D Neil Watkins

Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

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Publications (71)620.56 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Metaplasia can result when injury reactivates latent developmental signaling pathways that determine cell phenotype. Barrett's esophagus is a squamous-to-columnar epithelial metaplasia caused by reflux esophagitis. Hedgehog (Hh) signaling is active in columnar-lined, embryonic esophagus and inactive in squamous-lined, adult esophagus. We showed previously that Hh signaling is reactivated in Barrett's metaplasia and overexpression of Sonic hedgehog (SHH) in mouse esophageal squamous epithelium leads to a columnar phenotype. Here, our objective was to identify Hh target genes involved in Barrett's pathogenesis. By microarray analysis, we found that the transcription factor Foxa2 is more highly expressed in murine embryonic esophagus compared with postnatal esophagus. Conditional activation of Shh in mouse esophageal epithelium induced FOXA2, while FOXA2 expression was reduced in Shh knockout embryos, establishing Foxa2 as an esophageal Hh target gene. Evaluation of patient samples revealed FOXA2 expression in Barrett's metaplasia, dysplasia, and adenocarcinoma but not in esophageal squamous epithelium or squamous cell carcinoma. In esophageal squamous cell lines, Hh signaling upregulated FOXA2, which induced expression of MUC2, an intestinal mucin found in Barrett's esophagus, and the MUC2-processing protein AGR2. Together, these data indicate that Hh signaling induces expression of genes that determine an intestinal phenotype in esophageal squamous epithelial cells and may contribute to the development of Barrett's metaplasia.
    The Journal of clinical investigation. 08/2014;
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    ABSTRACT: Originating from Primordial Germ Cells/gonocytes and developing via a precursor lesion called Carcinoma In Situ (CIS), Germ Cell Cancers (GCC) are the most common cancer in young men, subdivided in seminoma (SE) and non-seminoma (NS). During physiological germ cell formation/maturation, epigenetic processes guard homeostasis by regulating the accessibility of the DNA to facilitate transcription. Epigenetic deregulation through genetic and environmental parameters (i.e. genvironment) could disrupt embryonic germ cell development, resulting in delayed or blocked maturation. This potentially facilitates the formation of CIS and progression to invasive GCC. Therefore, determining the epigenetic and functional genomic landscape in GCC cell lines could provide insight into the pathophysiology and etiology of GCC and provide guidance for targeted functional experiments.
    PLoS ONE 06/2014; 9(6):e98330. · 3.53 Impact Factor
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    ABSTRACT: Although neoadjuvant chemotherapy (NAC) for locally advanced breast cancer can improve operability and local disease control, there is a lack of reliable biomarkers that predict response to chemotherapy or long-term survival. Since expression of ALDEHYDE DEHYDROGENASE-1 (ALDH1) is associated with the stem-like properties of self-renewal and innate chemoresistance in breast cancer, we asked whether expression in serial tumour samples treated with NAC could identify women more likely to benefit from this therapy. Women with locally advanced breast cancer were randomly assigned to receive four cycles of anthracycline-based chemotherapy, followed by four cycles of taxane therapy (Arm A), or the same regimen in reverse order (Arm B). Tumour specimens were collected at baseline, after four cycles, and then at surgical resection. ALDH1 expression was determined by immunohistochemistry and correlated with tumour response using Fisher's exact test while Kaplan-Meier method was used to calculate survival. A hundred and nineteen women were enrolled into the study. Fifty seven (48%) were randomized to Arm A and 62 (52%) to Arm B. Most of the women (90%) had ductal carcinoma and 10% had lobular carcinoma. Of these, 26 (22%) achieved a pathological complete response (pCR) after NAC. There was no correlation between baseline ALDH1 expression and tumour grade, stage, hormone receptor, HER2 status and Ki67 index. ALDH1 negativity at baseline was significantly associated with cPR (p = 0.004). The presence of ALDH1(+) cells in the residual tumour cells in non-responding women was strongly predictive of worse overall survival (p = 0.024). Moreover, serial analysis of specimens from non-responders showed a marked increase in tumour-specific ALDH1 expression (p = 0.028). Overall, there was no survival difference according to the chemotherapy sequence. However, poorly responding tumours from women receiving docetaxel chemotherapy showed an unexpected significant increase in ALDH1 expression. ALDH1 expression is a useful predictor of chemoresistance. The upregulation of ALDH1 after NAC predicts for poor survival in locally advanced breast cancer. Although the chemotherapy sequence had no effect on overall prognosis, our results suggest that anthracycline-based chemotherapy may be more effective at targeting ALDH1(+) breast cancer cells.Trial registration: ACTRN12605000588695.
