New Co-Author paper out now in SciTransMed: Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy
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.
New Co-Author paper: The E3 ubiquitin ligase UBR5 regulates centriolar satellite stability and primary cilia
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.
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
New Paper Published: MASTL overexpression promotes chromosome instability and metastasis in breast cancer
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
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.
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.
- 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.
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.
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
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.
Great news we have a new co-author publication in Oncogene!
This work was in collaboration with Prof. Neil Wakins here at the Garvan Institute and focuses on the role of Hedgehog (Hh) signaling in small cell lung cancer (SCLC). Small cell lung cancer is a common, aggressive malignancy with universally poor prognosis.
Full details can be found here [link]
TITLE: “The role of canonical and non-canonical Hedgehog signaling in tumor progression in a mouse model of small cell lung cancer”
Hedgehog (Hh) signaling regulates cell fate and self-renewal in development and cancer. Canonical Hh signaling is mediated by Hh ligand binding to the receptor Patched (Ptch), which in turn activates Gli-mediated transcription through Smoothened (Smo), the molecular target of the Hh pathway inhibitors used as cancer therapeutics. Small cell lung cancer (SCLC) is a common, aggressive malignancy with universally poor prognosis. Although preclinical studies have shown that Hh inhibitors block the self-renewal capacity of SCLC cells, the lack of activating pathway mutations have cast doubt over the significance of these observations. In particular, the existence of autocrine, ligand-dependent Hh signaling in SCLC has been disputed. In a conditional Tp53;Rb1 mutant mouse model of SCLC, we now demonstrate a requirement for the Hh ligand Sonic Hedgehog (Shh) for the progression of SCLC. Conversely, we show that conditional Shh overexpression activates canonical Hh signaling in SCLC cells, and markedly accelerates tumor progression. When compared to mouse SCLC tumors expressing an activating, ligand-independent Smo mutant, tumors overexpressing Shh exhibited marked chromosomal instability and Smoothened-independent upregulation of Cyclin B1, a putative non-canonical arm of the Hh pathway. In turn, we show that overexpression of Cyclin B1 induces chromosomal instability in mouse embryonic fibroblasts lacking both Tp53 and Rb1. These results provide strong support for an autocrine, ligand-dependent model of Hh signaling in SCLC pathogenesis, and reveal a novel role for non-canonical Hh signaling through the induction of chromosomal instability.