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Article ; Online: Clonal transcriptomics identifies mechanisms of chemoresistance and empowers rational design of combination therapies.

Wild, Sophia A / Cannell, Ian G / Nicholls, Ashley / Kania, Katarzyna / Bressan, Dario / Hannon, Gregory J / Sawicka, Kirsty

eLife

2022 Volume 11

Abstract: Tumour heterogeneity is thought to be a major barrier to successful cancer treatment due to the presence of drug resistant clonal lineages. However, identifying the characteristics of such lineages that underpin resistance to therapy has remained ... ...

Abstract	Tumour heterogeneity is thought to be a major barrier to successful cancer treatment due to the presence of drug resistant clonal lineages. However, identifying the characteristics of such lineages that underpin resistance to therapy has remained challenging. Here, we utilise clonal transcriptomics with WILD-seq;
MeSH term(s)	Humans ; Mice ; Animals ; Drug Resistance, Neoplasm/genetics ; Nuclear Proteins ; Transcriptome ; Asparagine ; Transcription Factors ; Triple Negative Breast Neoplasms/pathology ; Taxoids/pharmacology ; Taxoids/therapeutic use
Chemical Substances	Nuclear Proteins ; Asparagine (7006-34-0) ; Transcription Factors ; taxane (1605-68-1) ; Taxoids
Language	English
Publishing date	2022-12-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.80981
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Article ; Online: FOXC2 promotes vasculogenic mimicry and resistance to anti-angiogenic therapy.

Cannell, Ian G / Sawicka, Kirsty / Pearsall, Isabella / Wild, Sophia A / Deighton, Lauren / Pearsall, Sarah M / Lerda, Giulia / Joud, Fadwa / Khan, Showkhin / Bruna, Alejandra / Simpson, Kathryn L / Mulvey, Claire M / Nugent, Fiona / Qosaj, Fatime / Bressan, Dario / Dive, Caroline / Caldas, Carlos / Hannon, Gregory J

Cell reports

2023 Volume 42, Issue 8, Page(s) 112791

Abstract: Vasculogenic mimicry (VM) describes the formation of pseudo blood vessels constructed of tumor cells that have acquired endothelial-like properties. VM channels endow the tumor with a tumor-derived vascular system that directly connects to host blood ... ...

Abstract	Vasculogenic mimicry (VM) describes the formation of pseudo blood vessels constructed of tumor cells that have acquired endothelial-like properties. VM channels endow the tumor with a tumor-derived vascular system that directly connects to host blood vessels, and their presence is generally associated with poor patient prognosis. Here we show that the transcription factor, Foxc2, promotes VM in diverse solid tumor types by driving ectopic expression of endothelial genes in tumor cells, a process that is stimulated by hypoxia. VM-proficient tumors are resistant to anti-angiogenic therapy, and suppression of Foxc2 augments response. This work establishes co-option of an embryonic endothelial transcription factor by tumor cells as a key mechanism driving VM proclivity and motivates the search for VM-inhibitory agents that could form the basis of combination therapies with anti-angiogenics.
MeSH term(s)	Humans ; Neovascularization, Pathologic/metabolism ; Cell Line, Tumor ; Immunotherapy
Language	English
Publishing date	2023-07-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.112791
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Article ; Online: Salvaging the septic heart through targeting the interleukin-6/p38 mitogen-activated protein kinase signaling network.

Cannell, Ian G / Yaffe, Michael B

Critical care medicine

2011 Volume 39, Issue 7, Page(s) 1836–1837

MeSH term(s)	Heart/physiopathology ; Humans ; Inflammation Mediators/physiology ; Interleukin-6/physiology ; Molecular Targeted Therapy ; Signal Transduction/genetics ; Signal Transduction/physiology ; p38 Mitogen-Activated Protein Kinases/genetics ; p38 Mitogen-Activated Protein Kinases/physiology
Chemical Substances	Inflammation Mediators ; Interleukin-6 ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2011-10-01
Publishing country	United States
Document type	Comment ; Editorial
ZDB-ID	197890-1
ISSN	1530-0293 ; 0090-3493
ISSN (online)	1530-0293
ISSN	0090-3493
DOI	10.1097/CCM.0b013e3182204ad1
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Zs.A 1261: Show issues

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Article ; Online: Regulation of Myc by miR-34c: A mechanism to prevent genomic instability?

Cannell, Ian G / Bushell, Martin

Cell cycle (Georgetown, Tex.)

