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.
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.
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
Great news, we have a new Mini-Review published in Frontiers Oncology entitled “Clinical Overview of MDM2/X-Targeted Therapies“, which is apart of the Research Topic Human tumor-derived p53 mutants: a growing family of oncoproteins
Here is a little snippet from the Abstract to wet your appetite!
MDM2 and MDMX are the primary negative regulators of p53, which under normal conditions maintain low intracellular levels of p53 by targeting it to the proteasome for rapid degradation and inhibiting its transcriptional activity. Both MDM2 and MDMX function as powerful oncogenes and are commonly over-expressed in some cancers, including sarcoma (~20%) and breast cancer (~15%).
In this overview, we will review the current MDM2- and MDMX-targeted therapies in development, focusing particularly on compounds that have entered into early phase clinical trials. We will highlight the challenges pertaining to predictive biomarkers for and toxicities associated with these compounds, as well as identify potential combinatorial strategies to enhance its anti-cancer efficacy.
The article is Open Access, which means its free for everyone and anyone to read and download!
You can view and download it directly here [Link]
Great news we are currently looking for a new honours student for 2016.
The title of the project is “Developing novel biosensors to monitor DNA damage in cancer cells”.
Its a very exciting new project incorporating cutting edge microscopy and fluorescent biosensors.
If you think you have what it takes and are interested please feel free contact myself, or UNSW SoMS.
For more information on the UNSW honours program please visit: http://medicalsciences.med.unsw.edu.au/students/soms-honours/
Below is an example of the images that will be created during the project.
Great news, our latest article in @CellCycleJ is now online.
“Degrading Claspin away with Cdh1 and Cyclin A. Cell Cycle (2015)”
You can view the pre-print version here
The News and Views article is based on the recent publication by Oakes, V. et al. entitled “Cyclin A/Cdk2 regulates Cdh1 and claspin during late S/G2 phase of the cell cycle” Cell Cycle 13, 3302–3311 (2014).
Here is a sneak peak at the figure from our article.