Invasion and Metastasis

Introduction

Carlin head

Paradoxically, the immune system can both benefit and antagonise the growth of cancer. Therefore, understanding how the cells of the immune system interact with the cancer microenvironment is of crucial importance. In their updated seminal review 'Hallmarks of Cancer: The Next Generation', Hanahan and Weinberg underline the importance of 'Avoiding immune destruction' and 'Tumour-promoting inflammation' to cancer biology. The immune cell compartment of cancer is composed of tissue resident immune cells and leukocytes that infiltrate from the circulation. The development of the cancer immune environment is inherently dynamic and the processes that regulate immune cell recruitment and function are not well understood. In recent years, the field has discovered that immune cells play roles in initiation of primary tumours, tumour maintenance and growth, and in aiding cancer metastasis. Recent success in directing and strengthening the immune system's anti-cancer functions (e.g. Tumour Infiltrating Lymphocyte; TIL therapy and immune check-point inhibition) highlight the potential for new therapies that can come from better understanding of how leukocytes are (dys)regulated in inflammation and cancer. However, current tumour immunotherapy strategies do not work for all patients or cancers.

Left: 3D imaging of lung adenocarcinoma. Tumour (green), large blood vessels (red), bronchioles (magenta), perivascular space (yellow). Right: neutrophils in the vasculature of the lung

 Carlin image 2018 Neutrophils

We aim to better understand the immune system's role at the sites of primary tumour development and at the sites of cancer metastasis. All tumours have some influence on the local vasculature, either modifying it to meet their own needs or using it as a route to spread throughout the body. This has important consequences for our understanding of how the cells of the immune interact with the vasculature. Since it was first studied by microscopy more than 120 years ago, leukocyte extravasation has been refined in molecular detail in the post-capillary vessels, the major sites of immune cell infiltration in many (but, importantly, not all) anatomic sites. The way that leukocytes interact with the specialised vasculature of the lung, spleen, bone marrow, tumour co-opted vasculature and tumour neovasculature are relatively understudied often due to the technical difficulties of imaging some of these vascular beds. Due to the heterogeneity of the vasculature, these are exactly the areas that are least likely to fit the paradigms of leukocyte adhesion and transmigration established in the post-capillary venules. More recently, several innovative techniques have been developed to address these specialised sites by microscopy. This has helped to further investigate mechanisms of immune cell regulation, e.g. showing how immune cells interact with each other at sites of infection or injury to allow fine-tuning of the immune response and a greater portfolio of immune functions to be achieved. Therefore, a thorough examination of the localisation and regulation of leukocytes in situ is a clear unmet need to understand the fundamental mechanisms underlying onco-immunology.

We use advanced light microscopy in combination with other experimental approaches (flow cytometry, proteomics, transcriptomics) to better understand how the regulation of leukocyte dynamics contributes to the tumour environment in the context of both 'avoiding immune-destruction' and 'tumour-promoting inflammation'. Recent data point to multiple levels of immune regulation in cancer development and progression that parallel or redirect pathways that also mediate immune cell homeostasis and inflammation. Our overarching goal is to better understand how cancer evades and exploits the fundamental mechanisms of immune regulation and use this information to uncover new or better therapeutic strategies.

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Introduction

Norman head 051

Integrins are cell adhesion receptors involved in mediating the invasive migration, growth and metastasis of cancer cells. Data from our lab and our collaborators has established that Rab-regulated integrin trafficking contributes to cancer cell migration.

Indeed, we have now obtained detailed descriptions of the molecular machinery of integrin transport and determined how this contributes to invasive migration of cancer cells through three-dimensional matrices.

Furthermore, we have identified components of the cell's machinery for processing and transporting mRNA that make key contributions to cancer cell invasion. We are currently evaluating the molecular components of these novel pathways as potential targets for anti-cancer therapy and patient screening strategies.

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Introduction

SansomO

Colorectal cancer (CRC)—the third most common cancer in the UK and the second leading cause of cancer mortality—is a heterogeneous disease comprising distinct molecular subgroups that differ in their histopathological features, prognosis, and response to therapy. Despite advances in the detection and treatment of early-stage disease, patients with advanced, recurrent, or metastatic CRCs have few therapeutic options and a dismal prognosis. Utilising state-of-the-art preclinical models harbouring key driver mutations, our group is interrogating the molecular mechanisms underpinning CRC initiation, progression, response to therapy, and metastasis. Our overarching goals are to identify early-stage diagnostic biomarkers and develop stage- and subtype-specific targeted therapies.
As part of these efforts, we are major contributors to a number of large cancer consortia, with the aim of driving more effective therapeutic approaches in colorectal cancer. Our group leads a Europe-wide, CRUK-funded consortium of basic, translational, and clinical scientists (ACRCelerate—Colorectal Cancer Stratified Medicine Network) to identify new therapeutic targets for the different CRC subtypes and deliver molecular insights with the potential to inform clinical decision-making and patient stratification. Similarly, through participation in the CRUK Grand Challenge Rosetta consortium, we are working to therapeutically exploit the altered metabolic dependencies of oncogene-addicted CRCs, and determine how distinct tumour metabolic profiles can confer resistance or predict sensitivity to standard-of-care or novel targeted therapies. Moreover, as a key contributor to the CRUK Grand Challenge SpecifiCancer consortium, we are employing transcriptional, epigenetic, and proteomic approaches to understand why there are tissue- and cell type-specific differences in the response to oncogenic mutations, with the aim of developing methods to suppress the impact of these mutations in cancer.
In addition, we are partnering with a number of leading industry innovator to accelerate the path from bench to bedside. For example, in partnership with Novartis, we are working towards the development of novel KRAS inhibitors, to address a pressing clinical need in colorectal cancer.

