chromosome instability

New Publication: Hedgehog signaling in small cell lung cancer

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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”

ABSTRACT:

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.

 

Switching off Cancers Diversity

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JCS paper

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

 

AntiOxidants and Cancer: A complicated story

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A recent high profile publication in Science Translational Medicine proposed that antioxidants might increase the rate of metastasis in mice models of melanoma.

NAC and the soluble vitamin E analog Trolox markedly increased the migration and invasive properties of human malignant melanoma cells but did not affect their proliferation. Both antioxidants increased the ratio between reduced and oxidized glutathione in melanoma cells and in lymph node metastases, and the increased migration depended on new glutathione synthesis. Furthermore, both NAC and Trolox increased the activation of the small guanosine triphosphatase (GTPase) RHOA, and blocking downstream RHOA signaling abolished antioxidant-induced migration. These results demonstrate that antioxidants and the  system play a previously unappreciated role in malignant melanoma progression.

This goes against the common idea that anti-oxidants are cancer fighters!

So what is going on?

The answer, much like a Facebook relationship status, is “its complicated”. In fact anti-oxidants can have a wide range of effects on cells, including mitosis. Many “dietary antioxidants Resveratrol and Fisetin (found in red wine), inhibit Cdks, induce a G2 arrest and prevent entry into mitosis” (Burgess et al 2014). Furthermore, we recently showed that partial inhibition of Cdk1 can dramatically disrupt to mitosis. This caused increase cancer cell death… but also increased the rate of chromosome mis-segergations. (McCloy et al 2014). These mitotic errors can drive chromosome instability (CIN), which inturn can lead to the evolution of more aggressive, invasive tumours. Understanding the genetic background of each individual cancer will be key to determining why some cancer cells die and others thrive when given antioxidants.

If you would like to know more on how common stresses such as oxidation can disrupt mitosis, you can read our recent review Stressing Mitosis to Death.

Until then, if you have cancer and are thinking of taking antioxidants, make sure you consult your oncologist as they can significantly affect the efficacy of some chemotherapeutics, and hence maybe doing more harm than good.