The Early Cancer Institute funds a number of research projects which aim to understand the earliest steps of cancer development.
Principal Investigators: Dr Sarah Welsh, University of Cambridge; Miss Maxine Tran, University College London and Dr Tom Mitchell, Wellcome Sanger Institute.
Funded by: ACED Project Award 2022
Renal cell cancer (RCC) is the 7th commonest cancer and the most lethal urological malignancy with 50% of patients dying from their disease.
Small renal masses (SRMs; <4cm) represent a stage of RCC where progression and prognosis varies. Some SRMs never need intervention but current standard of care is surgical resection with significant risks. There is an urgent unmet clinical need to identify, at the point of diagnosis, which are likely to progress, and which are unlikely to cause future harm and avoid over-treatment.
This project will use novel DNA and RNA ‘molecular archaeology’ techniques (that look at current genomic evidence to understand past key genomic events that led to cancer) to time when these events occurred (n=240 patients) in RCCs.
By mapping molecular archaeology with tumour growth rates from 3D CT images we will identify whether the timing of genomic events can assess progression once an RCC is detected. We will also determine whether the downstream effects of key genomic events (using RNAseq and TCRseq) correlate with progression and the timing of the earliest progression defining changes.
The project will use paired blood, multi-region sampled RCCs and normal kidney, and serial CT scans from two complementary translational research trials at the UK’s highest volume RCC centres in a new collaboration. This will enable development of a multiparametric test to allow clinicians to tailor treatment according to how we think their tumour will progress and, if detectable in blood, addresses the urgent need to develop an RCC screening test.
Principal Investigators: Dr Walid Khaled, University of Cambridge and Dr Hisham Mohammed, Oregon Health & Science University
Funded by: ACED Project Award 2022
Principal Investigators: Dr John Lizhe Zhuang and Dr Alvin Ng, University of Cambridge.
Funded by: CRUK Early Detection Primer Award 2021
Oesophageal adenocarcinoma (OAC) has increased almost 6-fold in western countries in the past three decades, with a very poor prognosis of 15% five-year survival rate. OAC originates from a precursor lesion, known as Barrett’s oesophagus (BO), which bears a high mutation burden that is greater than many invasive cancer types. In this project, we have developed a number of BO organoid lines that derived from patients which serve as a comprehensive in-vitro platform to study the cancer and its precancerous lesion, and dissect the genomic heterogeneity and the malignant transformation. This understanding will aid accurate early detection and risk stratification of BO/OAC patients.
Principal Investigators: Dr Nora Pashayan, University College London; Dr Johannes Reiter, Stanford University; Prof Paul Pharoah, University of Cambridge; Dr Sylvia Plevritis, Stanford University
Funded by: ACED Project Award 2020
Drs Pashayan, Reiter, Plevritis and Prof Pharoah plan to construct mathematical models to simulate tumour growth, metastatic spread and biomarker shedding of lung, breast, prostate, kidney and ovarian cancer. Their models will be used to further understand the mechanistic underpinnings of cancer growth and progression and to anticipate the effect of early detection interventions. This work will aid the detection and early identification of aggressive cancers before they progress to an incurable stage and help to reduce the burden of overdiagnosis.
Principal Investigators: Dr Mona Shehata, University of Cambridge; Prof Emma Crosbie, University of Manchester and Dr Laura Heiser, Oregon Health & Science University
Funded by: ACED Pilot Award 2020
Drs Shehata and Heiser and Prof Crosbie will use clinically relevant human breast and endometrial organoid models to test the contribution of obese-related microenvironment components towards cancer initiation. The team's work will allow for the future development of biomarkers for the early detection of breast and endometrial cancers in obese and post-menopausal women.
Principal Investigators: Dr Jamie Blundell, University of Cambridge; Dr Hisham Mohammed, Oregon Health and Science University and Dr Ruth Etzioni, Oregon Health and Science University
Funded by: CRUK-OHSU Early Detection Joint Project Award 2020
The first genetic and epigenetic steps towards cancer occur in healthy tissue decades before cancer onset. This raises the possibility that these early events could be used as a bellwether for predicting who is most at risk of developing cancer. Serial blood samples collected annually from hundreds of thousands of initially healthy people in the UKCTOCS study afford a unique opportunity to do this. By 'zooming in' on the people who subsequently develop cancer, we can 'rewind' time by performing genetic and epigenetic analyses on blood samples collected years before the cancer was diagnosed.
An attractive initial target for this ambitious vision is the aggressive blood cancer Acute Myeloid Leukaemia (AML). Because AML is characterised by a relatively small number of genetic and epigenetic alterations, which are readily detectable in peripheral blood, it provides a unique opportunity to address one of the most fundamental questions in early detection: “How many years before diagnosis can cancer be reliably predicted?” Our principle aim in this project is to perform a range of methylation sequencing on pre-AML samples to paint a quantitative epigenetic portrait of how AML evolves from healthy tissue and use these data to develop statistical techniques to forecast blood-cancer risk.
