ORCID Profile
0000-0001-8375-4753
Current Organisations
Olivia Newton-John Cancer Research Institute
,
Southern University of Science and Technology
Does something not look right? The information on this page has been harvested from data sources that may not be up to date. We continue to work with information providers to improve coverage and quality. To report an issue, use the Feedback Form.
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.CELREP.2022.111479
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with a low 5-year survival rate and is associated with poor response to therapy. Elevated expression of the myeloid-specific hematopoietic cell kinase (HCK) is observed in PDAC and correlates with reduced patient survival. To determine whether aberrant HCK signaling in myeloid cells is involved in PDAC growth and metastasis, we established orthotopic and intrasplenic PDAC tumors in wild-type and HCK knockout mice. Genetic ablation of HCK impaired PDAC growth and metastasis by inducing an immune-stimulatory endotype in myeloid cells, which in turn reduced the desmoplastic microenvironment and enhanced cytotoxic effector cell infiltration. Consequently, genetic ablation or therapeutic inhibition of HCK minimized metastatic spread, enhanced the efficacy of chemotherapy, and overcame resistance to anti-PD1, anti-CTLA4, or stimulatory anti-CD40 immunotherapy. Our results provide strong rationale for HCK to be developed as a therapeutic target to improve the response of PDAC to chemo- and immunotherapy.
Publisher: Springer Science and Business Media LLC
Date: 15-06-2021
Publisher: Springer Science and Business Media LLC
Date: 31-10-2020
DOI: 10.1038/S41420-020-00348-1
Abstract: Despite having one of the lowest survival rates of all cancers, there have been no new approved treatments for malignant pleural mesothelioma (MPM) in over a decade. Standard-of-care treatment relies on Cisplatin plus Pemetrexed chemotherapy. Here, we tested a suite of BH3-mimetic drugs targeting BCL-2 pro-survival proteins of the intrinsic apoptotic pathway. We found BCL-XL is the dominant pro-survival protein in a panel of cell lines in vitro, though potent, synergistic cell killing occurred with MCL-1 co-targeting. This correlates with high-level expression of BCL-XL and MCL-1 in cell lines and a large cohort of patient tumour s les. BCL-XL inhibition combined with Cisplatin also enhanced cell killing. In vivo BCL-XL inhibition was as effective as Cisplatin, and the combination enhanced tumour growth control and survival. Genetic ablation of MCL-1 also enhanced the effects of BCL-XL inhibitors, in vivo. Combined, these data provide a compelling rationale for the clinical investigation of BH3-mimetics targeting BCL-XL in MPM.
Publisher: Cold Spring Harbor Laboratory
Date: 18-02-2022
DOI: 10.1101/2022.02.16.480779
Abstract: Although gastric cancer is a leading cause of cancer-related deaths, systemic treatment strategies remain scarce. Here we explore a metabolite-triggered circuit between epithelial tuft cells and innate lymphoid type 2 cells (ILC2) that is evolutionarily optimized for intestinal remodeling in response to helminth infection. We demonstrate that tuft cell-derived interleukin 25 (IL25) acts as an alarmin on ILC2s to induce the release of IL13 as a growth factor for tuft cells, and propose that this model drives early metaplastic remodeling and gastric tumor formation. Genetic ablation of tuft cells, ILC2s or antibody-mediated neutralization of IL13 or IL25 reduces the growth of established tumors. Thus, the tuft cell/ILC2 axis provides an opportunity to therapeutically inhibit preneoplastic lesions and early-stage gastric cancer through repurposing of antibody-mediated therapies. Tuft cells and type 2 innate lymphoid cells offer a new therapeutic target in gastric disease.