    Breast cancer research: BCR 04/2014; 16(2):R44. · 5.87 Impact Factor
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    Journal of Hepatology. 01/2014;
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    ABSTRACT: Patient-derived xenograft (PDX) models generated from surgical specimens are gaining popularity as preclinical models of cancer. However, establishment of PDX lines from small cell lung cancer (SCLC) patients is difficult due to very limited amount of available biopsy material. We asked whether SCLC cells obtained from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) could generate PDX lines that maintained the phenotypic and genetic characteristics of the primary tumor. Following successful EBUS-TBNA sampling for diagnostic purposes, we obtained an extra sample for cytologic analysis and implantation into the flanks of immunodeficient mice. Animals were monitored for engraftment for up to 6 months. Histopathologic and immunohistochemical analysis, and targeted next-generation re-sequencing, were then performed in both the primary sample and the derivative PDX line. A total of 12 patients were enrolled in the study. EBUS-TBNA aspirates yielded large numbers of viable tumor cells sufficient to inject between 18,750 and 1,487,000 cells per flank, and to yield microgram quantities of high-quality DNA. Of these, samples from 10 patients generated xenografts (engraftment rate 83%) with a mean latency of 104 days (range 63-188). All but one maintained a typical SCLC phenotype that closely matched the original sample. Identical mutations that are characteristic of SCLC were identified in both the primary sample and xenograft line. EBUS-TBNA has the potential to be a powerful tool in the development of new targeting strategies for SCLC patients by providing large numbers of viable tumor cells suitable for both xenografting and complex genomic analysis.
    PLoS ONE 01/2014; 9(9):e106862. · 3.53 Impact Factor
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    ABSTRACT: In vertebrates, canonical Hedgehog (Hh) pathway activation requires Smoothened (SMO) translocation to the primary cilium (Pc), followed by a GLI-mediated transcriptional response. In addition, a similar gene regulation occurs in response to growth factors/cytokines, although independently of SMO signalling. The Hh pathway plays a critical role in liver fibrosis/regeneration, however, the mechanism of activation in chronic liver injury is poorly understood. This study aimed to characterise Hh pathway activation upon thioacetamide (TAA)-induced chronic liver injury in vivo by defining Hh-responsive cells, namely cells harbouring Pc and Pc-localised SMO. C57BL/6 mice (wild-type or Ptc1+/-) were TAA-treated. Liver injury and Hh ligand/pathway mRNA and protein expression were assessed in vivo. SMO/GLI manipulation and SMO-dependent/independent activation of GLI-mediated transcriptional response in Pc-positive (Pc+) cells were studied in vitro. In vivo, Hh activation was progressively induced following TAA. At the epithelial-mesenchymal interface, injured hepatocytes produced Hh ligands. Progenitors, myofibroblasts, leukocytes and hepatocytes were GLI2+. Pc+ cells increased following TAA, but only EpCAM+/GLI2+ progenitors were Pc+/SMO+. In vitro, SMO knockdown/hGLI3-R overexpression reduced proliferation/viability in Pc+ progenitors, whilst increased proliferation occurred with hGLI1 overexpression. HGF induced GLI transcriptional activity independently of Pc/SMO. Ptc1+/- mice exhibited increased progenitor, myofibroblast and fibrosis responses. In chronic liver injury, Pc+ progenitors receive Hh ligand signals and process it through Pc/SMO-dependent activation of GLI-mediated transcriptional response. Pc/SMO-independent GLI activation likely occurs in Pc-/GLI2+ cells. Increased fibrosis in Hh gain-of-function mice likely occurs by primary progenitor expansion/proliferation and secondary fibrotic myofibroblast expansion, in close contact with progenitors.
