ORCID Profile
0000-0002-9681-6834
Current Organisation
Peter MacCallum Cancer Centre
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Publisher: Springer Science and Business Media LLC
Date: 08-05-2017
DOI: 10.1038/ONC.2017.121
Abstract: Toll-like receptors (TLRs) are key regulators of innate immune responses, and their dysregulation is observed in numerous inflammation-associated malignancies, including gastric cancer (GC). However, the identity of specific TLRs and their molecular targets which promote the pathogenesis of human GC is ill-defined. Here, we sought to determine the clinical utility of TLR2 in human GC. TLR2 mRNA and protein expression levels were elevated in >50% of GC patient tumors across multiple ethnicities. TLR2 was also widely expressed among human GC cell lines, and DNA microarray-based expression profiling demonstrated that the TLR2-induced growth responsiveness of human GC cells corresponded with the up-regulation of six anti-apoptotic (BCL2A1, BCL2, BIRC3, CFLAR, IER3, TNFAIP3) and down-regulation of two tumor suppressor (PDCD4, TP53INP1) genes. The TLR2-mediated regulation of these anti-apoptotic and tumor suppressor genes was also supported by their increased and reduced expression, respectively, in two independent genetic GC mouse models (gp130
Publisher: Wiley
Date: 07-01-2019
DOI: 10.1002/IJC.32060
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.INTIMP.2018.04.033
Abstract: Toll-like receptor (TLR) 2 is a key regulator of innate immune responses and has been shown to play an important role in inflammation-associated cancers. In this study, we aimed to evaluate the role of TLR2 in colorectal cancer (CRC). We demonstrated that TLR2 mRNA and protein expression was significantly upregulated in tumors from CRC patients and indicated poor prognosis. Using the TLR2 agonist Pam3Cys (P3C) to activate TLR2 signaling in human CRC cell lines, we showed that TLR2 drives cellular proliferation, which was dependent upon PI3K/Akt and NF-κB signaling pathways and was associated with the upregulation of anti-apoptotic genes BCL2A1, WISP1 and BIRC3. Likewise, pharmacological blockade of PI3K/Akt and NF-κB pathways mitigated the CRC pro-survival effects of TLR2 stimulation. Furthermore, genetic ablation of TLR2 using CRISPR/Cas9 suppressed CRC cell proliferation, invasion and migration. Taken together, these findings demonstrate that TLR2 plays an important role in colorectal tumorigenesis and may represent a promising therapeutic target in CRC.
Publisher: Elsevier BV
Date: 06-2020
Publisher: Elsevier BV
Date: 04-2017
DOI: 10.1016/J.CYTO.2017.01.015
Abstract: Deregulated gp130-dependent STAT3 signalling by the pleiotropic cytokine interleukin (IL)-11 has been implicated in the pathogenesis of gastric cancer (GC), the third most common cancer worldwide. While the IL-11-gp130-STAT3 signalling axis has traditionally been thought to exclusively use the membrane-bound IL-11 receptor (mIL-11R), recent evidence suggests that mIL-11R can be proteolytically cleaved to generate a soluble form (sIL-11R) which can elicit trans-signalling. Since the role of IL-11 trans-signalling in disease pathogenesis is unknown, here we have employed the IL-11-driven gp130
Publisher: Springer Science and Business Media LLC
Date: 30-07-2020
DOI: 10.1038/S41467-020-17669-5
Abstract: Detection of microbial components such as lipopolysaccharide (LPS) by Toll-like receptor 4 (TLR4) on macrophages induces a robust pro-inflammatory response that is dependent on metabolic reprogramming. These innate metabolic changes have been compared to aerobic glycolysis in tumour cells. However, the mechanisms by which TLR4 activation leads to mitochondrial and glycolytic reprogramming are unknown. Here we show that TLR4 activation induces a signalling cascade recruiting TRAF6 and TBK-1, while TBK-1 phosphorylates STAT3 on S727. Using a genetically engineered mouse model incapable of undergoing STAT3 Ser727 phosphorylation, we show ex vivo and in vivo that STAT3 Ser727 phosphorylation is critical for LPS-induced glycolytic reprogramming, production of the central immune response metabolite succinate and inflammatory cytokine production in a model of LPS-induced inflammation. Our study identifies non-canonical STAT3 activation as the crucial signalling intermediary for TLR4-induced glycolysis, macrophage metabolic reprogramming and inflammation.