Publisher: MDPI AG
Date: 11-12-2021
Abstract: Non-small cell lung cancer (NSCLC) is the most common type of lung cancer and accounts for 85% of lung cancer cases. Aberrant activation of the Signal Transducer and Activator of Transcription 3 (STAT3) is frequently observed in NSCLC and is associated with a poor prognosis. Pre-clinical studies have revealed an unequivocal role for tumor cell-intrinsic and extrinsic STAT3 signaling in NSCLC by promoting angiogenesis, cell survival, cancer cell stemness, drug resistance, and evasion of anti-tumor immunity. Several STAT3-targeting strategies have also been investigated in pre-clinical models, and include preventing upstream receptor/ligand interactions, promoting the degradation of STAT3 mRNA, and interfering with STAT3 DNA binding. In this review, we discuss the molecular and immunological mechanisms by which persistent STAT3 activation promotes NSCLC development, and the utility of STAT3 as a prognostic and predictive biomarker in NSCLC. We also provide a comprehensive update of STAT3-targeting therapies that are currently undergoing clinical evaluation, and discuss the challenges associated with these treatment modalities in human patients.
Publisher: Frontiers Media SA
Date: 12-03-2018
Publisher: MDPI AG
Date: 17-12-2022
Abstract: Aberrant expression of the oncoprotein c-Myc (Myc) is frequently observed in solid tumors and is associated with reduced overall survival. In addition to well-recognized cancer cell-intrinsic roles of Myc, studies have also suggested tumor-promoting roles for Myc in cells of the tumor microenvironment, including macrophages and other myeloid cells. Here, we benchmark Myc inactivation in tumor cells against the contribution of its expression in myeloid cells of murine hosts that harbor endogenous or allograft tumors. Surprisingly, we observe that LysMCre-mediated Myc ablation in host macrophages does not attenuate tumor growth regardless of immunogenicity, the cellular origin of the tumor, the site it develops, or the stage along the tumor progression cascade. Likewise, we find no evidence for Myc ablation to revert or antagonize the polarization of alternatively activated immunosuppressive macrophages. Thus, we surmise that systemic targeting of Myc activity may confer therapeutic benefits primarily through limiting Myc activity in tumor cells rather than reinvigorating the anti-tumor activity of macrophages.
Publisher: Elsevier BV
Date: 05-2014
Publisher: Springer Science and Business Media LLC
Date: 11-07-2019
DOI: 10.1038/S41418-019-0383-9
Abstract: Gastrointestinal epithelial cells provide a selective barrier that segregates the host immune system from luminal microorganisms, thereby contributing directly to the regulation of homeostasis. We have shown that from early embryonic development Bcl-G, a Bcl-2 protein family member with unknown function, was highly expressed in gastrointestinal epithelial cells. While Bcl-G was dispensable for normal growth and development in mice, the loss of Bcl-G resulted in accelerated progression of colitis-associated cancer. A label-free quantitative proteomics approach revealed that Bcl-G may contribute to the stability of a mucin network, which when disrupted, is linked to colon tumorigenesis. Consistent with this, we observed a significant reduction in Bcl-G expression in human colorectal tumors. Our study identifies an unappreciated role for Bcl-G in colon cancer.
Publisher: Wiley
Date: 07-2016
DOI: 10.1111/JGH.13297
Publisher: American Association for the Advancement of Science (AAAS)
Date: 30-09-2014
DOI: 10.1126/SCISIGNAL.2005411
Abstract: Partial suppression of the inflammatory gp130-Jak-Stat pathway inhibits intestinal tumor growth.