    Journal of Hepatology 08/2013; · 9.86 Impact Factor
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    ABSTRACT: Background/Aims: ALDH1 is a marker of cancer stem-like cells and has been shown to be associated with resistance to chemotherapy. The aim of this study was to evaluate the correlation between response to neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer and ALDH1 expression. A further aim was to explore whether the drug sequence (taxanes followed by anthracyclines or the drugs in reverse order) effects changes in the ALDH1 expression during NAC. Methods: Women with locally advanced breast cancer were randomly assigned to receive either drug sequence (anthracycline followed by taxane (Arm A) or drugs in the reverse order (Arm B)). Tumour specimens were taken at baseline, after four cycles and after eight cycles of NAC. ALDH1 expression was determined by immunohistochemistry. Results: A hundred and four women were enrolled into the study. Fifty two (50%) were randomized to Arm A and 52 (50%) to Arm B. Most of the women (90%) had ductal carcinoma and 10% had lobular carcinoma. Of these 21 (20%) achieved a pathological complete response (pCR), 22(21%) had residual node negative disease (pPR) and 61 (59%) had less significant response (NR). There was no correlation between baseline ALDH1 expression and tumour grade, stage, hormone receptor, HER2 status and Ki67 proliferation index. ALDH1 positivity at baseline was significantly associated with NR (p= 0.012). Moreover, serial measurement in non-responders showed enrichment for ALDH1 expression in sequential tumour specimens (p = 0.003). Overall there was no difference according to the sequence of chemotherapy used, however, women in Arm B showed a relatively higher ALDH1 enrichment after four cycles of taxane therapy. Conclusions: High ALDH1 expression is a predictor of poor pathological response to chemotherapy in breast cancer. Chemotherapy sequence has no effect on overall changes in ALDH1 expression; however, relative high resistance to taxane-based chemotherapy may require further investigation.
    MOGA 2013, Melbourne; 08/2013
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    ABSTRACT: Here we report that ILK localizes in the mouse primary cilium, a sensory organelle required for signalling by the Hedgehog (Hh) pathway. Genetic or pharmacological inhibition of ILK blocks ciliary accumulation of the Hh pathway effector smoothened (Smo) and suppresses the induction of Gli transcription factor mRNAs by SHh. Conditional deletion of ILK or Smo also inhibits SHh-driven activation of Gli2 in the embryonic mouse cerebellum. ILK regulation of Hh signalling probably requires the physical interaction of ILK and Smo in the cilium, and we also show selective cilia-associated interaction of ILK with β-arrestin, a known mediator of Smo-dependent signalling.
    EMBO Reports 07/2013; · 7.19 Impact Factor
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    ABSTRACT: Expression of aldehyde dehydrogenase 1A1 (ALDH1A1) and CD133 has been functionally associated with a stem cell phenotype in normal and malignant cells. The prevalence of such cells in solid tumours should therefore correlate with recurrence and/or metastasis following definitive surgical resection. The aim of this study was to evaluate the prognostic significance of ALDH1A1 and CD133 in surgically resected, early stage non-small cell lung cancer (NSCLC). A retrospective analysis of ALDH1A1 and CD133 expression in 205 patients with pathologic stage I NSCLC was performed using immunohistochemistry. The association between the expression of both markers and survival was determined. We identified 62 relapses and 58 cancer-related deaths in 144 stage 1A and 61 stage 1B patients, analysed at a median of 5-years follow-up. Overexpression of ALDH1A1 and CD133, detected in 68.7% and 50.7% of primary tumours, respectively, was an independent prognostic indicator for overall survival by multivariable Cox proportional hazard model (p=0.017 and 0.039, respectively). Overexpression of ALDH1A1, but not of CD133, predicted poor recurrence-free survival (p=0.025). When categorised into three groups according to expression of ALDH1A1/CD133, patients with overexpression of both ALDH1A1 and CD133 belonged to the group with the shortest recurrence-free and overall survival (p=0.015 and 0.017, respectively). Expression of ALDH1A1 and CD133, and coexpression of ALDH1A1 and CD133, is strongly associated with poor survival in early-stage NSCLC following surgical resection. These data are consistent with the hypothesis that expression of stem cell markers correlates with recurrence as an indirect measure of self-renewal capacity.
