Top 9 Biorxiv Papers Today in Cancer Biology


2.023 Mikeys
#1. Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma
Gabriel J Starrett, Manisha Thakuria, Tianqi Chen, Christina Marcelus, Jingwei Cheng, Jason Nomburg, Aaron R Thorner, Michael K Slevin, Winslow Powers, Robert T Burns, Caitlin Perry, Adriano Piris, Frank C Kuo, Guilherme Rabinowits, Anita Giobbie-Hurder, Laura E MacConaill, James A DeCaprio
Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine carcinoma of the skin mediated by the integration of Merkel cell polyomavirus (MCPyV) and expression of viral T antigens or by ultraviolet induced damage to the tumor genome from excessive sunlight exposure. An increasing number of deep sequencing studies of MCC have identified significant differences between the number and types of point mutations, copy number alterations, and structural variants between virus-positive and virus-negative tumors. In this study, we assembled a cohort of 71 MCC patients and performed deep sequencing with OncoPanel, a next-generation sequencing assay targeting over 400 cancer-associated genes. To improve the accuracy and sensitivity for virus detection compared to traditional PCR and IHC methods, we developed a hybrid capture baitset against the entire MCPyV genome. The viral baitset identified integration junctions in the tumor genome and generated assemblies that strongly support a model of a hybrid, virus-host, circular DNA...
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biorxivpreprint: Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma https://t.co/SPvr4XHOUj #bioRxiv
biorxiv_cancer: Clinical and molecular characterization of virus-positive and virus-negative Merkel cell carcinoma https://t.co/lK1b5mHydh #biorxiv_cancer
gstarrett: So excited to share my new preprint on high resolution virus integration sites in Merkel cell carcinoma in collaboration with Jim DeCaprio and many others. Also contains some surprising results on the immune suppression. https://t.co/wGOYu12Hil
gstarrett: So excited to share our new preprint on high resolution virus integration sites in Merkel cell carcinoma in collaboration with Jim DeCaprio and many others. Also contains some surprising results involving immune suppression. https://t.co/wGOYu12Hil
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Repository: oncovirus_tools
User: gstarrett
Language: Python
Stargazers: 0
Subscribers: 1
Forks: 0
Open Issues: 0
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Sample Sizes : [30, 22, 19, 30, 41, 48, 71, 71, 71, 71, 30, 41, 71, 61, 10]
Authors: 17
Total Words: 13731
Unqiue Words: 3956

1.997 Mikeys
#2. Spatial structure governs the mode of tumour evolution
Robert Noble, Dominik Burri, Jakob Nikolas Kather, Niko Beerenwinkel
Characterizing the mode -- the way, manner, or pattern -- of evolution in tumours is important for clinical forecasting and optimizing cancer treatment. DNA sequencing studies have inferred various modes, including branching, punctuated and neutral evolution, but it is unclear why a particular pattern predominates in any given tumour. Here we propose that differences in tumour architecture alone can explain the variety of observed patterns. We examine this hypothesis using spatially explicit population genetic models and demonstrate that, within biologically relevant parameter ranges, tumours are expected to exhibit diverse evolutionary modes including four archetypal "oncoevotypes": rapid clonal expansion (predicted in leukaemia); progressive diversification (in colorectal adenomas and early-stage colorectal carcinomas); branching evolution (in invasive glandular tumours); and almost neutral evolution (in certain non-glandular and poorly differentiated solid tumours). We thus provide a simple, mechanistic explanation for a wide...
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biorxivpreprint: Spatial structure governs the mode of tumour evolution https://t.co/c5rxxBQU20 #bioRxiv
biorxiv_cancer: Spatial structure governs the mode of tumour evolution https://t.co/du4U41Lmu4 #biorxiv_cancer
LizzieBillingt1: RT @biorxivpreprint: Spatial structure governs the mode of tumour evolution https://t.co/c5rxxBQU20 #bioRxiv
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Authors: 4
Total Words: 9846
Unqiue Words: 2682