Principal Investigators: Dr Matthew Hoare, University of Cambridge and Dr Ferdinando Pucci, Oregon Health and Science University
Funded by: CRUK-OHSU Early Detection Project Award 2020
Cellular senescence is a stress-responsive tumour suppressor mechanism. Senescent cells accumulate in chronic inflammatory cancer-prone tissues. Senescent cells have profound non-autonomous effects upon immunocytes, driving their own destruction. Failure of this immune reaction with persistent senescence leads to tumorigenesis. Understanding how senescent cells communicate with their microenvironment represents a promising strategy to detect incipient tumorigenesis.
Extracellular vesicles (EVs) are nanometer-scale membrane-bound vesicles, emitted from most cells types and are detectable in the circulation. Emerging evidence suggests they play a significant role in non-autonomous signalling. Tumor-derived EVs can be engulfed by and modulate the function of macrophages in distant lymph nodes. Previous in vitro studies have shown that senescent cells secrete EVs and that these carry specific nucleic acid and protein cargos, driving non-autonomous signaling. Nothing is known about senescent cell-derived extracellular vesicles (sEVs) in vivo.
The aim of the project is to define a signature of sEVs, define their fate and precise effect upon the immune system before validating the findings in patients.
Principal Investigator: Lucy Yates, Wellcome Sanger Institute
Funded by: Cancer Research UK Cambridge Centre Early Detection Programme Pump Priming Awards 2020
Lobular Carcinoma In-Situ (LCIS) has long been regarded as a ‘risk factor’ but not direct precursor of future invasive cancer. Reflecting this belief, clinical management of LCIS is focused on eliminating co-existent invasive disease. This has not changed, despite recent genomic analyses confirming that LCIS is actually a non-obligate precursor of Invasive Lobular Carcinoma (ILC), the second most common type of breast cancer. Differentiating between LCIS lesions that are destined to progress and those that will run an indolent course provides an opportunity for detecting and preventing breast cancer development at a very early stage.
In this project we will deepen our understanding of LCIS evolutionary biology with the ultimate goal of identifying biomarkers of future invasive disease. We will do so by using a novel spatial sequencing methodology that allows the individual subclones of a cancer to be mapped to the tissue section, permitting contextual analysis. The approach will be extremely useful for studying the wide-range of cancers that arise from precursor lesions and therefore lend themselves to early detection strategies.
Principal Investigator: Dr Philip Zegerman, Gurdon Institute/Department of Biochemistry
Funded by: Cancer Research UK Cambridge Centre Early Detection Programme Pump Priming Awards 2020
The clinical utility of ATR, CHK1, and WEE1 inhibitors, especially as single agents, will likely depend on identifying and targeting cancers that are dependent on DNA damage checkpoint activation. This study analysing checkpoint function during the development of AML will provide novel understanding of the role of checkpoint activation during the evolution of leukaemogenesis. This work has the potential to identify the DNA damage checkpoint as an early stage biomarker to assess AML disease outcome and inform therapy choices.
Brian Huntly is the scientific deputy director of the UK National Cancer Research Institute (NCRI) AML working group and he is currently setting up a clinic in Cambridge Universities Hospitals (CUH) for patients with AML-associated mutations but no current haematological disorder (a condition known as Clonal Haemopoiesis of Indeterminate Potential or CHIP). This line-of-sight to the clinic will facilitate the early translation of any therapeutic findings of this award. Similarly, if checkpoint activation is identified as an early event in experimental premalignancy then this will be checked in patient samples with myeloid pre-leukaemias and correlated with outcomes such as an increased risk of the development of AML.
Principal Investigator: Dr Maria Alcolea, Wellcome-MRC Cambridge Stem Cell Institute
Funded by: Worldwide Cancer Research, 2019
Dr Maria Alcolea at the University of Cambridge, England, wants to uncover new ways to diagnose oesophageal cancer early, when the patient has the best chance of survival. To do this, her team are studying the molecular processes that occur as oesophageal cancer develops. Through this work, they hope to identify molecular markers that can be used to detect oesophageal cancer as early as possible. Read more
Principal Investigators: Dr Daniel Muñoz-Espín (Cambridge) & Dr Jim Korkola (OHSU)
Funded by: OHSU-CRUK Project Award 2018
Senescence is a cell autonomous response to damage and oncogenic stress resulting in a stable cell cycle arrest. Senescent cells also accumulate with age in multiple tissues, and building evidence suggests they may contribute to inflammatory changes and tumourigenesis by secreting a complex cocktail of paracrine factors, the senescence-associated secretory phenotype (SASP). However, the precise SASP factors remain undefined because the tumour microenvironment is highly complex, and thus assigning functional impact to any single factor remains a challenge. We have developed microenvironment-microarrays (MEMA), a technology that allows us to screen thousands of unique combinations of matrix proteins and soluble ligands for their impact on cellular phenotypes. We propose to use MEMA to identify SASP factors that can drive proliferation, differentiation changes, and increased invasiveness in pre-cancerous and early lung and breast cancer cells.
