ARDC Research Link Australia

ORCID Profile
Orcid icon. 0000-0001-5442-2805

Current Organisations
McMaster Institute for Health Equity , Medizinischen Fakultät, Eberhard Karls Universität Tübingen , Eberhard-Karls-Universität Tübingen Medizinische Fakultät

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Publications

Publication

GATA3 and MDM2 are synthetic lethal in estrogen receptor-positive breast cancers

Publisher: Springer Science and Business Media LLC

Date: 19-04-2022

DOI: 10.1038/S42003-022-03296-X

Abstract: Synthetic lethal interactions, where the simultaneous but not in idual inactivation of two genes is lethal to the cell, have been successfully exploited to treat cancer. GATA3 is frequently mutated in estrogen receptor (ER)-positive breast cancers and its deficiency defines a subset of patients with poor response to hormonal therapy and poor prognosis. However, GATA3 is not yet targetable. Here we show that GATA3 and MDM2 are synthetically lethal in ER-positive breast cancer. Depletion and pharmacological inhibition of MDM2 significantly impaired tumor growth in GATA3 -deficient models in vitro, in vivo and in patient-derived organoids/xenograft (PDOs/PDX) harboring GATA3 somatic mutations. The synthetic lethality requires p53 and acts via the PI3K/Akt/mTOR pathway. Our results present MDM2 as a therapeutic target in the substantial cohort of ER-positive, GATA3 -mutant breast cancer patients. With MDM2 inhibitors widely available, our findings can be rapidly translated into clinical trials to evaluate in-patient efficacy.

Publication

Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis

Publisher: Springer Science and Business Media LLC

Date: 06-2007

DOI: 10.1038/NATURE05883

Publication

The effects of meditation on individuals facing loneliness: a scoping review

Publisher: Springer Science and Business Media LLC

Date: 22-05-2021

DOI: 10.1186/S40359-021-00585-8

Abstract: Meditation is defined as a mind and body practice focused on interactions between the brain, mind, body, and behaviour, containing four key elements: a quiet location with little distractions, a comfortable posture, a focus of attention, and an open attitude. We sought to review the benefits of meditation on the alleviation of loneliness. A scoping review was conducted based on Arksey and O’Malley’s five-stage framework. Eligibility criteria included primary studies of any type that investigated the effects of meditation on loneliness. Search strategies were developed and conducted on MEDLINE, EMBASE, AMED, and CINAHL. The National Center for Complementary and Integrative Health, and American Psychological Association websites were also searched. Articles meeting the inclusion criteria were critically reviewed using a descriptive-analytical narrative method. Thirteen studies met our inclusion criteria and were published between 2012 and 2020 across 10 countries. Eleven studies reported improvements in relation to loneliness. Of the remaining two studies (15%), one mentioned the alleviation of loneliness, but only looked primarily at social closeness in lonely in iduals. The other study found a correlation between loneliness and nuclear factor (NF)-κB levels, which was the measured outcome however, the direct effects of meditation on loneliness were unclear. Three main themes emerged from our analysis, as follows: 1) positive results across all studies, 2) relatively small randomized control trials conducted over the last decade, and 3) lack of erse demographic information. While a small number of studies exist at this intersection, given all included studies indicated positive findings, the effects of meditation in alleviating loneliness are promising. Future research should be directed at understanding how meditation mitigates loneliness and how this intervention can impact practice for healthcare professionals.

Publication

Transition of Mesenchymal and Epithelial Cancer Cells Depends on α1-4 Galactosyltransferase-Mediated Glycosphingolipids

Publisher: American Association for Cancer Research (AACR)