Publisher: Springer Science and Business Media LLC
Date: 21-06-2019
DOI: 10.1038/S41467-019-10676-1
Abstract: The contribution of mast cells in the microenvironment of solid malignancies remains controversial. Here we functionally assess the impact of tumor-adjacent, submucosal mast cell accumulation in murine and human intestinal-type gastric cancer. We find that genetic ablation or therapeutic inactivation of mast cells suppresses accumulation of tumor-associated macrophages, reduces tumor cell proliferation and angiogenesis, and diminishes tumor burden. Mast cells are activated by interleukin (IL)-33, an alarmin produced by the tumor epithelium in response to the inflammatory cytokine IL-11, which is required for the growth of gastric cancers in mice. Accordingly, ablation of the cognate IL-33 receptor St2 limits tumor growth, and reduces mast cell-dependent production and release of the macrophage-attracting factors Csf2, Ccl3, and Il6. Conversely, genetic or therapeutic macrophage depletion reduces tumor burden without affecting mast cell abundance. Therefore, tumor-derived IL-33 sustains a mast cell and macrophage-dependent signaling cascade that is amenable for the treatment of gastric cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2016
DOI: 10.1158/0008-5472.CAN-15-3089
Abstract: About 5% to 10% of human gastric tumors harbor oncogenic mutations in the KRAS pathway, but their presence alone is often insufficient for inducing gastric tumorigenesis, suggesting a requirement for additional mutagenic events or microenvironmental stimuli, including inflammation. Assessing the contribution of such events in preclinical mouse models requires Cre recombinase–mediated conditional gene expression in stem or progenitor cells of normal and transformed gastric epithelium. We therefore constructed a bacterial artificial chromosome containing transgene (Tg), comprising the regulatory elements of the trefoil factor 1 (Tff1) gene and the tamoxifen-inducible Cre recombinase (CreERT2)–coding sequence. The resulting Tg(Tff1-CreERT2) mice were crossed with mice harboring conditional oncogenic mutations in Kras or Braf. The administration of tamoxifen to the resulting adult Tg(Tff1-CreERT2) KrasLSL-G12D/+ and Tg(Tff1-CreERT2) BrafLSL-V600E/+ mice resulted in gastric metaplasia, inflammation, and adenoma development, characterized by excessive STAT3 activity. To assess the contribution of STAT3 to the spontaneously developing gastric adenomas in gp130F/F mice, which carry a knockin mutation in the Il6 signal transducer (Il6st), we generated Tg(Tff1-CreERT2) Stat3fl/fl gp130F/F mice that also harbor a conditional Stat3 knockout allele and found that tamoxifen administration conferred a significant reduction in their tumor burden. Conversely, excessive Kras activity in Tg(Tff1-CreERT2) KrasLSL-G12D/+ gp130F/F mice promoted more extensive gastric inflammation, metaplastic transformation, and tumorigenesis than observed in Tg(Tff1-CreERT2) KrasLSL-G12D/+ mice. Collectively, our findings demonstrate that advanced gastric tumorigenesis requires oncogenic KRAS or BRAF in concert with aberrant STAT3 activation in epithelial precursor cells of the glandular stomach, providing a new conditional model of gastric cancer in which to investigate candidate therapeutic targets and treatment strategies. Cancer Res 76(8) 2277–87. ©2016 AACR.
Publisher: Impact Journals, LLC
Date: 28-12-2017
Publisher: EMBO
Date: 18-03-2020
Publisher: Springer Science and Business Media LLC
Date: 29-04-2023
DOI: 10.1038/S41388-023-02701-X
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a 5-year survival rate of %. Aberrant activation or elevated expression of the tyrosine kinase c-SRC (SRC) is frequently observed in PDAC and is associated with a poor prognosis. Preclinical studies have revealed a multifaceted role for SRC activation in PDAC, including promoting chronic inflammation, tumor cell proliferation and survival, cancer cell stemness, desmoplasia, hypoxia, angiogenesis, invasion, metastasis, and drug resistance. Strategies to inhibit SRC signaling include suppressing its catalytic activity, inhibiting protein stability, or by interfering with signaling components of the SRC signaling pathway including suppressing protein interactions of SRC. In this review, we discuss the molecular and immunological mechanisms by which aberrant SRC activity promotes PDAC tumorigenesis. We also provide a comprehensive update of SRC inhibitors in the clinic, and discuss the clinical challenges associated with targeting SRC in pancreatic cancer.
