New Co-Author paper out now in SciTransMed: Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy

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Very exciting day to see this amazing work by the lab of Prof.Neil Watkins published in the prestigious Science Translational Medicine Journal.

A huge amount of work for a lot of very talented people over many many years went into this study, and hopefully it will result in significant improvements for the treatment of lung cancer patients using platinum based chemotherapies. You can access the fully article here [Link]

Platinum-based chemotherapy is a mainstay of treatment for lung cancer, but resistance to this therapy is a common problem, as are dose-limiting side effects, particularly kidney toxicity. To search for mechanisms that may contribute to treatment resistance, Marini et al. performed a whole-genome RNA interference screen and identified the activin pathway, which can be targeted. The authors demonstrated that inhibition of this pathway using a small molecule or a protein called follistatin can offer a dual benefit in that it potentiates the effects of platinum drugs in mouse models of cancer and also protects the animals from kidney damage. These findings suggest that activin inhibitors could be a valuable addition to platinum chemotherapy, enhancing the efficacy of treatment while also allowing the use of higher doses or longer periods of drug exposure.

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New Co-Author paper: The E3 ubiquitin ligase UBR5 regulates centriolar satellite stability and primary cilia

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Great news, we have recently published a co-author paper in collaboration with Darren Saunders Lab entitled “The E3 ubiquitin ligase UBR5 regulates centriolar satellite stability and primary cilia”. The work was pioneered by a very talented student (now Doctor), Robert Shearer.

 

You can access the full article here [Link]

ABSTRACT Primary cilia are crucial for signal transduction in a variety of pathways, including hedgehog and Wnt. Disruption of primary cilia formation (ciliogenesis) is linked to numerous developmental disorders (known as ciliopathies) and diseases, including cancer. The ubiqui- tin–proteasome system (UPS) component UBR5 was previously identified as a putative posi- tive regulator of ciliogenesis in a functional genomics screen. UBR5 is an E3 ubiquitin ligase that is frequently deregulated in tumors, but its biological role in cancer is largely uncharac- terized, partly due to a lack of understanding of interacting proteins and pathways. We validated the effect of UBR5 depletion on primary cilia formation using a robust model of ciliogenesis, and identified CSPP1, a centrosomal and ciliary protein required for cilia forma- tion, as a UBR5-interacting protein. We show that UBR5 ubiquitylates CSPP1, and that UBR5 is required for cytoplasmic organization of CSPP1-comprising centriolar satellites in centro- somal periphery, suggesting that UBR5-mediated ubiquitylation of CSPP1 or associated cen- triolar satellite constituents is one underlying requirement for cilia expression. Hence, we have established a key role for UBR5 in ciliogenesis that may have important implications in understanding cancer pathophysiology.

 

ACCM2019

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The Australian Cell Cycle Community

We are extremely excited to announce that ACCM 2019 will be on from June 17, 2019 – June 19, 2019
at the Powerhouse Museum in Sydney Australia.

The 2019 Meeting will be our biggest and best meeting ever, and we have already secured 3 outstanding plenary speakers:

Agnel Sfeir (Telomere Biology) [link]
– Skirball Institute of Biomolecular Medicine, New York University, Langone Medical Center, USA

Roger A Greenberg (DNA Repair) [link]
– The Perelman School of Medicine, University of Pennsylvania, USA

Agata Smogorzewska (Genome Maintenance) [link]
– Rockefeller University, New York, USA

We will also be annoucing an outstanding line-up of International, National and Local speakers.

More information will be added very soon.

Hope to see you all there

The 2019 ACCM Organising Committee
Hilda Picket
Andrew Deans
Liz Caldon
Tony Cesare
Liz Hinde
Andrew Burgess
Harret Gee

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New Paper Published: MASTL overexpression promotes chromosome instability and metastasis in breast cancer

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Very excited to announce that our latest paper entitled “MASTL overexpression promotes chromosome instability and metastasis in breast cancer” has just been published online with Oncogene. You can access the full article for free here:https://www.nature.com/articles/s41388-018-0295-z