2010 Volume 9, Issue 14, Page(s) 2726–2730

Abstract: Over the past 8 years several lines of compelling evidence have indicated that microRNAs are critical downstream effectors of classic oncogene/tumour suppressor networks. The archetypal examples of oncogene and tumour suppressor microRNAs are the miR-17- ... ...

Abstract	Over the past 8 years several lines of compelling evidence have indicated that microRNAs are critical downstream effectors of classic oncogene/tumour suppressor networks. The archetypal examples of oncogene and tumour suppressor microRNAs are the miR-17-92 (oncomir 1) polycistron and miR-34 respectively. Whilst the involvement of these two opposing families of microRNAs in oncogenesis has been known for some time, the mRNA targets through which they exert their phenotypes are only just beginning to be uncovered. Moreover, several recent reports have demonstrated that the relevant physiological targets of certain individual microRNAs are actually fairly limited, with repression of just one or two major targets sufficient to explain the observed phenotype. In this review we will discuss the emerging role of microRNAs in tumourigenesis with a specific focus on miR-34c-dependent regulation of Myc.
MeSH term(s)	DNA Damage ; Genomic Instability ; Humans ; MicroRNAs/metabolism ; Neoplasms/metabolism ; Proto-Oncogene Proteins c-myc/metabolism
Chemical Substances	MIRN34 microRNA, human ; MicroRNAs ; Proto-Oncogene Proteins c-myc
Language	English
Publishing date	2010-07-27
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
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Zs.A 5881: Show issues

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Article: An RNA Damage Response Network Mediates the Lethality of 5-FU in Clinically Relevant Tumor Types.

bioRxiv : the preprint server for biology

2023

Abstract: 5-fluorouracil (5-FU) is a successful and broadly used anti-cancer therapeutic. A major mechanism of action of 5-FU is thought to be through thymidylate synthase (TYMS) inhibition resulting in dTTP depletion and activation of the DNA damage response. ... ...

Abstract	5-fluorouracil (5-FU) is a successful and broadly used anti-cancer therapeutic. A major mechanism of action of 5-FU is thought to be through thymidylate synthase (TYMS) inhibition resulting in dTTP depletion and activation of the DNA damage response. This suggests that 5-FU should synergize with other DNA damaging agents. However, we found that combinations of 5-FU and oxaliplatin or irinotecan failed to display any evidence of synergy in clinical trials, and resulted in sub-additive killing in a panel of colorectal cancer (CRC) cell lines. In seeking to understand this antagonism, we unexpectedly found that an RNA damage response during ribosome biogenesis dominates the drug's efficacy in tumor types for which 5-FU shows clinical benefit. 5-FU has an inherent bias for RNA incorporation, and blocking this greatly reduced drug-induced lethality, indicating that accumulation of damaged RNA is more deleterious than the lack of new RNA synthesis. Using 5-FU metabolites that specifically incorporate into either RNA or DNA revealed that CRC cell lines and patient-derived colorectal cancer organoids are inherently more sensitive to RNA damage. This difference held true in cell lines from other tissues in which 5-FU has shown clinical utility, whereas cell lines from tumor tissues that lack clinical 5-FU responsiveness typically showed greater sensitivity to the drug's DNA damage effects. Analysis of changes in the phosphoproteome and ubiquitinome shows RNA damage triggers the selective ubiquitination of multiple ribosomal proteins leading to autophagy-dependent rRNA catabolism and proteasome-dependent degradation of ubiquitinated ribosome proteins. Further, RNA damage response to 5-FU is selectively enhanced by compounds that promote ribosome biogenesis, such as KDM2A inhibitors. These results demonstrate the presence of a strong RNA damage response linked to apoptotic cell death, with clear utility of combinatorially targeting this response in cancer therapy.
Language	English
Publishing date	2023-04-29
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.04.28.538590
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Article ; Online: Transite: A Computational Motif-Based Analysis Platform That Identifies RNA-Binding Proteins Modulating Changes in Gene Expression.

Krismer, Konstantin / Bird, Molly A / Varmeh, Shohreh / Handly, Erika D / Gattinger, Anna / Bernwinkler, Thomas / Anderson, Daniel A / Heinzel, Andreas / Joughin, Brian A / Kong, Yi Wen / Cannell, Ian G / Yaffe, Michael B

Cell reports

2020 Volume 32, Issue 8, Page(s) 108064

Abstract: RNA-binding proteins (RBPs) play critical roles in regulating gene expression by modulating splicing, RNA stability, and protein translation. Stimulus-induced alterations in RBP function contribute to global changes in gene expression, but identifying ... ...