Publisher: Impact Journals, LLC
Date: 10-06-2015
Abstract: The hematopoietic cell kinase (HCK) is a member of the SRC family of cytoplasmic tyrosine kinases (SFKs), and is expressed in cells of the myeloid and B-lymphocyte cell lineages. Excessive HCK activation is associated with several types of leukemia and enhances cell proliferation and survival by physical association with oncogenic fusion proteins, and with functional interactions with receptor tyrosine kinases. Elevated HCK activity is also observed in many solid malignancies, including breast and colon cancer, and correlates with decreased patient survival rates. HCK enhances the secretion of growth factors and pro-inflammatory cytokines from myeloid cells, and promotes macrophage polarization towards a wound healing and tumor-promoting alternatively activated phenotype. Within tumor associated macrophages, HCK stimulates the formation of podosomes that facilitate extracellular matrix degradation, which enhance immune and epithelial cell invasion. By virtue of functional cooperation between HCK and bona fide oncogenic tyrosine kinases, excessive HCK activation can also reduce drug efficacy and contribute to chemo-resistance, while genetic ablation of HCK results in minimal physiological consequences in healthy mice. Given its known crystal structure, HCK therefore provides an attractive therapeutic target to both, directly inhibit the growth of cancer cells, and indirectly curb the source of tumor-promoting changes in the tumor microenvironment.
Publisher: MDPI AG
Date: 08-06-2021
Abstract: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a 5-year survival rate of less than 10%. Macrophages are one of the earliest infiltrating cells in the pancreatic tumor microenvironment, and are associated with an increased risk of disease progression, recurrence, metastasis, and shorter overall survival. Pre-clinical studies have demonstrated an unequivocal role of macrophages in PDAC by contributing to chronic inflammation, cancer cell stemness, desmoplasia, immune suppression, angiogenesis, invasion, metastasis, and drug resistance. Several macrophage-targeting therapies have also been investigated in pre-clinical models, and include macrophage depletion, inhibiting macrophage recruitment, and macrophage reprogramming. However, the effectiveness of these drugs in pre-clinical models has not always translated into clinical trials. In this review, we discuss the molecular mechanisms that underpin macrophage heterogeneity within the pancreatic tumor microenvironment, and examine the contribution of macrophages at various stages of PDAC progression. We also provide a comprehensive update of macrophage-targeting therapies that are currently undergoing clinical evaluation, and discuss clinical challenges associated with these treatment modalities in human PDAC patients.
Publisher: Research Square Platform LLC
Date: 24-10-2022
DOI: 10.21203/RS.3.RS-2180571/V1
Abstract: Although gastric cancer is a leading cause of cancer-related deaths, systemic treatment strategies remain scarce. Here, we report the pro-tumorigenic properties of the crosstalk between intestinal tuft cells and type 2 innate lymphoid cells (ILC2) that is evolutionarily optimized for epithelial remodeling in response to helminth infection. We demonstrate that tuft cell-derived interleukin 25 (IL25) drives ILC2 activation, inducing the release of IL13 and promoting epithelial tuft cell hyperplasia. While the resulting tuft cell - ILC2 feed-forward circuit promotes gastric metaplasia and tumor formation, genetic depletion of tuft cells or ILC2s, or therapeutic targeting of IL13 or IL25 alleviates these pathologies in mice. In gastric cancer patients, tuft cell and ILC2 gene signatures predict worsening survival in intestinal-type gastric cancer where ~40% of the corresponding cancers show enriched co-existence of tuft cells and ILC2s. Our findings suggest novel roles for ILC2 and tuft cells, along with their associated cytokine IL13 and IL25 as gatekeepers and enablers of metaplastic transformation and gastric tumorigenesis, thereby providing novel therapeutic vulnerabilities of for the treatment of these pathologies.
Publisher: Elsevier BV
Date: 03-2023
Publisher: Springer Science and Business Media LLC
Date: 28-10-2023
Publisher: American Association for the Advancement of Science (AAAS)
Date: 24-06-2022
Abstract: Although immunotherapy has revolutionized cancer treatment, many immunogenic tumors remain refractory to treatment. This can be largely attributed to an immunologically “cold” tumor microenvironment characterized by an accumulation of immunosuppressive myeloid cells and exclusion of activated T cells. Here, we demonstrate that genetic ablation or therapeutic inhibition of the myeloid-specific hematopoietic cell kinase (HCK) enables activity of antagonistic anti–programmed cell death protein 1 (anti-PD1), anti-CTLA4, or agonistic anti-CD40 immunotherapies in otherwise refractory tumors and augments response in treatment-susceptible tumors. Mechanistically, HCK ablation reprograms tumor-associated macrophages and dendritic cells toward an inflammatory endotype and enhances CD8 + T cell recruitment and activation when combined with immunotherapy in mice. Meanwhile, therapeutic inhibition of HCK in humanized mice engrafted with patient-derived xenografts counteracts tumor immunosuppression, improves T cell recruitment, and impairs tumor growth. Collectively, our results suggest that therapeutic targeting of HCK activity enhances response to immunotherapy by simultaneously stimulating immune cell activation and inhibiting the immunosuppressive tumor microenvironment.
