A5009997754- Immune Cell Function and Interaction
- Single-cell and spatial transcriptomics
- Cancer Cells and Metastasis
- Microtubule and mitosis dynamics
- Cancer Genomics and Diagnostics
- IL-33, ST2, and ILC Pathways
- Cell Image Analysis Techniques
- Immunotherapy and Immune Responses
- Eosinophilic Disorders and Syndromes
- Eosinophilic Esophagitis
- Cancer Immunotherapy and Biomarkers
- Renal and related cancers
- Cancer-related molecular mechanisms research
- CAR-T cell therapy research
- Gene expression and cancer classification
- MicroRNA in disease regulation
- TGF-β signaling in diseases
- Acute Lymphoblastic Leukemia research
- Immune cells in cancer
- T-cell and B-cell Immunology
- Epigenetics and DNA Methylation
- Digestive system and related health
- Advanced Proteomics Techniques and Applications
- Chronic Myeloid Leukemia Treatments
- RNA modifications and cancer
Walter and Eliza Hall Institute of Medical Research
2017-2024
The University of Melbourne
2018-2024
Technical University of Munich
2023-2024
Helmholtz Zentrum München
2022-2024
Queensland University of Technology
2022
Rockefeller University
2020
Natural killer (NK) cell activity is essential for initiating antitumor responses and may be linked to immunotherapy success. NK cells other innate immune components could exploitable cancer treatment, which drives the need tools methods that identify therapeutic avenues. Here, we extend our gene-set scoring method singscore investigate infiltration by applying RNA-seq analysis samples from bulk tumors. Computational have been developed deconvolution of types within solid We taken gene...
Abstract The increasing availability of large-scale single-cell atlases has enabled the detailed description cell states. In parallel, advances in deep learning allow rapid analysis newly generated query datasets by mapping them into reference atlases. However, existing data transformations learned to map are not easily explainable using biologically known concepts such as genes or pathways. Here we propose expiMap, a informed deep-learning architecture that enables mapping. ExpiMap learns...
MicroRNAs (miRNAs) are important post-transcriptional regulators of gene expression, functioning in part by facilitating the degradation target mRNAs. They have an established role controlling epithelial-mesenchymal transition (EMT), a reversible phenotypic program underlying normal and pathological processes. Many studies demonstrate individual miRNAs using overexpression at levels greatly exceeding physiological abundance. This can influence transcripts with relatively poor targeting may...
Despite increasing recognition of the importance GM-CSF in autoimmune disease, it remains unclear how is regulated at sites tissue inflammation. Using fate reporter mice, we show that synovial NK cells produce autoantibody-mediated inflammatory arthritis. Synovial promote a neutrophilic cell infiltrate, and persistent arthritis, via production, as deletion cells, or specific ablation production abrogated disease. IL-18–dependent. Furthermore, cytokine-inducible SH2-containing protein (CIS)...
Abstract The recognition of the immune system as a key component tumor microenvironment (TME) led to promising therapeutics. Because such therapies benefit only subsets patients, understanding activities cells in TME is required. Eosinophils are an integral part especially mucosal tumors. Nonetheless, their role and environmental cues that direct largely unknown. We report breast cancer lung metastases characterized by resident recruited eosinophils. Eosinophil recruitment metastatic sites...
The increasing generation of population-level single-cell atlases has the potential to link sample metadata with cellular data. Constructing such references requires integration heterogeneous cohorts varying metadata. Here we present population level (scPoli), an open-world learner that incorporates generative models learn and cell representations for data integration, label transfer reference mapping. We applied scPoli on lung peripheral blood mononuclear cells, latter consisting 7.8...
KAT6A, and its paralog KAT6B, are histone lysine acetyltransferases (HAT) that acetylate H3K23 exert an oncogenic role in several tumor types including breast cancer where KAT6A is frequently amplified/overexpressed. However, pharmacologic targeting of to achieve therapeutic benefit has been a challenge. Here we describe identification highly potent, selective, orally bioavailable KAT6A/KAT6B inhibitor CTx-648 (PF-9363), derived from benzisoxazole series, which demonstrates anti-tumor...
Natural killer (NK) cells are innate lymphocytes that play a major role in immunosurveillance against tumor initiation and metastatic spread. The signals checkpoints regulate NK cell fitness function the microenvironment not well defined. Transforming growth factor-β (TGF-β) is suppressor of inhibits interleukin-15 (IL-15)-dependent signaling events increases abundance receptors promote tissue residency. Here, we showed express type I activin receptor ALK4, which, upon binding to its ligand...
Most cancer deaths are due to metastasis, and epithelial-to-mesenchymal transition (EMT) plays a central role in driving cell metastasis. EMT is induced by different stimuli, leading signaling patterns therapeutic responses. TGFβ one of the best-studied drivers EMT, many drugs available target this pathway. A comprehensive bioinformatics approach was employed derive signature for TGFβ-induced which can be used score TGFβ-driven cells clinical specimens. Considering pan-cancer tumor datasets,...
