Dr Ralitsa Madsen - Cell State Control of Oncogenic Signalling

Introduction

Ralitsa Madsen

The Madsen Lab is dedicated to a systems understanding of signalling plasticity within the growth-promoting phosphoinositide 3-kinase (PI3K) signalling pathway. Our work is inspired directly by observations from human disorders such as cancer and PIK3CA-related overgrowth spectrum (PROS). Over the last five years, we uncovered previously unappreciated allele dose-dependent effects of PIK3CA mutations in human pluripotent stem cells and cancer. Recently, we also developed a versatile single-cell experimental framework for studies of quantitative, PI3K-dependent information transfer, demonstrating for the first time that the most frequent oncogenic PIK3CA mutation, PIK3CAH1047R, is not a simple ON switch of the pathway as commonly assumed. Instead, PIK3CAH1047R corrupts the ability of cells to resolve the identity of different growth factors, akin to “blurred” signal transfer. Supported by a UKRI Future Leaders Fellowship and CRUK funding, we now seek to develop context-dependent and therapeutically predictive PI3K signalling maps by leveraging state-of-the-art quantitative technologies (mass cytometry, scRNAseq, live-cell imaging), computational modelling and novel experimental systems for controllable expression of pathological PIK3CA variants in disease-relevant contexts.

 

Prof Ramanuj DasGupta - Cancer Systems Biology and Tumour Evolution

Introduction

Ram DasGupta

Unlocking the Developmental Origins of Cancer

Cancer remains one of the most complex, and devastating diseases of our time, characterized by its ability to evade treatment and adapt to an ever-changing biological landscape with diverse selective pressures. At the forefront of this challenge, our laboratory is pioneering the use of next-generation single-cell and spatial biology tools, paired with functional genomic technologies and relevant murine models, to unravel the developmental origins of cancer. Specifically, we investigate how damage-associated regenerative programs, activated in the context of chronic inflammatory diseases (fatty liver/MASLD, viral hepatis, colitis, IBD) contribute to cancer initiation and progression.

The Origins of Cancer: A Crossroads of Regeneration and Dysfunction

Recent work from our laboratory and others has elucidated remarkable foetal-like, developmental remodelling of the tumour microenvironment (TME) in human hepatocellular carcinoma (HCC) (Sharma et al., 2020, Cell; Nguyen et al., 2022, Nature Communications). Our current research is rooted in understanding how chronic inflammation, a hallmark of diseases such as colitis, chronic hepatitis, or pancreatitis, can activate similar developmental programs to establish a “pro-tumourigenic niche” or a fertile soil for tumourigenesis (Balakrishnan et al., 2024, Journal of Hepatology; Cappellesso et al., 2022, Nature Cancer; Scolaro et al., 2024, Nature Cancer). Using advanced single-cell and spatial biology tools (single cell RNA-seq, scATAC-seq, spatial transcriptomics, proteomics and metabolomics, and multi-parametric flow cytometry), we study the cellular and molecular mechanisms underlying this transition from chronic inflammatory “non-healing wounds” to cancer. Finally, our understanding of the molecular mechanisms of cross-regulatory interactions between tumour cells and their ecosystem is paving the way for innovative therapeutic approaches that we, in close collaborations with clinicians, are implementing as part of clinical trials aimed at interrogating the efficacy of combining drugs targeting the tumour microenvironment or tumour stroma (eg. anti-angiogenics) along with immune checkpoint inhibitors (Chong et al., 2025, Lancet Oncology). 

legendlocalizing cell types and cell states to their spatial coordinates in NPC
Cells to location: localizing cell types and cell states to their spatial coordinates in NPC

A Focus on Co-Evolutionary Mechanisms in the Tumour Microenvironment

Cancers do not evolve in isolation. It emerges and thrives in the context of its microenvironment, engaging in dynamic cross-regulatory interactions with surrounding cells. Our work centres on uncovering these co-evolutionary mechanisms that shape tumour initiation, tissue remodelling, and progression.