    Thorax 07/2013; · 8.38 Impact Factor
  • Muhammad Alamgeer, Vinod Ganju, D Neil Watkins
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    ABSTRACT: Oncogenic driver mutations frequently occur in lung cancer and play role in carcinogenesis. These mutations are usually associated with distinct clinical and histological features and are attractive targets for anticancer therapy. Recently, several molecularly distinct phenotypes of NSCLC based on specific and mutually exclusive genetic derangements have been described. Few targets like epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) gene rearrangements have successfully been targeted with EGFR tyrosine kinase inhibitors (TKIs) and crizotinib, respectively. Many more inhibitors of specific driver mutations involving genes like ROS, c-MET, FGFR, mTOR, IGFR and RET are currently under development. However, efforts to target some mutated genes like K-RAS have been unsuccessful. Moreover, the emerging challenge of acquired resistance to initially effective therapy is becoming another major concern. In this review recent data on novel molecular targets and their future prospects are discussed.
    Current Opinion in Pharmacology 04/2013; · 5.44 Impact Factor
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    ABSTRACT: The cancer stem cell model is based on a myriad of experimental and clinical observations suggesting that the malignant phenotype is sustained by a subset of cells characterized by the capacity for self-renewal, differentiation and innate resistance to chemotherapy and radiation. Cancer stem cells may be responsible for disease recurrence after definitive therapy and may therefore be functionally synonymous with minimal residual disease. Similar to other solid tumours, several putative surface markers for lung cancer stem cells have been identified, including CD133 and CD44. In addition, expression and/or activity of the cytoplasmic enzyme ALDH, and capacity of cells to exclude membrane permeable dyes (known as the "side population") correlate with stem-like function in vitro and in vivo. Embryonic stem cell pathways such as Hedgehog, Notch and WNT may also be active in lung cancers stem cells, and therefore may be therapeutically targetable for maintenance therapy in patients achieving a complete response to surgery, radiotherapy or chemotherapy. This paper will review the evidence regarding the existence and function of lung cancer stem cells in the context of the experimental and clinical evidence and discuss some ongoing controversies regarding this model.
    Respirology 04/2013; · 2.78 Impact Factor
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    ABSTRACT: Despite the progress achieved in breast cancer screening and therapeutic innovations, the basal-like subtype of breast cancer (BLBC) still represents a particular clinical challenge. In order to make an impact on survival in this type of aggressive breast cancer, new targeted therapeutic agents are urgently needed. Aberrant activation of the Hedgehog (Hh) signalling pathway has been unambiguously tied to cancer development and progression in a variety of solid malignancies, and the recent approval of vismodegib, an orally bioavailable small-molecule inhibitor of Smoothened, validates Hh signalling as a valuable therapeutic target. A number of recent publications have highlighted a role for Hh signalling in breast cancer models and clinical specimens. Interestingly, Hh ligand overexpression is associated with the BLBC phenotype and a poor outcome in terms of metastasis and breast cancer-related death. In this review, we provide a comprehensive overview of the canonical Hh signalling pathway in mammals, highlight its roles in mammary gland development and breast carcinogenesis and discuss its potential therapeutic value in BLBC.