Abstract	RNA-binding proteins (RBPs) play critical roles in regulating gene expression by modulating splicing, RNA stability, and protein translation. Stimulus-induced alterations in RBP function contribute to global changes in gene expression, but identifying which RBPs are responsible for the observed changes remains an unmet need. Here, we present Transite, a computational approach that systematically infers RBPs influencing gene expression through changes in RNA stability and degradation. As a proof of principle, we apply Transite to RNA expression data from human patients with non-small-cell lung cancer whose tumors were sampled at diagnosis or after recurrence following treatment with platinum-based chemotherapy. Transite implicates known RBP regulators of the DNA damage response and identifies hnRNPC as a new modulator of chemotherapeutic resistance, which we subsequently validated experimentally. Transite serves as a framework for the identification of RBPs that drive cell-state transitions and adds additional value to the vast collection of publicly available gene expression datasets.
MeSH term(s)	DNA Damage/genetics ; Gene Expression/genetics ; Humans ; RNA-Binding Proteins/metabolism
Chemical Substances	RNA-Binding Proteins
Language	English
Publishing date	2020-08-26
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2020.108064
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Article ; Online: Lineage Plasticity in SCLC Generates Non-Neuroendocrine Cells Primed for Vasculogenic Mimicry.

Pearsall, Sarah M / Williamson, Stuart C / Humphrey, Sam / Hughes, Ellyn / Morgan, Derrick / García Marqués, Fernando J / Awanis, Griselda / Carroll, Rebecca / Burks, Laura / Shue, Yan Ting / Bermudez, Abel / Frese, Kristopher K / Galvin, Melanie / Carter, Mathew / Priest, Lynsey / Kerr, Alastair / Zhou, Cong / Oliver, Trudy G / Humphries, Jonathan D /

Humphries, Martin J / Blackhall, Fiona / Cannell, Ian G / Pitteri, Sharon J / Hannon, Gregory J / Sage, Julien / Dive, Caroline / Simpson, Kathryn L

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer

2023 Volume 18, Issue 10, Page(s) 1362–1385

Abstract: Introduction: Vasculogenic mimicry (VM), the process of tumor cell transdifferentiation to endow endothelial-like characteristics supporting de novo vessel formation, is associated with poor prognosis in several tumor types, including SCLC. In ... ...

Abstract	Introduction: Vasculogenic mimicry (VM), the process of tumor cell transdifferentiation to endow endothelial-like characteristics supporting de novo vessel formation, is associated with poor prognosis in several tumor types, including SCLC. In genetically engineered mouse models (GEMMs) of SCLC, NOTCH, and MYC co-operate to drive a neuroendocrine (NE) to non-NE phenotypic switch, and co-operation between NE and non-NE cells is required for metastasis. Here, we define the phenotype of VM-competent cells and molecular mechanisms underpinning SCLC VM using circulating tumor cell-derived explant (CDX) models and GEMMs. Methods: We analyzed perfusion within VM vessels and their association with NE and non-NE phenotypes using multiplex immunohistochemistry in CDX, GEMMs, and patient biopsies. We evaluated their three-dimensional structure and defined collagen-integrin interactions. Results: We found that VM vessels are present in 23/25 CDX models, 2 GEMMs, and in 20 patient biopsies of SCLC. Perfused VM vessels support tumor growth and only NOTCH-active non-NE cells are VM-competent in vivo and ex vivo, expressing pseudohypoxia, blood vessel development, and extracellular matrix organization signatures. On Matrigel, VM-primed non-NE cells remodel extracellular matrix into hollow tubules in an integrin β1-dependent process. Conclusions: We identified VM as an exemplar of functional heterogeneity and plasticity in SCLC and these findings take considerable steps toward understanding the molecular events that enable VM. These results support therapeutic co-targeting of both NE and non-NE cells to curtail SCLC progression and to improve the outcomes of patients with SCLC in the future.
MeSH term(s)	Animals ; Mice ; Humans ; Lung Neoplasms/pathology ; Neovascularization, Pathologic/genetics ; Cell Transdifferentiation ; Cell Line, Tumor
Language	English
Publishing date	2023-07-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2432037-7
ISSN	1556-1380 ; 1556-0864
ISSN (online)	1556-1380
ISSN	1556-0864
DOI	10.1016/j.jtho.2023.07.012
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Zs.A 6664: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular ab Jg. 2022: Lesesaal (EG)
Zs.MO 652: Show issues

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Article ; Online: Is post-transcriptional stabilization, splicing and translation of selective mRNAs a key to the DNA damage response?