Principal Investigators: Dr John Lizhe Zhuang (CRUK) & Dr Young Hwan Chang (OHSU)
Funded by: OHSU-CRUK SPARK Award 2018
r John Lizhe Zhuang (Fitzgerald Lab) and Dr Young Hwan Chang (OHSU) have been awarded funding for their project ‘Deciphering the immune microenvironment in oesophageal adenocarcinoma and pre-cancerous lesions to a single cell resolution’.
The project aims for a comprehensive characterisation of immune complexity of oesophageal adenocarcinoma using a novel sequential multiplex immunohistochemistry technique combined with computational image analysis. The method allows us to study the dynamic changes of immune populations along the progression of the disease from metaplasia to cancer, as well as the immune association with different tumour mutation signatures. In addition, using a machine learning algorithm, we will deep analyse the multi-parametric data on a single cell basis and look for more specific identification of cell subsets. The study will shed a light on an unclear field in oesophageal adenocarcinoma and better facilitate patient stratification, therapy and prognosis.
Principal Investigator: Dr Masashi Narita, CRUK Cambridge Institute
Co-Investigator: Professor Tuomas Knowles, Department of Physical Chemistry
Funded by: Cancer Research UK Cambridge Centre Early Detection Programme Pump Priming Awards 2016
The goal of this interdisciplinary project is to develop an experimental system for analysing cell-cell communication at the single cell level in the context of Oncogene Induced Senescence (OIS), a premalignant cell model. Non-autonomous activities of senescence, through senescence associated secretory phenotype (SASP) and cell-cell contact, reinforce and propagate the phenotype within the tumour microenvironment, potentially facilitating the malignant progression of ‘unstable OIS’ cells, depending on the cellular context.
Taking advantage of innovative microfluidic technology, our system would potentially offer a unique opportunity to gain a better understanding of the ‘very’ early history of tumorigenesis by directly visualising 1) how the OIS phenotype propagates across cells in different cellular contexts, and 2) how modulation of cell-cell communication affects the process.
In addition, the system will be optimised for single cell isolation compatible with RNAseq library preparation, opening the opportunity to generate data, effectively equivalent to ‘in situ RNAseq’. Such information would provide not only mechanistic insights into OIS/premalignancy development, but also new ‘context dependant OIS/premalignant biomarkers’.
Considering our recent data suggesting that the manipulation of the SASP program can enhance immune-mediated OIS cell clearance, our system would also help to identify targets for the ‘early treatment’ of premalignant cells.
Principal Investigator: Dr Jamie Blundell
Funded by: Cancer Research UK Cambridge Centre Early Detection Programme startup funding 2017
Cancer develops through an evolutionary process in which genetic and epigenetic changes accumulate in our tissues. The first steps of this evolutionary path to cancer occur in healthy tissue decades before cancer onset. This raises the possibility of using these early events as a bellwether for predicting who is most at risk of developing cancer. However, at present, we are unable to reliably identify which mutant clones will progress to lethal cancers.
Serial blood samples collected annually from hundreds of thousands of initially healthy people give us a superpower to better predict which clones are the bad actors. By “zooming in” on the people who develop cancer, we can “rewind” time by analysing blood samples collected years before the cancer was diagnosed. By analysing these data using mathematical techniques from evolutionary theory and population genetics, we aim to identify the clones that are most likely to progress to lethal cancers in order to intervene before cancer develops.
Principal Investigator: Dr Daniel Muñoz-Espín
Funded by: Cancer Research UK Cambridge Centre Early Detection Programme startup funding 2016 & MRC
Lung malignancies are the most common cause of cancer-related deaths worldwide. Out of the 8 million of the cancer-associated deceases taking place every year the estimates put over 1.5 of them as directly assigned to lung cancer. Although the efforts devoted to lung cancer research over the last decades have been formidable the underlying processes and mechanisms promoting malignant transformations have not been completely deciphered and, in most of the cases, the cell of origin of lung cancer remains largely unknown. Consequently, the available tools to achieve lung cancer early diagnosis, as well as the therapeutic approaches, are not good enough to tackle this disease. Most of the cases are diagnosed at advanced stages and ~90% of the patients die within a 5-year window from the first diagnosis.
Our group works at the interface between cellular senescence, plasticity and the fundamental processes and mechanisms that lie at the origin of cancer. We are also developing novel tools and nanodevices for cancer therapy and diagnosis.
Principal Investigator: Dr Charlie Massie
Funded by: Cancer Research UK Cambridge Centre Early Detection Programme startup funding 2017