    Breast cancer research: BCR 03/2013; 15(2):203. · 5.87 Impact Factor
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    ABSTRACT: Histone deacetylase inhibitors (HDACi) were identified nearly four decades ago based on their ability to induce cellular differentiation. However, the clinical development of these compounds as cancer therapies has focused on their capacity to induce apoptosis in hematologic and lymphoid malignancies, often in combination with conventional cytotoxic agents. In many cases, HDACi doses necessary to induce these effects result in significant toxicity. Since osteosarcoma cells express markers of terminal osteoblast differentiation in response to DNA methyltransferase inhibitors, we reasoned that the epigenetic reprogramming capacity of HDACi might be exploited for therapeutic benefit. Here, we show that continuous exposure of osteosarcoma cells to low concentrations of HDACi LBH589 (Panobinostat) over a three-week period induces terminal osteoblast differentiation and irreversible senescence without inducing cell death. Remarkably, transcriptional profiling revealed that HDACi therapy initiated gene signatures characteristic of chondrocyte and adipocyte lineages in addition to marked upregulation of mature osteoblast markers. In a mouse xenograft model, continuous low dose treatment with LBH589 induced a sustained cytostatic response accompanied by induction of mature osteoblast gene expression. These data suggest that the remarkable capacity of osteosarcoma cells to differentiate in response to HDACi therapy could be exploited for therapeutic benefit without inducing systemic toxicity.
    Sarcoma 01/2013; 2013:608964.
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    ABSTRACT: Next-generation sequencing (NGS) studies in cancer are limited by the amount, quality and purity of tissue samples. In this situation, primary xenografts have proven useful preclinical models. However, the presence of mouse-derived stromal cells represents a technical challenge to their use in NGS studies. We examined this problem in an established primary xenograft model of small cell lung cancer (SCLC), a malignancy often diagnosed from small biopsy or needle aspirate samples. Using an in silico strategy that assign reads according to species-of-origin, we prospectively compared NGS data from primary xenograft models with matched cell lines and with published datasets. We show here that low-coverage whole-genome analysis demonstrated remarkable concordance between published genome data and internal controls, despite the presence of mouse genomic DNA. Exome capture sequencing revealed that this enrichment procedure was highly species-specific, with less than 4% of reads aligning to the mouse genome. Human-specific expression profiling with RNA-Seq replicated array-based gene expression experiments, whereas mouse-specific transcript profiles correlated with published datasets from human cancer stroma. We conclude that primary xenografts represent a useful platform for complex NGS analysis in cancer research for tumours with limited sample resources, or those with prominent stromal cell populations.
    PLoS ONE 01/2013; 8(9):e74432. · 3.53 Impact Factor
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    ABSTRACT: The Hedgehog (HH) signaling pathway is critical for embryonic development and adult homeostasis. Recent studies have identified regulatory roles for this pathway in certain cancers with mutations in the HH pathway genes. The extent to which mutations of the HH pathway genes are involved in the pathogenesis of malignant mesothelioma (MMe) is unknown. Real-time PCR analysis of HH pathway genes PTCH1, GLI1 and GLI2 were performed on 7 human MMe cell lines. Exon sequencing of 13 HH pathway genes was also performed in cell lines and human MMe tumors. In silico programs were used to predict the likelihood that an amino-acid substitution would have a functional effect. GLI1, GLI2 and PTCH1 were highly expressed in MMe cells, indicative of active HH signaling. PTCH1, SMO and SUFU mutations were found in 2 of 11 MMe cell lines examined. A non-synonymous missense SUFU mutation (p.T411M) was identified in LO68 cells. In silico characterization of the SUFU mutant suggested that the p.T411M mutation might alter protein function. However, we were unable to demonstrate any functional effect of this mutation on Gli activity. Deletion of exons of the PTCH1 gene was found in JU77 cells, resulting in loss of one of two extracellular loops implicated in HH ligand binding and the intracellular C-terminal domain. A 3-bp insertion (69_70insCTG) in SMO, predicting an additional leucine residue in the signal peptide segment of SMO protein was also identified in LO68 cells and a MMe tumour. We identified the first novel mutations in PTCH1, SUFU and SMO associated with MMe. Although HH pathway mutations are relatively rare in MMe, these data suggest a possible role for dysfunctional HH pathway in the pathogenesis of a subgroup of MMe and help rationalize the exploration of HH pathway inhibitors for MMe therapy.