Reinhardt, H Christian / Cannell, Ian G / Morandell, Sandra / Yaffe, Michael B

Cell cycle (Georgetown, Tex.)

2011 Volume 10, Issue 1, Page(s) 23–27

Abstract: In response to DNA damage, cells activate a complex, kinase-based signaling network that consist of two components--a rapid phosphorylation-driven signaling cascade that results in immediate inhibition of Cdk/cyclin complexes to arrest the cell cycle ... ...

Abstract	In response to DNA damage, cells activate a complex, kinase-based signaling network that consist of two components--a rapid phosphorylation-driven signaling cascade that results in immediate inhibition of Cdk/cyclin complexes to arrest the cell cycle along with recruitment of repair machinery to damaged DNA, followed by a delayed transcriptional response that promotes cell cycle arrest through the induction of Cdk inhibitors, such as p21. In recent years a third layer of complexity has emerged that involves post-transcriptional control of mRNA stability, splicing, and translation as a critical part of the DNA damage response. Here, we describe recent work implicating DNA damage-dependent modification of RNA-binding proteins that are responsible for some of these mRNA effects, highlighting recent work on post-transcriptional regulation of the cell cycle checkpoint protein/apoptosis inducer Gadd45a by the checkpoint kinase MAPKAP Kinase-2.
MeSH term(s)	Animals ; DNA Damage/genetics ; Humans ; Protein Biosynthesis/genetics ; RNA Processing, Post-Transcriptional/genetics ; RNA Splicing/genetics ; RNA Stability/genetics ; RNA, Messenger/genetics ; Signal Transduction/genetics
Chemical Substances	RNA, Messenger
Language	English
Publishing date	2011-01-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2146183-1
ISSN	1551-4005 ; 1538-4101 ; 1554-8627
ISSN (online)	1551-4005
ISSN	1538-4101 ; 1554-8627
DOI	10.4161/cc.10.1.14351
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Zs.A 5881: Show issues

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Article ; Online: How do microRNAs regulate gene expression?

Cannell, Ian G / Kong, Yi Wen / Bushell, Martin

Biochemical Society transactions

2008 Volume 36, Issue Pt 6, Page(s) 1224–1231

Abstract: miRNAs (microRNAs) are short non-coding RNAs that regulate gene expression post-transcriptionally. They generally bind to the 3'-UTR (untranslated region) of their target mRNAs and repress protein production by destabilizing the mRNA and translational ... ...

Abstract	miRNAs (microRNAs) are short non-coding RNAs that regulate gene expression post-transcriptionally. They generally bind to the 3'-UTR (untranslated region) of their target mRNAs and repress protein production by destabilizing the mRNA and translational silencing. The exact mechanism of miRNA-mediated translational repression is yet to be fully determined, but recent data from our laboratory have shown that the stage of translation which is inhibited by miRNAs is dependent upon the promoter used for transcribing the target mRNA. This review focuses on understanding how miRNA repression is operating in light of these findings and the questions that still remain.
MeSH term(s)	Animals ; Gene Expression Regulation ; Humans ; MicroRNAs/metabolism ; Peptides/metabolism ; Promoter Regions, Genetic/genetics ; Protein Biosynthesis ; RNA Caps/metabolism
Chemical Substances	MicroRNAs ; Peptides ; RNA Caps
Language	English
Publishing date	2008-11-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	184237-7
ISSN	1470-8752 ; 0300-5127
ISSN (online)	1470-8752
ISSN	0300-5127
DOI	10.1042/BST0361224
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Zs.A 944: Show issues

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Article ; Online: A Pleiotropic RNA-Binding Protein Controls Distinct Cell Cycle Checkpoints to Drive Resistance of p53-Defective Tumors to Chemotherapy.

Cannell, Ian G / Merrick, Karl A / Morandell, Sandra / Zhu, Chang-Qi / Braun, Christian J / Grant, Robert A / Cameron, Eleanor R / Tsao, Ming-Sound / Hemann, Michael T / Yaffe, Michael B

Cancer cell

2015 Volume 28, Issue 6, Page(s) 831

Language	English
Publishing date	2015-12-14
Publishing country	United States
Document type	Published Erratum
ZDB-ID	2078448-X
ISSN	1878-3686 ; 1535-6108
ISSN (online)	1878-3686
ISSN	1535-6108
DOI	10.1016/j.ccell.2015.11.003
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Zs.A 5650: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MG 104: Show issues

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