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"Scott, Kenneth"
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PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis
Glioblastoma is a universally lethal form of brain cancer that exhibits an array of pathophysiological phenotypes, many of which are mediated by interactions with the neuronal microenvironment
1
,
2
. Recent studies have shown that increases in neuronal activity have an important role in the proliferation and progression of glioblastoma
3
,
4
. Whether there is reciprocal crosstalk between glioblastoma and neurons remains poorly defined, as the mechanisms that underlie how these tumours remodel the neuronal milieu towards increased activity are unknown. Here, using a native mouse model of glioblastoma, we develop a high-throughput in vivo screening platform and discover several driver variants of PIK3CA. We show that tumours driven by these variants have divergent molecular properties that manifest in selective initiation of brain hyperexcitability and remodelling of the synaptic constituency. Furthermore, secreted members of the glypican (GPC) family are selectively expressed in these tumours, and GPC3 drives gliomagenesis and hyperexcitability. Together, our studies illustrate the importance of functionally interrogating diverse tumour phenotypes driven by individual, yet related, variants and reveal how glioblastoma alters the neuronal microenvironment.
Glioblastoma tumours expressing oncogenic PIK3CA variants secrete the glycan GPC3, which promotes the formation of neural synapses, brain synaptic hyperexcitability and gliomagenesis.
Journal Article
Red Hood and The Outlaws. Volume 2, The starfire
As if Batman's former sidekick Jason Todd, now known as the Red Hood, didn't have enough problems leading the team of outlaws such as Arsenal and Starfire, now his \"estranged\" brother Red Robin is knocking on his door because \"The Night of Owls\" is here! With Batman in dire need of help, will Red Hood answer the call?
Book
The RNA-binding protein AKAP8 suppresses tumor metastasis by antagonizing EMT-associated alternative splicing
Alternative splicing has been shown to causally contribute to the epithelial–mesenchymal transition (EMT) and tumor metastasis. However, the scope of splicing factors that govern alternative splicing in these processes remains largely unexplored. Here we report the identification of A-Kinase Anchor Protein (AKAP8) as a splicing regulatory factor that impedes EMT and breast cancer metastasis. AKAP8 not only is capable of inhibiting splicing activity of the EMT-promoting splicing regulator hnRNPM through protein–protein interaction, it also directly binds to RNA and alters splicing outcomes. Genome-wide analysis shows that AKAP8 promotes an epithelial cell state splicing program. Experimental manipulation of an AKAP8 splicing target CLSTN1 revealed that splice isoform switching of CLSTN1 is crucial for EMT. Moreover, AKAP8 expression and the alternative splicing of CLSTN1 predict breast cancer patient survival. Together, our work demonstrates the essentiality of RNA metabolism that impinges on metastatic breast cancer.
Splice isoform switching regulated by the heterogeneous nuclear ribonucleoprotein M (hnRNPM) induces EMT and metastasis. Here, the authors report that AKAP8 is a metastasis suppressor that inhibits the splicing activity of hnRNPM and antagonizes genome-wide EMT-associated alternative splicing to maintain epithelial cell state.
Journal Article
Integrative Genome Comparison of Primary and Metastatic Melanomas
A cardinal feature of malignant melanoma is its metastatic propensity. An incomplete view of the genetic events driving metastatic progression has been a major barrier to rational development of effective therapeutics and prognostic diagnostics for melanoma patients. In this study, we conducted global genomic characterization of primary and metastatic melanomas to examine the genomic landscape associated with metastatic progression. In addition to uncovering three genomic subclasses of metastastic melanomas, we delineated 39 focal and recurrent regions of amplification and deletions, many of which encompassed resident genes that have not been implicated in cancer or metastasis. To identify progression-associated metastasis gene candidates, we applied a statistical approach, Integrative Genome Comparison (IGC), to define 32 genomic regions of interest that were significantly altered in metastatic relative to primary melanomas, encompassing 30 resident genes with statistically significant expression deregulation. Functional assays on a subset of these candidates, including MET, ASPM, AKAP9, IMP3, PRKCA, RPA3, and SCAP2, validated their pro-invasion activities in human melanoma cells. Validity of the IGC approach was further reinforced by tissue microarray analysis of Survivin showing significant increased protein expression in thick versus thin primary cutaneous melanomas, and a progression correlation with lymph node metastases. Together, these functional validation results and correlative analysis of human tissues support the thesis that integrated genomic and pathological analyses of staged melanomas provide a productive entry point for discovery of melanoma metastases genes.