    PLoS ONE 01/2013; 8(6):e66685. · 3.53 Impact Factor
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    ABSTRACT: Renal primary cilia are microscopic sensory organelles found on the apical surface of epithelial cells of the nephron and collecting duct. They are based upon a microtubular cytoskeleton, bounded by a specialized membrane, and contain an array of proteins that facilitate their assembly, maintenance and function. Cilium-based signalling is important for the control of epithelial differentiation and has been implicated in the pathogenesis of various cystic kidney diseases and in renal repair. As such, visualising renal primary cilia and understanding their composition has become an essential component of many studies of inherited kidney disease and mechanisms of epithelial regeneration. Primary cilia were initially identified in the kidney using electron microscopy and this remains a useful technique for the high resolution examination of these organelles. New reagents and techniques now also allow the structure and composition of primary cilia to be analyzed in detail using fluorescence microscopy. Primary cilia can be imaged in situ in sections of kidney, and many renal-derived cell lines produce primary cilia in culture providing a simplified and accessible system in which to investigate these organelles. Here we outline microscopy-based techniques commonly used for studying renal primary cilia.
    Nephrology 12/2012; · 1.69 Impact Factor
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    ABSTRACT: The molecular mechanism underlying the development of Barrett's esophagus (BE), the precursor to esophageal adenocarcinoma (EAC) remains unknown. Our previous work implicated sonic hedgehog (Shh) signaling as a possible driver of BE via bone morphogenic protein 4 (Bmp4) and Sox9. Here we have utilized a novel in vivo tissue reconstitution model to investigate the relative roles of Bmp4 and Sox9 in driving metaplasia. Epithelia reconstituted from squamous epithelial cells or empty vector (EV) transduced cells had a stratified squamous phenotype, reminiscent of normal esophagus. Expression of Bmp4 in the stromal compartment activated signaling in the epithelium but did not alter the squamous phenotype. In contrast, expression of Sox9 in squamous epithelial cells induced formation of columnar-like epithelium with expression of the columnar differentiation marker Ck8 and the intestinal specific glycoprotein, A33. In patient tissue, A33 protein was expressed specifically in BE and not normal esophagus. Expression of Cdx2, another putative driver of BE alone had no affect on reconstitution of a squamous epithelium. Furthermore, epithelium co-expressing Cdx2 and Sox9 had a similar phenotype to epithelium expressing Sox9 alone. Our results demonstrate that Sox9 is sufficient to drive columnar differentiation of squamous epithelium and expression of an intestinal differentiation marker, reminiscent of BE. These data suggest that Shh-mediated expression of Sox9 may be an important early event in the development of BE, and that the potential for inhibitors of the hedgehog signaling pathway to be used in the treatment of BE and/or EAC could be tested in the near future.
    AJP Gastrointestinal and Liver Physiology 10/2012; · 3.65 Impact Factor
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    ABSTRACT: The hedgehog signaling pathway is important in embryogenesis and post natal development. Constitutive activation of the pathway due to mutation of pathway components occurs in ~25% of medulloblastomas and also in basal cell carcinomas. In many other malignancies the therapeutic role for hedgehog inhibition though intriguing, based on preclinical data, is far from assured. Hedgehog inhibition is not an established part of the treatment paradigm of sarcoma but the scientific rationale for a possible benefit is compelling. In chondrosarcoma there is evidence of hedgehog pathway activation and an ontologic comparison between growth plate chondrocyte differentiation and different chondrosarcoma subtypes. Immunostaining epiphyseal growth plate for Indian hedgehog is particularly positive in the zone of pre-hypertrophic chondrocytes which correlates ontologically with conventional chondrosarcoma. In Ewing sarcoma/PNET tumors the Gli1 transcription factor is a direct target of the EWS-FLI1 oncoprotein present in 85% of cases. In many cases of rhabdomyosarcomas there is increased expression of Gli1 (Ragazzini et al., 2004). Additionally, a third of embryonal rhabdomyosarcomas have loss of Chr.9q22 that encompasses the patched locus (Bridge et al., 2000). The potential to treat osteosarcoma by inhibition of Gli2 and the role of the pathway in ovarian fibromas and other connective tissue tumors is also discussed (Nagao et al., 2011; Hirotsu et al., 2010). Emergence of acquired secondary resistance to targeted therapeutics is an important issue that is also relevant to hedgehog inhibition. In this context secondary resistance of medulloblastomas to treatment with a smoothened antagonist in two tumor mouse models is examined.
