329 research outputs found
Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures.
Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan-cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including 18F-fluorodeoxy-glucose (FDG) avidity of patient tumors, and increased proliferation. The primary CNA signature is enriched for p53 mutations and is associated with glycolysis through coordinate amplification of glycolytic genes and other cancer-linked metabolic enzymes. A pan-cancer and cross-species comparison of CNAs highlighted 26 consistently altered DNA regions, containing 11 enzymes in the glycolysis pathway in addition to known cancer-driving genes. Furthermore, exogenous expression of hexokinase and enolase enzymes in an experimental immortalization system altered the subsequent copy number status of the corresponding endogenous loci, supporting the hypothesis that these metabolic genes act as drivers within the conserved CNA amplification regions. Taken together, these results demonstrate that metabolic stress acts as a selective pressure underlying the recurrent CNAs observed in human tumors, and further cast genomic instability as an enabling event in tumorigenesis and metabolic evolution
Single-Mode Squeezed Light Generation and Tomography with an Integrated Optical Parametric Oscillator
Quantum optical technologies promise advances in sensing, computing, and
communication. A key resource is squeezed light, where quantum noise is
redistributed between optical quadratures. We introduce a monolithic,
chip-scale platform that exploits the nonlinearity of a thin-film
lithium niobate (TFLN) resonator device to efficiently generate squeezed states
of light. Our system integrates all essential components -- except for the
laser and two detectors -- on a single chip with an area of one square
centimeter, significantly reducing the size, operational complexity, and power
consumption associated with conventional setups. Our work addresses challenges
that have limited previous integrated nonlinear photonic implementations that
rely on either nonlinear resonators or on integrated waveguide
parametric amplifiers. Using the balanced homodyne measurement
subsystem that we implemented on the same chip, we measure a squeezing of 0.55
dB and an anti-squeezing of 1.55 dB. We use 20 mW of input power to generate
the parametric oscillator pump field by employing second harmonic generation on
the same chip. Our work represents a substantial step toward compact and
efficient quantum optical systems posed to leverage the rapid advances in
integrated nonlinear and quantum photonics.Comment: 21 pages; 4 figures in main body, 8 supplementary figure
CCAT2, a novel noncoding RNA mapping to 8q24, underlies metastatic progression and chromosomal instability in colon cancer
The functional roles of SNPs within the 8q24 gene desert in the cancer phenotype are not yet well understood. Here, we report that CCAT2, a novel long noncoding RNA transcript (lncRNA) encompassing the rs6983267 SNP, is highly overexpressed in microsatellite-stable colorectal cancer and promotes tumor growth, metastasis, and chromosomal instability. We demonstrate that MYC, miR-17-5p, and miR-20a are up-regulated by CCAT2 through TCF7L2-mediated transcriptional regulation. We further identify the physical interaction between CCAT2 and TCF7L2 resulting in an enhancement of WNT signaling activity. We show that CCAT2 is itself a WNT downstream target, which suggests the existence of a feedback loop. Finally, we demonstrate that the SNP status affects CCAT2 expression and the risk allele G produces more CCAT2 transcript. Our results support a new mechanism of MYC and WNT regulation by the novel lncRNA CCAT2 in colorectal cancer pathogenesis, and provide an alternative explanation of the SNP-conferred cancer risk
Telomerase and breast cancer
Current therapies for breast cancer include treatments that are toxic and often result in drug resistance. Telomerase, a cellular reverse transcriptase that maintains the ends of chromosomes (telomeres), is activated in the vast majority of breast cancers (over 90% of breast carcinomas) but not in normal adjacent tissues. Telomerase is thus an attractive target for both diagnosis and therapy because of its distinct pattern of expression. We address the use of telomerase in the diagnostics of breast pathology, as well as the use of telomerase inhibitors in the treatment and prevention of breast cancer
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