Publisher: Elsevier BV
Date: 12-2023
Publisher: American Association for Cancer Research (AACR)
Date: 04-2020
DOI: 10.1158/2326-6066.CIR-19-0623
Abstract: Persistent activation of the latent transcription factor STAT3 is observed in gastric tumor epithelial and immune cells and is associated with a poor patient prognosis. Although targeting STAT3-activating upstream kinases offers therapeutically viable targets with limited specificity, direct inhibition of STAT3 remains challenging. Here we provide functional evidence that myeloid-specific hematopoietic cell kinase (HCK) activity can drive STAT3-dependent epithelial tumor growth in mice and is associated with alternative macrophage activation alongside matrix remodeling and tumor cell invasion. Accordingly, genetic reduction of HCK expression in bone marrow–derived cells or systemic pharmacologic inhibition of HCK activity suppresses alternative macrophage polarization and epithelial STAT3 activation, and impairs tumor growth. These data validate HCK as a molecular target for the treatment of human solid tumors harboring excessive STAT3 activity.
Publisher: Springer Science and Business Media LLC
Date: 28-05-2021
DOI: 10.1038/S41420-021-00505-0
Abstract: Malignant pleural mesothelioma (MPM) is an aggressive cancer with treatment limited to Cisplatin and Pemetrexed chemotherapy. Recently, we showed that drugs targeting the BCL-2-regulated apoptosis pathway could kill MPM cell lines in vitro, and control tumor growth in vivo. These studies showed BCL-XL was the dominant pro-survival BCL-2 family member correlating with its high-level expression in cells and patient tumor s les. In this study we show another inhibitor, AZD4320 that targets BCL-XL (and BCL-2), can also potently kill MPM tumor cells in vitro (EC 50 values in the 200 nM range) and this effect is enhanced by co-inhibition of MCL-1 using AZD5991. Moreover, we show that a novel nanoparticle, AZD0466, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer, was as effective as standard-of-care chemotherapy, Cisplatin, at inhibiting tumor growth in mouse xenograft studies, and this effect was enhanced when both drugs were combined. Critically, the degree of thrombocytopenia, an on-target toxicity associated with BCL-XL inhibition, was significantly reduced throughout the treatment period compared to other BCL-XL-targeting BH3-mimetics. These pre-clinical findings provide a rationale for the future clinical evaluation for novel BH3-mimetic formulations in MPM, and indeed, other solid tumor types dependent on BCL-XL.
Publisher: Springer Science and Business Media LLC
Date: 14-08-2017
DOI: 10.1038/NPHYS4208
Location: United States of America
Start Date: 2018
End Date: 2018
Funder: Austin Medical Research Foundation
View Funded ActivityStart Date: 2017
End Date: 2017
Funder: Cancer Council Victoria
View Funded ActivityStart Date: 2020
End Date: 2021
Funder: Jack Brockhoff Foundation
View Funded ActivityStart Date: 2019
End Date: 2019
Funder: Understanding Disease Research Focus Area Grant, La Trobe University
View Funded ActivityStart Date: 2019
End Date: 2023
Funder: National Health and Medical Research Council
View Funded ActivityStart Date: 2018
End Date: 2019
Funder: American Association For Cancer Research
View Funded ActivityStart Date: 2019
End Date: 2019
Funder: Cure Cancer Australia Foundation
View Funded Activity