Key areas of focus include:

  • Endothelial Dysfunction: Endothelial cells play a critical role in maintaining vascular integrity and regulating tissue homeostasis. In chronic inflammation, persistent endothelial dysfunction can promote abnormal angiogenesis, hypoxia, and endothelial anergy, fostering tumour growth and metastasis.
  • Fibrosis: Fibroblasts, activated during tissue repair, can become cancer-associated fibroblasts (CAFs) that contribute to a fibrotic tumour microenvironment. This fibrosis not only supports tumour growth but also serves as a barrier to effective drug delivery, or immune-cell infiltration, making tumours more resistant to treatment.
  • Immune Dysregulation: Chronic inflammation disrupts immune homeostasis, leading to immune suppression and the recruitment of tumour-promoting immune cells, such as pro-remodelling macrophages and regulatory T cells (Tregs). By studying how tumours exploit immune-stromal interactions, we aim to identify new therapeutic strategies targeting the tumour ecosystem to restore immune balance.

Approach: Bridging Technologies to Decode Tumour Evolution

Our laboratory employs an integrated approach, leveraging cutting-edge single cell and spatial multi-Omics technologies to study mechanisms of damage-associated chronic disease progression to cancer:

  • Single-Cell Analysis: Tools like single-cell RNA sequencing (scRNA-seq, ATAC-seq) allow us to dissect cellular heterogeneity of disease-associated cell states (DACs) within tumours and their microenvironments, as well as gene regulatory networks and signalling pathways that specify the transcriptomic signatures of DACs
  • Spatial Biology: Advanced imaging technologies enable us to visualize the geo-spatial organization and cellular interactions within tissue architecture, capturing the spatial dynamics of DACs or tumour cells with their ecosystem, including endothelial cells, fibroblasts and immune cells.
  • Functional Genomics: CRISPR-based screens and drug libraries in relevant murine and patient-derived cell line/organoid models enable the identification of genes and pathways that drive tumour evolution, offering insights into potential therapeutic vulnerabilities.

image005

Spatial organization of individual cell type within a tumour (left); spatial distribution of distinct neighbourhoods of interacting cells (niches) identified within tumour biopsies

From Discovery to Clinical Translation

Our ultimate goal is to translate these discoveries into tangible clinical benefits. By understanding the developmental origins of cancer and the role of co-evolutionary mechanisms, we aim to:

  • Identify early biomarkers that predict tumour initiation and progression.
  • Develop preventative therapies targeting the regenerative programs (especially those targeting the tissue/tumour ecosystem) that are hijacked during chronic inflammation.
  • Create strategies to disrupt tumour-immune-stromal cross-regulatory interactions in order to prevent tumour progression into treatment-resistant, metastatic disease.

A Vision for the Future

The intersection of inflammation, chronic disease and cancer provides a unique opportunity to address some of the most pressing questions in oncology. By integrating next-generation single-cell and spatial biology tools with functional genomics/validation in preclinical models, we are not only uncovering the fundamental mechanisms driving cancer but also paving the way for innovative therapeutic approaches. Our laboratory remains committed to advancing this field, with the hope that our work will lead to earlier interventions and improved outcomes for patients battling cancer. Stay tuned as we continue to push the boundaries of cancer research and move closer to a future where precision medicine transforms the landscape of oncology.

 

 

 

Dr Johan Vande Voorde - Metabolic Crosstalk in Cancer

Introduction

Johan Vande Voorde

Cancer is a multifactorial disease with widespread effects on patients’ health. Cancer cells undergo metabolic rewiring to sustain continued proliferation and to survive in hostile environments. This includes alterations in the uptake and utilization of nutrients and metabolites. As such, the tumour microenvironment is important for metabolite supply to cancer cells and the presence of a tumour affects the normal function of its host organ. In addition, cancer is associated with systemic metabolic changes that can dramatically impact quality of life for patients and their fitness to undergo treatments. Research in our laboratory focuses on metabolic crosstalk between the host and tumours, ultimately aiming to develop new, more efficient therapies.