Want to find out more about Professor Sansom's work?

Read about his 2009 Nature paper on the CRUK science blog and listen to him talking about bowel cancer stem cells.

See a Google Hangout on the subject of red meat and cancer featuring Owen Sansom and Kathryn Bradbury from the University of Oxford: https://www.youtube.com/watch?v=jS1QW74wJRw​

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Introduction

Zanivan 2023

Discovery Research

Cancer associated fibroblasts (CAFs) have emerged as a promising therapeutic target in cancer because it is now well established that they actively contribute to tumour pathology. CAFs are a unique cell type in that they are highly secretory, and their secretome dictates the structure of a tumour and influences the behaviour of cancer cells and other cell types.
With our research we want to understand the molecular mechanisms through which CAFs alter the tumour microenvironment (TME) to influence cancer aggressiveness and resistance to therapy.

 Zanivan research1

High-grade serous ovarian cancer and triple negative breast cancer are the major focus of our research because there are limited therapies against the cancer cells of these tumour types. However, CAFs are highly abundant in these tumours, and our overarching goal is to find ways to target CAFs in combination with other anti-cancer therapies to improve survival of cancer patients.

In the last few years, our work has described unprecedented ways through which CAFs create a TME that supports tumour invasion and metastasis by altering the structure of the extracellular matrix (ECM), and tumour blood vessels' and cancer cells' functions. A major focus of our on-going research is the metabolism of CAFs. We have found that cell metabolism is a major epigenetic regulator of CAF functions and that it can influence the translation of pro-tumorigenic ECM proteins. Our on-going research aims to investigate these aspects further and to understand how targeting specific metabolic pathways affects the composition and structure of the ECM and the immune-TME, and whether it can be exploited to halt cancer progression and improve effectiveness of conventional therapeutic treatments.

Our research is unique in that we mostly work with patient-derived cells that we generate in the lab from tissues that patients kindly donate to research. We also work with pre-clinical models relevant for ovarian and breast cancer. Moreover, because of our established expertise in mass spectrometry (MS)-proteomics, we develop tailored technology to study CAF biology, including their crosstalk signalling with other cell types in co-cultures in vitro and their metabolism in vivo.

Clinical Research

Recently, we have joined the effort to improve early detection of cancer in patients, since detecting cancer at an early stage can dramatically increase opportunities for curative intervention. To tackle this challenge, we are developing novel MS proteomic-based technology for biomarker discovery in body fluids. This research is funded by the CRUK Early Detection and Diagnosis Research scheme.

Zanivan research2

This research is funded by the Stand Up to Cancer campaign for Cancer Research UK

SU2C-logo

Video 1 Video 2

 

Introduction

Bryant head 012

Our lab focuses on a fundamental, yet largely unanswered question: How is the normal organisation of tissue disrupted to allow cells to form disarrayed tumours?

Cells of many tissues are polarised. That is that cells collectively form configurations tailored to the needs of a tissue. During tumourigenesis this exquisite organisation is lost. Despite the loss of tissue polarity being an obligate event in cancer progression, we know little about this basic process.

 

bryant model of polarity

We use mini-avatars of tumours ex vivo to understand how cells collectively organise. Our efforts are focused on colorectal and prostate cancers. We take two approaches to unravel the complexity of this process:
1) building new tools to analyse tumour avatars ex vivo, and
2) identifying the signalling processes that drive collective tumour invasion and metastasis. We collaborate extensively for a multi-disciplinary approach to understand tumour metastasis (Sansom, Zanivan, Blyth, Leung, Miller Labs @ CRUK Scotland Institute).

To develop better tools to understand how tumour cells loos polarity, we have developed cutting-edge, high-content microscopy and computational image analysis of tumour spheroids and organoids, live-imaging how normal cells become tumours. Molecularly, we focus on two pathways: phosphoinositide signalling (including the kinases and phosphatases that produce them, and master regulatory of their function: the ARF GTPases ), and the role of the metastasis-promoting sialomucin, Podocalyxin. We are particularly interested in how these participate in metastasis.

Our ultimate aim is to investigate such changes in cell polarity as potential future biomarkers of cancer in patients, and possible targets for future therapeutic interventions.

Cell scientist to watch − David Bryant

Click here to read David's interview with the Journal of Cell Science.


