in others (LUAD). Clonality was associated with the prevalence of V600 mutations and its selective amplification, a frequent occurrence in melanoma. We modelled the propagation and selection of tumors containing distinct categories of BRAF mutations to estimate their evolutionary trajectories. Hyperactivating BRAF mutant cells rapidly swept to clonality, resulting in a significant reduction of genetic diversity in the affected tumors. Mutations with differential activation of the Braf signaling pathway conferred a "softer" clonal sweep or remained subclonal maintaining tumor genetic diversity. Subclones containing BRAF variants had significant therapeutic implications for both targeted inhibitors of BRAF and/or MEK and genotoxic stress, conferring attenuated responses to both therapies. Conclusion: Our study uncovers patterns of distinct BRAF clonal evolutionary dynamics and nominates new radiotherapeutic strategies based on both the type of mutation and its subclone composition.

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