I am very excited to announce our new review paper which is out now in Front Cell Dev Biol [Link]. This is also the first paper from Dr Kamila Marzec who recently joined the lab. Great work!
MASTL kinase is a master regulator of mitosis, essential for ensuring that mitotic substrate phosphorylation is correctly maintained. It achieves this through the phosphorylation of alpha-endosulfine and subsequent inhibition of the tumour suppressor PP2A-B55 phosphatase. In recent years MASTL has also emerged as a novel oncogenic kinase that is upregulated in a number of cancer types, correlating with chromosome instability and poor patient survival. While the chromosome instability is likely directly linked to MASTL’s control of mitotic phosphorylation, several new studies indicated that MASTL has additional effects outside of mitosis and beyond regulation of PP2A-B55. These include control of normal DNA replication timing, and regulation of AKT/mTOR and Wnt/β-catenin oncogenic kinase signalling. In this review, we will examine the phenotypes and mechanisms for how MASTL, ENSA and PP2A-B55 deregulation drives tumour progression and metastasis. Finally, we will explore the rationale for the future development of MASTL inhibitors as new cancer therapeutics.
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 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.
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.
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]