Abstract

MASTL kinase is essential for correct progression through mitosis, with loss of MASTL causing chromosome segregation errors, mitotic collapse and failure of cytokinesis. However, in cancer MASTL is most commonly amplified and overexpressed. This correlates with increased chromosome instability in breast cancer and poor patient survival in breast, ovarian and lung cancer. Global phosphoproteomic analysis of immortalised breast MCF10A cells engineered to overexpressed MASTL revealed disruption to desmosomes, actin cytoskeleton, PI3K/AKT/mTOR and p38 stress kinase signalling pathways. Notably, these pathways were also disrupted in patient samples that overexpress MASTL. In MCF10A cells, these alterations corresponded with a loss of contact inhibition and partial epithelial–mesenchymal transition, which disrupted migration and allowed cells to proliferate uncontrollably in 3D culture. Furthermore, MASTL overexpression increased aberrant mitotic divisions resulting in increased micronuclei formation. Mathematical modelling indicated that this delay was due to continued inhibition of PP2A-B55, which delayed timely mitotic exit. This corresponded with an increase in DNA damage and delayed transit through interphase. There were no significant alterations to replication kinetics upon MASTL overexpression, however, inhibition of p38 kinase rescued the interphase delay, suggesting the delay was a G2 DNA damage checkpoint response. Importantly, knockdown of MASTL, reduced cell proliferation, prevented invasion and metastasis of MDA-MB-231 breast cancer cells both in vitro and in vivo, indicating the potential of future therapies that target MASTL. Taken together, these results suggest that MASTL overexpression contributes to chromosome instability and metastasis, thereby decreasing breast cancer patient survival.

Research Position (Full-time) Available Now.

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Great news, we are looking for a full-time research assistant or junior post-doctoral researcher.

We are seeking a highly motivated BSc (Hons) graduate who is interested in pursuing a career in biomedical research with particular focus on cancer cell biology. The successful applicant will have demonstrated a high level of undergraduate achievement and applicants graduating with Honours will be highly regarded. The successful applicant will work closely with the Principal Hospital Scientist and perform a variety of advanced molecular and cellular biology techniques to elucidate novel mechanisms that drive chromosome instability and drug resistance in breast and lung cancer. Essential criteria include experience in mammalian cell culture, cellular and molecular biology techniques, with experience with mass spectrometry, and/or microscopy and flow cytometry viewed favourably. Candidates should have excellent written and verbal communication skill and a history of publication would be viewed favourably.

The ANZAC Research Institute is situated on the Concord Hospital campus and is affiliated academically with the University of Sydney. The ANZAC Research institute is a multidisciplinary facility, for more information about the institute please see http://www.anzac.edu.au.

This position is open to Australian and New Zealand citizens, permanent residency or people with valid working visa status. It is available for one (1) year initially with prospect of renewal for 3-yrs total, subject to progress and grant applications. Level of appointment will be according to qualifications and experience.

Please apply online via seek and submit the following

Current CV, copy of academic transcript, a cover letter addressing the selection criteria below, provide two current referees, and evidence of work rights within Australia.

Selection Criteria

  • Minimum BSc (Hons I preferred) with a focus on cancer cell biology.
  • Experience in in mammalian tissue culture (transfection, stable cell line production, 3D spheroid culture, gene knockdown/out, CRISPR etc).
  • Experience in molecular and cellular biology techniques (western blotting, PCR, cloning, etc).
  • Experience in Mass Spectrometry (phosphoproteomics), confocal microscopy or flow cytometry will be viewed favourably.
  • Demonstrated capacity to work independently and collaboratively in a team environment
  • Must possess excellent time management, organisational and analytical problem-solving skills.
  • Demonstrate excellent oral and written communication skills.
  • Strong computer software literacy and an understanding of statistics.
  • A history of publication and/or an interest in completing a PhD would be highly regarded.

User guide: Export microscope images from ImageJ/FIJI into Adobe Photoshop and Illustrator

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Here is a step-by-step guide that I made to help people export microscope images from ImageJ/FIJI and then import and alter colours/levels etc in Photoshop. The guide also shows you how to easily move from Photoshop to illustrator to make montage images etc for publication.

PDF Download: Guide to FIJI-Photoshop Image manipulation

New Co-author Publication: Hic1 maintains chromosomal stability independent of p53

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Great news, we have a new co-author publication out in the journal Oncogene! The work was lead by Professor Neil Watkins, and is titled “The tumor suppressor Hic1 maintains chromosomal stability independent of Tp53”.

You can access the full article here [Link]

ABSTRACT: Hypermethylated-in-Cancer 1 (Hic1) is a tumor suppressor gene frequently inactivated by epigenetic silencing and loss-of- heterozygosity in a broad range of cancers. Loss of HIC1, a sequence-specific zinc finger transcriptional repressor, results in deregulation of genes that promote a malignant phenotype in a lineage-specific manner. In particular, upregulation of the HIC1 target gene SIRT1, a histone deacetylase, can promote tumor growth by inactivating TP53. An alternate line of evidence suggests that HIC1 can promote the repair of DNA double strand breaks through an interaction with MTA1, a component of the nucleosome remodeling and deacetylase (NuRD) complex. Using a conditional knockout mouse model of tumor initiation, we now show that inactivation of Hic1 results in cell cycle arrest, premature senescence, chromosomal instability and spontaneous transformation in vitro. This phenocopies the effects of deleting Brca1, a component of the homologous recombination DNA repair pathway, in mouse embryonic fibroblasts. These effects did not appear to be mediated by deregulation of Hic1 target gene expression or loss of Tp53 function, and rather support a role for Hic1 in maintaining genome integrity during sustained replicative stress. Loss of Hic1 function also cooperated with activation of oncogenic KRas in the adult airway epithelium of mice, resulting in the formation of highly pleomorphic adenocarcinomas with a micropapillary phenotype in vivo. These results suggest that loss of Hic1 expression in the early stages of tumor formation may contribute to malignant transformation through the acquisition of chromosomal instability.