Journal Article
TMEM106B drives lung cancer metastasis by inducing TFEB-dependent lysosome synthesis and secretion of cathepsins
Metastatic lung cancer is the leading cause of cancer-associated mortality worldwide, therefore necessitating novel approaches to identify specific genetic drivers for lung cancer progression and metastasis. We recently performed an in vivo gain-of-function genetic screen to identify driver genes of lung cancer metastasis. In the study reported here, we identify
TMEM106B
as a primary robust driver of lung cancer metastasis. Ectopic expression of
TMEM106B
could significantly promote the synthesis of enlarged vesicular lysosomes that are laden with elevated levels of active cathepsins. In a
TFEB
-dependent manner,
TMEM106B
could modulate the expression of lysosomal genes of the coordinated lysosomal expression and regulation (CLEAR) pathway in lung cancer cells and patient samples. We also demonstrate that
TMEM106B
-induced lysosomes undergo calcium-dependent exocytosis, thereby releasing active lysosomal cathepsins necessary for
TMEM106B
-mediated cancer cell invasion and metastasis in vivo, which could be therapeutically prevented by pharmacological inhibition of cathepsins. Further, in TCGA LUAD data sets, 19% of patients show elevated expression of
TMEM106B
, which predicts for poor disease-free and overall-survival.
One of the major causes of cancer-related mortality is represented by metastatic lung cancer. Here the authors characterize the role of
TMEM106B
in driving metastatic lung adenocarcinoma and suggest that
TMEM106B
-mediated secretion of cathespin impacts cell migration and invasion of lung cancer cells, increasing metastatic spreading.
Journal Article
The sculpture of Kenneth Armitage
The Sculpture of Kenneth Armitage', which is being published to coincide with the artist's centenary in 2016, is the first book to feature a fully illustrated inventory of all of Armitage's known sculptures. It will be the only available illustrated reference book on the sculptural work of this important 20th-century artist. Through an inventory of c.300 pieces and an accompanying narrative text, the book undertakes an examination of Armitage's significant contribution to sculpture nationally and internationally during the second half of the 20th century, starting with the 'geometry of fear' exhibition at the 1952 Venice Biennale and Armitage's solo contribution to the Biennale in 1958. It will be an essential reference resource for researchers, curators, dealers and collectors which will complement the complete sculpture catalogues already produced for Armitage's sculptor contemporaries Lynn Chadwick, Elisabeth Frink, Robert Adams and Reg Butler, enhancing our understanding of post-war British sculpture.
Book
RNA editing derived epitopes function as cancer antigens to elicit immune responses
In addition to genomic mutations, RNA editing is another major mechanism creating sequence variations in proteins by introducing nucleotide changes in mRNA sequences. Deregulated RNA editing contributes to different types of human diseases, including cancers. Here we report that peptides generated as a consequence of RNA editing are indeed naturally presented by human leukocyte antigen (HLA) molecules. We provide evidence that effector CD8
+
T cells specific for edited peptides derived from cyclin I are present in human tumours and attack tumour cells that are presenting these epitopes. We show that subpopulations of cancer patients have increased peptide levels and that levels of edited RNA correlate with peptide copy numbers. These findings demonstrate that RNA editing extends the classes of HLA presented self-antigens and that these antigens can be recognised by the immune system.
RNA editing is a biological process that creates sequence variation. Here the authors show that peptides generated as a consequence of RNA editing are naturally presented by human leukocyte antigen (HLA) and serve as antigens to elicit anti-tumour immune responses.
Journal Article