Interleukin (IL)-17–producing CD8+ T (Tc17) cells have emerged as key players in host-microbiota interactions, infection, and cancer. The factors that drive their development, contrast to interferon (IFN)-γ–producing effector cells, are not clear. Here we demonstrate the transcription factor TCF-1 (Tcf7) regulates cell fate decisions double-positive (DP) thymocytes through sequential suppression of MAF RORγt, parallel with TCF-1–driven modulation chromatin state. Ablation resulted enhanced...
Abstract B lymphoid development is initiated by the differentiation of hematopoietic stem cells into lineage committed progenitors, ultimately generating mature cells. This highly regulated process generates clonal immunological diversity via recombination immunoglobulin V, D and J gene segments. While several transcription factors that control cell V(D)J have been defined, how these processes are coordinated a precise regulatory network remains poorly understood. Here, we show factor ETS...
Chronic inflammation of the gastrointestinal (GI) tract contributes to colorectal cancer (CRC) progression. While role adaptive T cells in CRC is now well established, innate immune cells, specifically lymphoid (ILCs), not understood. To define ILCs we employed complementary heterotopic and chemically-induced mouse models. We discovered that were abundant tumours contributed anti-tumour immunity. focused on ILC2 showed ILC2-deficient mice developed a higher tumour burden compared with...
Abstract Intellectual disability (ID) and autism spectrum disorder (ASD) are the most common neurodevelopmental disorders characterized by substantial impairment in intellectual adaptive functioning, with their genetic molecular basis remaining largely unknown. Here, we identify biallelic variants gene encoding one of Elongator complex subunits, ELP2, patients ID ASD. Modelling mice recapitulates patient features, brain imaging tractography analysis revealing microcephaly, loss white matter...
Abstract Antibodies targeting “immune checkpoints” have revolutionized cancer therapy by reactivating tumor-resident cytotoxic lymphocytes, primarily CD8+ T cells. Interest in analogous pathways other lymphocytes is growing. Natural killer (NK) cells are key to immunosurveillance eradicating metastases and driving solid tumor inflammation. NK-cell antitumor function dependent on the cytokine IL15. Ablation of IL15 signaling inhibitor CIS (Cish) enhances immunity increasing metabolism...
Abstract Spatial omics technologies are increasingly leveraged to characterize how disease disrupts tissue organization and cellular niches. While multiple methods analyze spatial variation within a sample have been published, statistical computational approaches compare cell across samples or conditions mostly lacking. We present GraphCompass, comprehensive set of omics-adapted graph analysis quantitatively evaluate the arrangement cells in representing diverse biological conditions....
Abstract Improving survival outcomes in adult B-cell acute lymphoblastic leukemia (B-ALL) remains a clinical challenge. Relapsed disease has poor prognosis despite the use of tyrosine kinase inhibitors (TKIs) for Philadelphia chromosome positive (Ph+ ALL) cases and immunotherapeutic approaches, including blinatumomab chimeric antigen receptor T cells. Targeting aberrant cell pathways with selective small molecule BH3-mimetic BCL-2 (venetoclax, S55746), BCL-XL (A1331852), or MCL1 (S63845) is...
MiR-21 was identified as a gene whose expression correlated with the extent of metastasis murine mammary tumours. Since miR-21 is recognised being associated poor prognosis in cancer, we investigated its contribution to tumour growth and tumours capacity for spontaneous metastasis. Unexpectedly, found that suppression activity highly metastatic resulted regression primary immunocompetent mice but did not impede immunocompromised mice. Analysis immune infiltrate at time when started regress...
Abstract The increasing generation of population-level single-cell atlases with hundreds or thousands samples has the potential to link demographic and technical metadata high-resolution cellular tissue data in homeostasis disease. Constructing such comprehensive references requires large-scale integration heterogeneous cohorts varying capturing information. Here, we present population level (scPoli) , a semi-supervised conditional deep generative model for integration, label transfer...
Philadelphia chromosome–positive B cell acute lymphoblastic leukemia (B-ALL), characterized by the BCR::ABL1 fusion gene, remains a poor prognosis cancer needing new therapeutic approaches. Transcriptomic profiling identified up-regulation of oncogenic transcription factors ERG and c-MYC in B-ALL with required for murine human models. Profiling ERG- c-MYC–dependent gene expression analysis ChIP-seq data established coordinate regulatory network that controls genes involved several biological...
Abstract Multimodal analysis of single-cell samples from healthy and diseased tissues at various stages provides a comprehensive view that identifies disease-specific cells, their molecular features aids in patient stratification. Here, we present MultiMIL, novel weakly-supervised multimodal model designed to construct references prioritize phenotype-specific cells via classification. MultiMIL effectively integrates modalities, even when they only partially overlap, providing robust...
Abstract Targeted spatial transcriptomic methods capture the topology of cell types and states in tissues at single-cell subcellular resolution by measuring expression a predefined set genes. The selection an optimal probed genes is crucial for capturing signals present tissue. This requires selecting most informative, yet minimal, to profile (gene selection) which it possible build probes (probe design). However, current selections often rely on marker genes, precluding them from detecting...