Date: 31-05-2018

DOI: 10.1158/0008-5472.CAN-17-2223

Abstract: The reversible transitions of cancer cells between epithelial and mesenchymal states comprise cellular and molecular processes essential for local tumor growth and respective dissemination. We report here that globoside glycosphingolipid (GSL) glycosyltransferase-encoding genes are elevated in epithelial cells and correlate with characteristic EMT signatures predictive of disease outcome. Depletion of globosides through CRISPR-Cas9–mediated deletion of the key enzyme A4GALT induces EMT, enhances chemoresistance, and increased CD24low/CD44high cells. The cholera toxin–induced mesenchymal-to-epithelial transition occurred only in cells with functional A4GALT. Cells undergoing EMT lost E-cadherin expression through epigenetic silencing at the promoter region of CDH1. However, in ΔA4GALT cells, demethylation was able to rescue E-cadherin–mediated cell–cell adhesion only in the presence of exogenous A4GALT. Overall, our data suggest another class of biomolecules vital for epithelial cancer cells and for maintaining cell integrity and function. Significance: This study highlights the essential role of glycosphingolipids in the maintenance of epithelial cancer cell properties. Cancer Res 78(11) 2952–65. ©2018 AACR.

Publication

Prominent Oncogenic Roles of EVI1 in Breast Carcinoma

Publisher: American Association for Cancer Research (AACR)

Date: 13-04-2017

DOI: 10.1158/0008-5472.CAN-16-0593

Abstract: Overexpression of the EVI1 oncogene is associated typically with aggressive myeloid leukemia, but is also detectable in breast carcinoma where its contributions are unexplored. Analyzing a tissue microarray of 608 breast carcinoma patient specimens, we documented EVI1 overexpression in both estrogen receptor–positive (ER+) and estrogen receptor–negative (ER−) breast carcinomas. Here, we report prognostic relevance of EVI1 overexpression in triple-negative breast carcinoma but not in the HER2-positive breast carcinoma subset. In human breast cancer cells, EVI1 silencing reduced proliferation, apoptosis resistance, and tumorigenicity, effects rescued by estrogen supplementation in ER+ breast carcinoma cells. Estrogen addition restored ERK phosphorylation in EVI1-silenced cells, suggesting that EVI1 and estradiol signaling merge in MAPK activation. Conversely, EVI1 silencing had no effect on constitutive ERK activity in HER2+ breast carcinoma cells. Microarray analyses revealed G-protein–coupled receptor (GPR) signaling as a prominent EVI1 effector mechanism in breast carcinoma. Among others, the GPR54-ligand KISS1 was identified as a direct transcriptional target of EVI1, which together with other EVI1-dependent cell motility factors such as RHOJ regulated breast carcinoma cell migration. Overall, our results establish the oncogenic contributions of EVI1 in ER- and HER2-negative subsets of breast cancer. Cancer Res 77(8) 2148–60. ©2017 AACR.

Publication

Oncogenic KrasG12D causes myeloproliferation via NLRP3 inflammasome activation

Publisher: Springer Science and Business Media LLC

Date: 03-04-2020

DOI: 10.1038/S41467-020-15497-1

Abstract: Oncogenic Ras mutations occur in various leukemias. It was unclear if, besides the direct transforming effect via constant RAS/MEK/ERK signaling, an inflammation-related effect of KRAS contributes to the disease. Here, we identify a functional link between oncogenic Kras G12D and NLRP3 inflammasome activation in murine and human cells. Mice expressing active Kras G12D in the hematopoietic system developed myeloproliferation and cytopenia, which is reversed in Kras G12D mice lacking NLRP3 in the hematopoietic system. Therapeutic IL-1-receptor blockade or NLRP3-inhibition reduces myeloproliferation and improves hematopoiesis. Mechanistically, Kras G12D -RAC1 activation induces reactive oxygen species (ROS) production causing NLRP3 inflammasome-activation. In agreement with our observations in mice, patient-derived myeloid leukemia cells exhibit KRAS/RAC1/ROS/NLRP3/IL-1β axis activity. Our findings indicate that oncogenic KRAS not only act via its canonical oncogenic driver function, but also enhances the activation of the pro-inflammatory RAC1/ROS/NLRP3/IL-1β axis. This paves the way for a therapeutic approach based on immune modulation via NLRP3 blockade in KRAS-mutant myeloid malignancies.

Publication