1.993 Mikeys
#3. Serum Flt3 ligand is a biomarker of progenitor cell mass and prognosis in acute myeloid leukemia
Paul Milne, Charlotte Wilhelm-Benartzi, Michael R Grunwald, Venetia Bigley, Amy Publicover, Sarah Pagan, Helen Marr, Gail Jones, Anne Dickinson, Angela Grech, Alan Burnett, Nigel Russell, Mark Levis, Steven Knapper, Matthew Collin
Fms-like tyrosine kinase 3 (Flt3) is a hematopoietic growth factor receptor expressed on lymphomyeloid progenitors and frequently, by AML blasts. Its ligand, Flt3L, has non-hematopoietic and lymphoid origins, is detectable during homeostasis and increases to high levels in states of hypoplasia due to genetic defects or treatment with cytoreductive agents. Measurement of Flt3L by ELISA reveals that Flt3+ AML, is associated with depletion of Flt3L to undetectable levels. After induction chemotherapy, Flt3L is restored in patients entering complete remission (CR), but remains depressed in those with refractory disease. Weekly sampling reveals marked differences in the kinetics of Flt3L response during the first 6 weeks of treatment, proportionate to the clearance of blasts and cellularity of the BM. In the UK NCRI AML17 trial, Flt3L was measured at day 26 in a subgroup of 135 patients with Flt3 mutation randomized to the tyrosine kinase inhibitor lestaurtinib. In these patients, attainment of CR was associated with higher Flt3L at...
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Authors: 15
Total Words: 8429
Unqiue Words: 2493

1.992 Mikeys
#4. Nilotinib, an approved leukemia drug, inhibits Smoothened signaling in Hedgehog-dependent medulloblastoma
Kirti Kandhwal Chahal, Jie Li, Irina Kufareva, Milind Parle, Donald D Durden, Robert Wechsler-Reya, Clarck C Chen, Ruben Abagyan
Dysregulation of the seven-transmembrane (7TM) receptor Smoothened (SMO) and other components of the Hedgehog (Hh) signaling pathway contributes to the development of cancers including basal cell carcinoma (BCC) and medulloblastoma (MB). However, SMO-specific antagonists produced mixed results in clinical trials, marked by limited efficacy and high rate of acquired resistance in tumors. Here we discovered that Nilotinib, an approved inhibitor of several kinases, possesses an anti-Hh activity, at clinically achievable concentrations, due to direct binding to SMO and inhibition of SMO signaling. Nilotinib was more efficacious than the SMO-specific antagonist Vismodegib in inhibiting growth of two Hh-dependent MB cell lines. It also reduced tumor growth in subcutaneous MB mouse xenograft model. These results indicate that in addition to its known activity against several tyrosine-kinase-mediated proliferative pathways, Nilotinib is a direct inhibitor of the Hh pathway. The newly discovered extension of Nilotinib’s target profile...
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Sample Sizes : [3, 3, 2, 3, 3]
Authors: 8
Total Words: 14958
Unqiue Words: 4731

1.992 Mikeys
#5. MgO nanoparticles coated with Polyethylene Glycol as carrier for 2-Methoxyestradiol anticancer drug.
Aline Alfaro, Andrea León, Eduardo Guajardo, Patricia Reuquen, Francisco Torres, Mario Mery, Rodrigo Segura, Paula Zapata, pedro orihuela
Novel Magnesium Oxide (MgO) nanoparticles (NPs) modified with the polymer poliethylene glycol (PEG) were synthesized as carrier for the anticancer drug 2-Methoxyestradiol (2ME) to improve its clinical application. The functionalized NPs were characterized by Infrared spectroscopy with Fourier transform to elucidate the vibration modes of this conjugate, indicating the formation of the MgO-PEG-2ME nanocomposite. The studies of absorption and liberation determined that MgO-PEG-2ME NPs incorporated 98.51 % of 2ME while liberation of 2ME was constant during 7 days at pH 2, 5 and 7.35. Finally, the MgO-PEG-2ME NPs decreased the viability of the prostate cancer cell line LNCap suggesting that this nanocomposite is suitable as a drug delivery system for anticancer prostate therapy.
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Authors: 9
Total Words: 0
Unqiue Words: 0

1.991 Mikeys
#6. Distinct immune evasion in APOBEC-enriched, HPV-negative HNSCC
Clemens Messerschmidt, Benedikt Obermayer, Konrad Klinghammer, Sebastian Ochsenreither, Denise Treue, Albrecht Stenzinger, Hanno Glimm, Stefan Fröhling, Thomas Kindler, Christian H Brandts, Klaus Schulze-Osthoff, Wilko Weichert, Ingeborg Tinhofer, Frederick Klauschen, Ulrich Keilholz, Dieter Beule, Damian T Rieke
Immune checkpoint inhibition leads to response in some patients with head and neck squamous cell carcinoma (HNSCC). Robust biomarkers are lacking to date. We analyzed viral status, gene expression signatures, mutational load and mutational signatures in whole exome and RNA-sequencing data of the HNSCC TCGA dataset (N = 496) and a validation set (DKTK MASTER cohort, N = 10). Public single-cell gene expression data from 17 HPV-negative HNSCC were separately re-analyzed. Among HPV-negative HNSCC, APOBEC3-associated TCW motif mutations but not total single nucleotide variant burden were significantly associated with inflammation. APOBEC3-enriched HPV-negative HNSCC showed higher T-cell inflammation and immune checkpoint expression. Mutations in immune-evasion pathways were enriched in these tumors. APOBEC3B and 3C expression was identified in tumor cells and correlated with tumor inflammation. We identified an APOBEC-enriched subgroup of HPV-negative HNSCC with a distinct immunogenic phenotype, potentially mediating response to immunotherapy.
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Authors: 17
Total Words: 7390
Unqiue Words: 2523

