LMTK3 AND CANCER
LMTK3 AND CANCER
LMTK3 (Lemur Tail Kinase 3), has emerged as a critical player in cancer progression and therapeutic resistance in breast cancer as well as in other malignancies. Initially identified through a kinome-wide siRNA screen, LMTK3 was found to regulate estrogen receptor-alpha (ERα) activity, a key driver in hormone-responsive breast cancers. Beyond ERα modulation, LMTK3 influences multiple signalling pathways that promote tumour survival and metastasis. High LMTK3 expression in breast cancer correlates with poor prognosis, disease recurrence, and resistance to therapies like tamoxifen as well as chemotherapy, positioning it as both a prognostic marker and therapeutic target.
The Giamas lab has been pivotal in elucidating LMTK3’s oncogenic roles. Our seminal 2011 study revealed LMTK3’s evolutionary significance in humans and its functional link to ERα signalling, establishing it as a novel therapeutic target. Subsequent work by our team demonstrated LMTK3’s dual role in cancer: extracellularly, it enhances tumour microenvironment interactions, while nuclear LMTK3 suppresses tumour-suppressive genes, exacerbating malignancy.
We have also solved the crystal structure of LMTK3 kinase domain and have identified a novel, potent LMTK3 inhibitor that confers cytotoxic & antitumor effects. Our ongoing research focuses on identifying LMTK3-associated biomarkers in liquid biopsies and targeting its signalling pathways, aiming to translate these findings into clinical applications.
In aggregate, by integrating molecular, clinical, and evolutionary insights, our work has advanced the understanding of LMTK3’s multifaceted roles in cancer, offering new avenues for precision oncology. These efforts underscore LMTK3’s prospect as a therapeutic target in cancer and therefore the development of oral LMTK3 inhibitors may have the potential for broad clinical use, either as monotherapy or as a combinational therapy.
01
GLIOBLASTOMA
GLIOBLASTOMA
Glioblastoma (GBM) is the most aggressive primary brain tumour, characterised by rapid proliferation, extensive infiltration into brain tissue, and resistance to therapies like temozolomide (TMZ) and radiation. Its lethality stems from inter- and intratumoral heterogeneity, driven by glioblastoma stem cells (GSCs) and dynamic interactions with the tumour microenvironment (TME). Despite advances in understanding TME complexity and engineered biomaterial models mimicking brain extracellular matrix (ECM), GBM prognosis remains poor, with median survival under 15 months.
Our lab has identified extracellular vesicles (EVs) as key mediators of GBM cell communication and potential diagnostic tools. By isolating and analysing EVs in patients’ blood, we have demonstrated elevated levels in GBM patients compared to healthy individuals and identified a comprehensive multi-omics/spectral plasma EVs biomarker signature, proposing non-invasive liquid biopsies to detect tumour-specific biomarkers, which could replace invasive brain biopsies. This work, further underscores EVs' role in tumour progression and their utility in personalised therapy.
In addition to the EV-based liquid biopsies, our lab focuses on the identification of druggable targets within the GBM TME aiming to translate findings into clinical applications.
In summary, our innovative approaches offer promising avenues for early GBM detection and therapeutic monitoring. By bridging molecular insights with clinical tools, our projects address critical gaps in managing this devastating disease.
02
TUMOUR MICROENVIRONMENT
TUMOUR MICROENVIRONMENT
The tumour microenvironment (TME) is a dynamic ecosystem critical to cancer progression, comprising malignant cells, stromal components (e.g., fibroblasts, immune cells), extracellular matrix (ECM), and signalling molecules. This complex network facilitates tumour growth, immune evasion, metastasis, and therapy resistance by creating a supportive niche. Hypoxia and metabolic reprogramming further shape the TME, driving epithelial-mesenchymal transition (EMT) and resistance to therapies such as chemotherapy and immunotherapy. Additionally, extracellular vesicles (EVs) mediate crosstalk between tumour cells and the TME, transferring oncogenic cargo that enhances drug resistance and immune suppression in breast cancer.
Our lab has contributed to understanding how tumour cells manipulate their microenvironment through exosomal communication and kinase-driven pathways, areas critical for developing therapies targeting TME-mediated resistance. Moreover, we have previously identified fibroblast-expressed PIK3Cδ (f-PIK3Cδ) as a key regulator of triple negative breast cancer (TNBC) progression, which supports the rationale for clinical use of PIK3Cδ inhibitors for the treatment of TNBC.