    Pharmacology [?] Therapeutics 08/2012; 136(2):153-68. · 7.79 Impact Factor
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    ABSTRACT: Small-cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer for which there is no effective treatment. Using a mouse model in which deletion of Rb1 and Trp53 in the lung epithelium of adult mice induces SCLC, we found that the Hedgehog signaling pathway is activated in SCLC cells independently of the lung microenvironment. Constitutive activation of the Hedgehog signaling molecule Smoothened (Smo) promoted the clonogenicity of human SCLC in vitro and the initiation and progression of mouse SCLC in vivo. Reciprocally, deletion of Smo in Rb1 and Trp53-mutant lung epithelial cells strongly suppressed SCLC initiation and progression in mice. Furthermore, pharmacological blockade of Hedgehog signaling inhibited the growth of mouse and human SCLC, most notably following chemotherapy. These findings show a crucial cell-intrinsic role for Hedgehog signaling in the development and maintenance of SCLC and identify Hedgehog pathway inhibition as a therapeutic strategy to slow the progression of disease and delay cancer recurrence in individuals with SCLC.
    Nature medicine 10/2011; 17(11):1504-8. · 27.14 Impact Factor
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    ABSTRACT: The Hedgehog (Hh) pathway is a conserved signalling system essential for embryonic development and for the maintenance of self-renewal pathways in progenitor cells. Mutations that deregulate Hh signalling are directly implicated in basal cell carcinoma and medulloblastoma. The mechanisms of Hh pathway activation in cancers in which no pathway mutations have been identified are less clear, but of great translational significance. Small molecule inhibitors of the pathway, many of which are in early phase clinical trials, may shed further light on this question. Canonical Hh signalling promotes the expression of target genes through the Glioma-associated oncogene (GLI) transcription factors. There is now increasing evidence suggesting that 'non-canonical' Hh signalling mechanisms, some of which are independent of GLI-mediated transcription, may be important in cancer and development. The focus of this review is to summarise some of the known mechanisms of Hh signalling as well as its emerging role in cancer.
    Growth factors (Chur, Switzerland) 08/2011; 29(6):221-34. · 2.47 Impact Factor

Publication Stats

5k Citations
620.56 Total Impact Points

Institutions

  • 2014
    • Garvan Institute of Medical Research
      Darlinghurst, New South Wales, Australia
    • The Kinghorn Cancer Centre
      Darlinghurst, New South Wales, Australia
  • 2010–2014
    • Monash University (Australia)
      Melbourne, Victoria, Australia
  • 2013
    • Monash University (Malaysia)
      Labuan, Labuan, Malaysia
    • Peter MacCallum Cancer Centre
      • Peter MacCallum Cancer Center
      Melbourne, Victoria, Australia
  • 2003–2009
    • Johns Hopkins University
      • • Department of Surgery
      • • Department of Medicine
      Baltimore, MD, United States
  • 2007
    • The University of Hong Kong
      • Department of Medicine
      Hong Kong, Hong Kong
    • Centre for Cancer Biology
      Tarndarnya, South Australia, Australia
  • 2003–2004
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States
  • 1998–2002
    • University of Western Australia
      Perth City, Western Australia, Australia
  • 2000
    • Sir Charles Gairdner Hospital
      Perth City, Western Australia, Australia
  • 1997–1999
    • The Queen Elizabeth Hospital
      Tarndarnya, South Australia, Australia