1.946 Mikeys
#7. Direct genome editing of patient-derived xenografts using CRISPR-Cas9 enables rapid in vivo functional genomics
Christopher H Hulton, Emily A Costa, Nisargbhai S Shah, Alvaro Quintanal-Villalonga, Glenn Heller, Elisa de Stanchina, Charles M Rudin, John T Poirier
Patient-derived xenografts (PDXs) constitute a powerful set of preclinical models for in vivo cancer research, reflecting the spectrum of genomic alterations and therapeutic liabilities of human cancers. In contrast to either cancer cell lines or genetically engineered mouse models, the utility of PDXs has been limited by the inability to perform targeted genome editing of these tumors. To address this limitation, we have generated a lentiviral platform for CRISPR-Cas9 editing of PDXs using a tightly regulated, inducible Cas9 vector that does not require in vitro culture for selection of transduced cells. We demonstrate the utility of this platform in PDXs (1) to analyze genetic dependencies by targeted gene disruption and (2) to analyze mechanisms of acquired drug resistance by site-specific gene editing using templated homology-directed repair. This flexible system has broad application to other explant models and substantially augments the utility of PDXs as genetically programmable models of human cancer.
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Authors: 8
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1.946 Mikeys
#8. VHL Synthetic Lethality Signatures Uncovered by Genotype-specific CRISPR-Cas9 Screens
Ning Sun, Sakina Petiwala, Charles Lu, Jessica E Hutti, Min Hu, Mufeng Hu, Marc H Domanus, Diya Mitra, Sadiya N Addo, Christopher P Miller, Namjin Chung
Background: Genome-wide CRISPR-Cas9 essentiality screening represents a powerful approach to identify genetic vulnerabilities in cancer cells. Here, we applied this technology and designed a strategy to identify target genes that are synthetic lethal (SL) with von Hippel-Lindau (VHL) tumor suppressor gene. Inactivation of VHL has been frequently found in clear cell renal cell carcinoma (ccRCC). Its SL partners serve as potential drug targets for the development of targeted cancer therapies. Results: We performed parallel genome-wide CRISPR screens in two pairs of isogenic ccRCC cell lines that differ only in the VHL status. Comparative analyses of screening results not only confirmed a well-known role for mTOR signaling in renal carcinoma, but also identified DNA damage response and selenocysteine biosynthesis pathways as major SL targets in VHL-inactivated cancer cells. Follow-up studies provided cellular and mechanistic insights into SL interactions of these pathway genes with the VHL gene. Conclusions: Using isogenic CRISPR...
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Authors: 11
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1.946 Mikeys
#9. Development of a drug repressible β-catenin mutant mouse to examine effect of activated β-catenin signaling on long-term maintenance of mammary tumor growth
Jennifer L Gorman, Jessica R Adams, Emma M Jones, Sean E Egan, James R Woodgett
Stabilized β-catenin expression is a well described initiator of mammary tumorigenesis in the mouse and elevated nuclear expression of this protein has been observed in human triple-negative tumor samples. However, the importance of stabilized β-catenin to continued tumor growth after initiation, and in the context of other driver mutations, has yet to be elucidated. To ascertain the importance of stabilized β-catenin after tumor initiation, we generated a novel transgenic mouse model, utilizing the tet-off system, to control expression of a stabilized mutant of β-catenin. Pups from early litters carrying one allele of regulatable stabilized β-catenin at the Rosa26 locus, but not targeted by Cre, were smaller in size compared with wildtype littermates and also developed skin lesions, requiring euthanasia. Maintenance of breeding cages on doxycycline chow allowed for healthy transgenic pups to survive past 3 weeks of age and 6 animal cohorts were established. We used two different mammary Cre strains, WAP-Cre and MMTV-NLST-Cre,...
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Authors: 5
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