 

New Co-Author Publication in Gut: CDK4 inhibitors for treatment of Pancreatic Cancer

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More great news, we have another co-author publication in the outstanding journal Gut. This fabulous work was pioneered by the very talented Dr Marina Pajic and her group at the Garvan Institute. We were very honoured to be involved in such amazing work.

The title of the publication is “Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer”. You can read and access the full article for free here [Link]

Abstract

Objective Extensive molecular heterogeneity of pancreatic ductal adenocarcinoma (PDA), few effective therapies and high mortality make this disease a prime model for advancing development of tailored therapies. The p16-cyclin D-cyclin-dependent kinase 4/6-retinoblastoma (RB) protein (CDK4) pathway, regulator of cell proliferation, is deregulated in PDA. Our aim was to develop a novel personalised treatment strategy for PDA based on targeting CDK4.

Design Sensitivity to potent CDK4/6 inhibitor PD-0332991 (palbociclib) was correlated to protein and genomic data in 19 primary patient-derived PDA lines to identify biomarkers of response. In vivo efficacy of PD-0332991 and combination therapies was determined in subcutaneous, intrasplenic and orthotopic tumour models derived from genome-sequenced patient specimens and genetically engineered model. Mechanistically, monotherapy and combination therapy were investigated in the context of tumour cell and extracellular matrix (ECM) signalling. Prognostic relevance of companion biomarker, RB protein, was evaluated and validated in independent PDA patient cohorts (>500 specimens).

Results Subtype-specific in vivo efficacy of PD-0332991-based therapy was for the first time observed at multiple stages of PDA progression: primary tumour growth, recurrence (second-line therapy) and metastatic setting and may potentially be guided by a simple biomarker (RB protein). PD-0332991 significantly disrupted surrounding ECM organisation, leading to increased quiescence, apoptosis, improved chemosensitivity, decreased invasion, metastatic spread and PDA progression in vivo. RB protein is prevalent in primary operable and metastatic PDA and may present a promising predictive biomarker to guide this therapeutic approach.

Conclusion This study demonstrates the promise of CDK4 inhibition in PDA over standard therapy when applied in a molecular subtype-specific context.

New Co-Author Publication! Ensa controls S-phase length by modulating Treslin levels.

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Great news, we have published a co-authored paper entitled ‘Ensa controls S-phase length by modulating Treslin levels’ in the prestigious journal ‘Nature Communications’. This work was started back in 2011 when I was a Post-Doc in the laboratory of Anna Castro in France. It’s exciting to see those inital discoveries transition into the finished paper.
The article is Open Access and free to download, which you can do so here: http://www.nature.com/articles/s41467-017-00339-4

 

ABSTRACT

The Greatwall/Ensa/PP2A-B55 pathway is essential for controlling mitotic substrate phos- phorylation and mitotic entry. Here, we investigate the effect of the knockdown of the Gwl substrate, Ensa, in human cells. Unexpectedly, Ensa knockdown promotes a dramatic extension of S phase associated with a lowered density of replication forks. Notably, Ensa depletion results in a decrease of Treslin levels, a pivotal protein for the firing of replication origins. Accordingly, the extended S phase in Ensa-depleted cells is completely rescued by the overexpression of Treslin. Our data herein reveal a new mechanism by which normal cells regulate S-phase duration by controlling the ubiquitin-proteasome degradation of Treslin in a Gwl/Ensa-dependent pathway.

New Publication in Cell! The Phosphoregulation of Mitosis

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We are incredibly excited to announce that our SnapShot is out today in Cell!
This snapshot of mitosis collates hundreds of phosphorylation events and directly links them with their regulatory kinases and counterbalancing phosphatases, in both time and space, in a highly innovative ‘circtanglar’ cell layout. More importantly, the static PDF version is accompanied by an interactive website that enables users to access direct links to PubMed, UniProt, and Aquaria 3D protein structures for each and every phosphorylation event shown. The pop-up boxes also contain over 100 additional phosphorylation sites on dozens of proteins essential for mitosis. You can access the interactive web version here:  http://www.cell.com/cell/enhanced/odonoghue2
Even better news is that until August 04, 2017 the PDF version of the SnapShot is freely accessible for everyone at the following link https://authors.elsevier.com/a/1VDWh_278yyILK
A big thank-you to Jenny, Sam, Marcos and Sean for helping me put together what I hope will be an amazing resource for anyone interested in how cells divide and phosphorylation in general.