Our current areas of focus are:

  1. Metabolic implications of the gut microbiome in cancer

Gut microbiome dysbiosis is associated with various malignancies and this has implications for cancer onset, progression and therapy sensitivity. We study metabolic interactions between microbiota and host cells using preclinical cancer models and patient samples. Because of its unique association with the gut microbiome, we have a particular interest in colorectal cancer.

  1. Metabolic determinants of cancer-associated cachexia

Cancer cachexia is a wasting syndrome defined by ongoing loss of skeletal muscle mass, with or without loss of fat mass, which cannot be restored by conventional nutritional support. At present, there is no cure and the underlying mechanisms of this debilitating condition are poorly understood. We use advanced preclinical models to study cachexia and identify underlying metabolic mechanisms.

Other funding:

CRUK CRUK Scotland Centre MRC NMGN
BCC Logo CRHlogo

 

 

Prof Laura Greaves - Mitochondrial Genetics in Cancer

Introduction

Laura Greaves

Mitochondria are essential intracellular metabolic hubs, performing numerous crucial roles in bioenergetics and cellular biosynthesis. Alterations in mitochondrial metabolism are well-established hallmarks of both ageing and cancer. Age remains the greatest risk factor for many cancer types, prompting important questions about whether age-associated mitochondrial dysfunction directly influences cancer development. Our work investigates this link, particularly through somatic mutations in the mitochondrial DNA (mtDNA), a feature commonly observed in both ageing tissues and cancer cells.

We focus on the role of mtDNA mutations in colorectal cancer pathogenesis. These mutations are prevalent in both normal human colonocytes and colorectal tumours and can lead to altered mitochondrial function. This suggests that mtDNA mutations and consequent metabolic changes may act as early modulators of colorectal cancer development and progression. To interrogate these mechanisms, we employ state-of-the-art preclinical models combining key oncogenic nuclear drivers with relevant mtDNA mutations. This approach enables us to interrogate the molecular mechanisms by which mitochondrial dysfunction influences colorectal cancer progression, metastasis, and response to therapy.

Cell scientist to watch - Laura Greaves | Journal of Cell Science | The Company of Biologists

 

Funding:

Newcastle University Newcastle University MRC NMGNCRUK LifeArc Centre logo

 

 

Prof Srikala Raghavan - Epithelial Homeostasis and Immune Regulation at Barrier Surfaces

Introduction

LeQuesne John

The mammalian skin is an excellent model system to functionally interrogate fundamental cell biological processes required for epithelial homeostasis. The intricate and dynamic relationship between cell adhesion, migration, and basement membrane organisation, in the context of the local immune microenvironment, is critical to normal skin development and healthy tissue function. Gaining insight into the complex interplay between these processes allows us to understand how they go awry in pathological conditions such as inflammatory skin disorders and cancer.

Our work is organized into two major research programs:

1. Epithelial-Immune Metabolic Crosstalk and Inflammatory Skin Diseases. This program focuses on understanding the crosstalk between epithelial cells, immune cells, and the extracellular matrix (ECM) in maintaining homeostasis and exploring the metabolic drivers of inflammatory skin diseases and cancer. 

Epithelial Immune Metabolic Crosstalk and Inflammatory Skin Diseases Image

2. Stem Cell Homeostasis and Nuclear Mechanosensing. This program focuses on understanding the mechanical underpinning of the crosstalk between the ECM and cell junctions with the cytoskeleton and nucleus in maintaining stem cell quiescence and the role altered nuclear mechanotransduction in driving diseases such as metastatic cancers.  

Stem Cell Homeostasis and Nuclear Mechanosensing Image

 

 

  1. Dr Philip Dunne - Phenotypic Plasticity in Colorectal Cancer
  2. Dr Ke Yuan - AI for Cancer Research
  3. Dr Maximiliano Portal - Cell Plasticity & Epigenetics
  4. Dr Xiao Fu - Integrative Modelling

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