Publisher: Wiley
Date: 19-02-2018
DOI: 10.1002/IJC.31298
Publisher: American Association for Cancer Research (AACR)
Date: 28-02-2018
DOI: 10.1158/0008-5472.CAN-17-1887
Abstract: Inflammasomes are key regulators of innate immunity in chronic inflammatory disorders and autoimmune diseases, but their role in inflammation-associated tumorigenesis remains ill-defined. Here we reveal a protumorigenic role in gastric cancer for the key inflammasome adaptor apoptosis-related speck-like protein containing a CARD (ASC) and its effector cytokine IL18. Genetic ablation of ASC in the gp130F/F spontaneous mouse model of intestinal-type gastric cancer suppressed tumorigenesis by augmenting caspase-8-like apoptosis in the gastric epithelium, independently from effects on myeloid cells and mucosal inflammation. This phenotype was characterized by reduced activation of caspase-1 and NF-κB activation and reduced expression of mature IL18, but not IL1β, in gastric tumors. Genetic ablation of IL18 in the same model also suppressed gastric tumorigenesis, whereas blockade of IL1β and IL1α activity upon genetic ablation of the IL1 receptor had no effect. The specific protumorigenic role for IL18 was associated with high IL18 gene expression in the gastric tumor epithelium compared with IL1β, which was preferentially expressed in immune cells. Supporting an epithelial-specific role for IL18, we found it to be highly secreted from human gastric cancer cell lines. Moreover, IL18 blockade either by a neutralizing anti-IL18 antibody or by CRISPR/Cas9-driven deletion of ASC augmented apoptosis in human gastric cancer cells. In clinical specimens of human gastric cancer tumors, we observed a significant positive correlation between elevated mature IL18 protein and ASC mRNA levels. Collectively, our findings reveal the ASC/IL18 signaling axis as a candidate therapeutic target in gastric cancer. Significance: Inflammasome activation that elevates IL18 helps drive gastric cancer by protecting cancer cells against apoptosis, with potential implications for new therapeutic strategies in this setting. Cancer Res 78(5) 1293–307. ©2017 AACR.
Publisher: Elsevier BV
Date: 11-2016
DOI: 10.1016/J.CYTO.2016.05.019
Abstract: The JAK-STAT3 signaling pathway is engaged by many cytokines and growth factor stimuli to control erse biological processes including proliferation, angiogenesis, survival, immune modulation, and metabolism. For over two decades it has been accepted that STAT3-dependent biology is due to its potency as a transcription factor capable of regulating the expression of many hundreds of genes. However, recent evidence of non-canonical and non-genomic activities of STAT3 has emerged. The most exciting of these activities is its capacity to translocate into the mitochondria where it regulates the activity of the electron transport chain and the opening of the mitochondrial permeability transition pore. These have broad consequences including cell survival and the production of reactive oxygen species and ATP in both normal tissue and under pathological conditions. Despite these fascinating observations there are many key unanswered questions about the mechanism of STAT mitochondrial activity.
Publisher: Springer Singapore
Date: 2017
DOI: 10.1007/978-981-10-5987-2_9
Abstract: Toll-like receptors (TLRs) are one of the best characterised families of pattern recognition receptors (PRRs) and play a critical role in the host defence to infection. Accumulating evidence indicates that TLRs also participate in maintaining tissue homeostasis by controlling inflammation and tissue repair, as well as promoting antitumour effects via activation and modulation of adaptive immune responses. TLR agonists have successfully been exploited to ameliorate the efficacy of various cancer therapies. In this chapter, we will discuss the rationales of using TLR agonists as adjuvants to cancer treatments and summarise the recent findings of preclinical and clinical studies of TLR agonist-based cancer therapies.
Publisher: EMBO
Date: 04-03-2019
Publisher: American Association for Cancer Research (AACR)
Date: 14-03-2018
DOI: 10.1158/1078-0432.CCR-17-2485
Abstract: Purpose: The majority of gastric cancer patients are diagnosed with late-stage disease, for which distinct molecular subtypes have been identified that are potentially amenable to targeted therapies. However, there exists no molecular classification system with prognostic power for early-stage gastric cancer (EGC) because the molecular events promoting gastric cancer initiation remain ill-defined. Experimental Design: miRNA microarrays were performed on gastric tissue from the gp130F/F preclinical EGC mouse model, prior to tumor initiation. Computation prediction algorithms were performed on multiple data sets and independent gastric cancer patient cohorts. Quantitative real-time PCR expression profiling was undertaken in gp130F/F-based mouse strains and human gastric cancer cells genetically engineered for suppressed activation of the oncogenic latent transcription factor STAT3. Human gastric cancer cells with modulated expression of the miR-200 family member miR-429 were also assessed for their proliferative response. Results: Increased expression of miR-200 family members is associated with both tumor initiation in a STAT3-dependent manner in gp130F/F mice and EGC (i.e., stage IA) in patient cohorts. Overexpression of miR-429 also elicited contrasting pro- and antiproliferative responses in human gastric cancer cells depending on their cellular histologic subtype. We also identified a miR-200 family–regulated 15-gene signature that integrates multiple key current indicators of EGC, namely tumor invasion depth, differentiation, histology, and stage, and provides superior predictive power for overall survival compared with each EGC indicator alone. Conclusions: Collectively, our discovery of a STAT3-regulated, miR-200 family–associated gene signature specific for EGC, with predictive power, provides a molecular rationale to classify and stratify EGC patients for endoscopic treatment. Clin Cancer Res 24(6) 1459–72. ©2018 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 15-10-2019
DOI: 10.1158/0008-5472.CAN-19-0974
Abstract: These findings reveal a new transcriptional role and mandatory requirement for constitutive STAT3 serine phosphorylation in gastric cancer.
Publisher: Elsevier BV
Date: 06-2020
No related grants have been discovered for Jesse Balic.