In summary, the TME’s multifaceted role in cancer underscores the need for therapies targeting both tumour and stromal components.
03
EXTRACELLULAR VESICLES & CANCER
EXTRACELLULAR VESICLES & CANCER
Extracellular vesicles (EVs)—nanoscale particles released by cells—play pivotal roles in cancer progression by mediating intercellular communication, modulating the tumour microenvironment (TME), and promoting metastasis, drug resistance, and immune evasion. EVs transport bioactive cargo such as proteins, lipids, and nucleic acids, including non-coding RNAs (ncRNAs), which regulate oncogenic pathways and stromal interactions. In breast cancer.
Our work to date on GBM underscores EVs as reservoirs of tumour-specific biomarkers, which correlate with aggressive subtypes and patient survival. By analysing EV proteomic profiles, we have demonstrated that GBM-derived EVs reflect cellular heterogeneity, offering a liquid biopsy tool to improve diagnosis and monitor treatment responses. This aligns with the lab’s broader focus on EVs in cancer progression and their clinical utility.
In another study, we revealed that GBM cells internalise the anti-angiogenic drug bevacizumab and shed it via EVs, effectively reducing drug bioavailability and fostering therapy resistance. This discovery highlights EVs as mediators of therapeutic escape and suggests targeting EV biogenesis to enhance treatment efficacy. Our research further links EV cargo alterations to pro-tumoral signalling, emphasising EVs’ role in reshaping the TME. By bridging EV biology with clinical applications, our work paves the way for innovative strategies to disrupt tumour-EV crosstalk, mitigate resistance, and improve patient outcomes.
In summary, EVs are central to cancer biology, and our lab’s contributions—spanning biomarker discovery, therapeutic resistance mechanisms, and EV-driven TME modulation—have profoundly enriched our understanding of their clinical potential. Our research underscores the need for EV-targeted therapies to complement conventional treatments, offering hope for more effective cancer management.
04
SPATIAL PROTEOMICS
SPATIAL PROTEOMICS
Spatial biology is a transformative field that integrates high-resolution molecular analysis with tissue architecture to map cellular interactions and heterogeneity within complex biological systems. Central to this is spatial proteomics, which investigates the spatial distribution, dynamics, and functional networks of proteins in tissues, offering unprecedented insights into disease mechanisms and therapeutic targets.
Unlike traditional proteomics, spatial proteomics combines advanced techniques such as fluorescence-based imaging and mass spectrometry to preserve spatial context while quantifying protein expression and interactions. These methods are particularly valuable in cancer research, where tumour microenvironments (TMEs) exhibit intricate cellular diversity and spatial organization that drive progression and therapy resistance.
Our lab uses state-of-the-art, spatial proteomics technologies (e.g. PhenoCycler-Fusion 2.0; AKOYA Biosciences), to unravel intra-tumoral heterogeneity and TME complexity, highlighting how spatial profiling can identify rare cell states and TME-based subtypes, enabling biomarker discovery and resistance mechanism analysis.
In summary, spatial proteomics is revolutionising our understanding of diseases by contextualising molecular data within tissue architecture. offering new avenues for targeted interventions, while enhancing diagnostic precision and personalised treatment strategies.
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PROTEIN KINASES & CANCER
PROTEIN KINASES & CANCER
Protein kinases and phosphatases are central regulators in cellular activities and perturbations of their signalling —through mutations, amplifications, or epigenetic alterations—drives oncogenesis by promoting uncontrolled proliferation, survival, and metastasis. Our work to date has advanced understanding of understudied kinases (e.g. LMTK3, KSR1, PANK4) in cancer progression.
The elucidation of novel signalling pathways has transformed cancer research by revealing mechanisms underlying tumour heterogeneity, immune evasion, and therapeutic resistance. Identifying these pathways uncovers biomarkers for early detection and prognostication, as well as druggable targets for precision therapies. Furthermore, understanding signalling crosstalk and compensatory mechanisms is critical to overcoming drug resistance. Advances in multi-omics and single-cell technologies now enable dynamic mapping of signalling flux, offering unprecedented insights into tumour evolution and adaptive responses.
By implementing a variety of molecular, cellular and biochemical techniques along with established in vitro/in vivo models and patients' specimens our lab studies relevant pathways in different cancers, including breast, lung, colon, prostate and others.
Ultimately, by bridging molecular mechanisms with clinical applications, our research exemplifies how targeting specific genes/proteins can unveil novel therapeutic avenues, ultimately enhancing precision oncology approaches.
