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.
It was a great pleasure to be apart of this amazing research by Claire Venin and Paul Timpson, which was recently published in Science Translational Medicine, one of the very best journals in the world.
Here is a brief intro into the research.
ROCK-ing pancreatic cancer to the core
Pancreatic cancer, one of the most deadly and difficult-to-treat tumor types in patients, usually has a dense stroma that can be difficult for drugs to penetrate. Stromal characteristics can also affect multiple other aspects of tumor biology, including metastatic spread, vascular supply, and immune response. Vennin et al. used Fasudil, a drug that inhibits a protein called ROCK and is already used for some conditions in people, to demonstrate the feasibility including short-term tumor stroma remodeling as part of cancer treatment. In genetically engineered and patient-derived mouse models of pancreatic cancer, priming with Fasudil disrupted the tumors’ extracellular matrix and improved the effectiveness of subsequent treatment with standard-of-care chemotherapy for this disease.
If you would like to know more you can read the full article here:
Vennin, C. et al. 2017. Transient tissue priming via ROCK inhibition uncouples pancreatic cancer progression, sensitivity to chemotherapy, and metastasis. Science translational medicine. 9, 384 (Apr. 2017).
Great news, we have had a co-author review published in the Journal of Molecular and Cellular Biology.
You can check out the full review here.
The major cause of death from breast cancer is not the primary tumour, but relapsing, drug-resistant, metastatic disease. Identifying factors that contribute to aggressive cancer offers important leads for therapy. Inherent defense against carcinogens depends on the individual molecular make-up of each person. Important molecular determinants of these responses are under the control of the mouse double minute (MDM) family: comprised of the proteins MDM2 and MDM4. In normal, healthy adult cells, the MDM family functions to critically regulate measured, cellular responses to stress and subsequent recovery. Proper function of the MDM family is vital for normal breast development, but also for preserving genomic fidelity. The MDM family members are best characterized for their negative regulation of the major tumour suppressor p53 to modulate stress responses. Their impact on other cellular regulators is emerging. Inappropriately elevated protein levels of the MDM family are highly associated with an increased risk of cancer incidence. Exploration of the MDM family members as cancer therapeutic targets is relevant for designing tailored anti-cancer treatments, but successful approaches must strategically consider the impact on both the target cancer and adjacent healthy cells and tissues. This review focuses on recent findings pertaining to the role of the MDM family in normal and malignant breast cells.
- Julia P. Cooper (Telomere Biology Center for Cancer Research Bethesda USA),
- Daniel Durocher (DNA Damage The Lunenfeld-Tanenbaum Research Institute Toronto Ontario Canada),
- Marcos Malumbres (CNIO Spain)
- Antoine van Oijen (Single-molecule biophysics, DNA replication, School of Chemistry, University of Wollongong NSW Australia).
- ‘+’ lots more
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8th Garvan Signalling Symposium
We welcome scientists at all levels, including students, post-docs, research staff and senior lab heads. The intimate nature of the meeting and enjoyable social functions promotes a collegial atmosphere and excellent networking opportunities. A poster session will be held on the Monday afternoon with generous prizes. Slots have been reserved for short (15 minutes) talks to be selected from submitted abstracts.
The meeting is held at the Garvan Institute in the glamorous Darlinghurst region of Sydney, close to the city, Oxford Street, King’s Cross and the harbour.
This years exciting program features state-of-the-art technologies to investigate a wide range of diseases including cancer, immunology, neuroscience and metabolic disorders. Special sessions focus on in vivo/intravital signalling, proteomics, control of gene regulation and the structural basis of signalling.
Click Here for more information and to register
The 16th Australian Cell Cycle Meeting: “Cell Cycle, DNA Damage Response & Telomeres” will be held from Monday the 27th to Wednesday the 29th of March, 2017 at the Powerhouse Museum, in Sydney Australia.
The 2017 meeting will be the largest ever ACCM meeting, bringing together the fields of Cell Cycle, DNA Damage Response, and Telomere biology into one amazing meeting.
We are also very excited to announce 4x Plenary Lectures for #ACCM2017:
- Julia P. Cooper
Telomere Biology Center for Cancer Research (NCI) Bethesda, MD, USA
- Daniel Durocher
DNA Damage The Lunenfeld-Tanenbaum Research Institute Toronto, Ontario Canada
- Marcos Malumbres
Cell Division & Cancer National Cancer Research Centre (CNIO) Madrid, Spain
- Antoine van Oijen
Single-molecule biophysics, DNA replication Head School of Chemistry, University of Wollongong NSW, Australia
Registration for the ACCM2017 will open in October 2016, and more details, including a fantastic line up of National speakers will be announced…
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Dr Cesare’s laboratory has postdoctoral positions, fully funded for three years, starting in late 2016 or early 2017. We are in search of exceptional young scientists, interested in pursuing research on telomeres and genome stability. Opportunities exist in my lab for post-doctoral scientists to investigate:
1) the interplay between genomic DNA replication stress, or DNA damage, and telomere deprotection
2) mechanisms of telomere deprotection during ageing and in cancer
3) telomere biology in mitosis
4) mitotic chromosome dynamics
5) post-translational modifications in telomere deprotection signalling
6) nuclear architecture in the DNA damage response
Ideal candidates will be hard working, independent, and creative in their experimental approach. I also welcome candidates with established excellence in CRISPR/Cas9 mediated gene-editing, quantitative microscopy and/or automated imaging analysis, super-resolution microscopy, proteomics, ChIP-seq and RNA-seq.
Dr Cesare’s is located at the Children’s Medical Research Institute (CMRI) in Sydney, Australia. CMRI is home to the highest concentration of telomere research labs at a…
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A defining feature in over 2/3rds of all solid tumours is the continual loss and gain of whole are small parts of chromosomes. This instability, or CIN for short, strongly implicated in tumour initiation, progression, chemoresistance and poor prognosis. CIN is created through failures during mitosis, whereby whole or parts of a chromosome are segregated incorrectly, thereby created daughter cells with unequal chromosome numbers. Consequently, understanding how mitosis is regulated is essential for uncovering the mechanisms allowing CIN to arise and drive cancer. In our recent publication, we discovered the mechanisms controlling the key regulatory pathway critical to ensuring cells exit mitosis correctly. At the centre of this pathway is a gene call MASTL (short for ‘Microtubule Associated Serine/Threonine Kinase-Like’). The primary function of MASTL is to ensure that the cellular breaks (the phosphatase PP2A), is turned off during mitosis so that the accelerator (Cdk1 kinase) can drive the cell into mitosis. Much like a car, having the accelerator and breaks on at the same time is a bad idea, unless you like the smell of burning rubber. To successfully exit mitosis, and to perfectly segregate chromosomes, the cell must take the foot off the accelerator and turn on the breaks. Because MASTL is the central regulator ensuring the breaks are coordinated with the accelerator, it is essential to understand how MASTL is controlled. To this end, we uncovered that MASTL must be rapidly turned off to allow cells to exit mitosis, and this inactivation is carried out by another cellular brake call PP1 phosphatase (Rogers et al, JCS 2016). Now that we have identified and mapped this novel mitotic exit switch, we hope to be able to shed new light on how CIN drives the initiation and evolution cancer. We believe that with further study we will be able to better predict patient response to chemotherapy, and also identify new ways to ‘switch off’ highly unstable tumours, thereby improving treatment for patients that currently have a very poor prognosis.
Image of Interphase HeLa cell stained for Actin (red), DNA (blue) and the co-localisation of MASTL and PP1 by Proximity Ligation Assay (PLA; green).
Credit: Sam Rogers and Cell Division Lab