University of Glasgow webpage

Google Scholar Account

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Introduction

Coffelt head 20202 078

Understanding how cancer spreads from its primary site of origin to distant organs is one of the major challenges in cancer research. What has become evident in recent years is that mutations in cancer cells are not sufficient to drive metastasis formation – cancer cells need assistance from surrounding healthy cells. Among these various healthy cells, immune cells have emerged as powerful instigators of metastasis formation but, at the same time, immune cells can also prevent cancer cells from spreading.

Our lab focuses on these dichotomous roles of immune cells and how tumours control immune cell behaviour. We study these concepts in the context of breast, pancreatic and colorectal cancers. We are particularly interested in γδ T cells, a rare population of T cells with properties that are distinct from conventional CD4 and CD8 T cells, as γδ T cells can be both pro-tumourigenic and anti-tumourigenic. Our ultimate goal is to understand how γδ T cells and other immune cells participate in the metastatic process and to develop new immunotherapies that counteract metastatic lesions.

Researchers discover key to 'supercharging' breast cancer treatment

Find out more about Seth's recent research in this article by STV News here.

Young Glasgow ovarian cancer survivor speaks out about life after the disease

Read the story from the Evening Times here.

Glasgow doctor reveals why he has taken on the city's fight against cancer

Read about Seth's background and move to Glasgow here.

 
 
 
 
 
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Introduction

Morton head 2020 092

Every year around 340,000 people die of pancreatic cancer worldwide, and by 2030 pancreatic cancer is predicted to be the second commonest cause of cancer death in the western world. Most patients present too late for surgery, with aggressive invasive or metastatic disease. Furthermore, current chemotherapies offer little benefit, so we urgently need to better understand the disease and identify better options for clinicians and patients.

To do this, we model different genetic subsets of the disease in genetically engineered models. These models mimic human tumours in terms of the genes altered, and also because they develop a dense desmoplastic stroma of fibroblasts, stellate cells, immune cells, and extracellular matrix proteins such as collagen.

By studying our models, we can determine the importance of specific genetic and transcriptomic changes identified in human tumours, identify novel targets for therapy, both in tumour cells and in the microenvironment, and test new therapies pre-clinically.

See the following CRUK blogs for more details about Prof Morton's work:

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Introduction

Blyth 23 266 Beatson Lab Groups 000046

In vivo models are an important tool to recapitulate human cancer and interrogate aspects of the disease within a biological context. Validating in vitro discoveries in physiologically relevant models in this way will expedite novel therapeutic approaches for patient benefit. The group has expertise in modelling different cancer types but has a specific interest in breast cancer, and how metabolic pathways and certain signalling nodes such as the RUNX/CBFβ transcriptional complex and pro-survival factor MCL-1, contribute to tumour progression and metastasis.

The RUNX genes are essential regulators in mammalian development, most notably for bone and blood cell lineages. Like many genes important for normal development, the RUNX genes are linked to human cancer, but interestingly have been found to both promote and suppress tumour formation, a paradox we are exploring. We have shown that high expression of RUNX1 and RUNX2 in breast cancer correlates with specific subtypes of the disease and with poorer patient prognosis. We are now investigating the functionality of these genes in epithelial cancers and have shown that RUNX2 has a role in mammary stem/progenitor cells.

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Honorary Consultant Hepatologist, University of Edinburgh and Royal Infirmary of Edinburgh

Wellcome Trust Intermediate Research Fellow

Introduction

Bird heas 2020 075

Liver cancer is the third most common cause of cancer-related death worldwide. It is becoming an increasing problem, particularly in the Western world, and its rates have trebled in Scotland in the last 20 years. Despite some improvements in outcomes for those patients in whom the disease is detected early, there remains a limited range of only minimally effective treatment options for the overwhelming majority of patients who have their disease detected at a later stage. Precision medicine offers the potential to target more effective therapies to individuals with different forms of this disease, across this highly heterogeneous cancer.

My group has been interested in studying the regenerative responses to injury and aberrant proliferative responses in cancer of hepatocytes, the principle functional cell of the liver. These cells show immense regenerative capacity but are also the source of the most common primary liver cancer, hepatocellular carcinoma (HCC).

We have described how these cells enter a state of shock, named senescence, in response to injury, and how preventing them from doing so can promote liver regeneration. We are also investigating how this same senescent state occurs during early cancer formation as an anti- cancer therapeutic target.

To further understand these processes, we have developed a state-of-the-art suite of genetically engineered models of HCC, which mimics key features of the human condition. This suite is based upon the range of genetic mutations which drive HCC across the spectrum of human disease. Cross comparing between the models and patients we are able to identify novel pathways for therapy and some drug combinations which are highly effective in our cancer models. Working with academic and industrial collaborators, we are using these avatar-like models to uncover and test novel therapies, which could be used to target precision medicine dependent on the underlying characteristics of tumours in different patients.

Exposing liver cancer

Read about Tom's collaboration with the University of Edinburgh's Centre for Statistics to improve early detection of liver cancer here.

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