WP1: Cell Fate / ESR1
Project title: Molecular origins of metastatic transcriptional programs (Helsinki)
Leticia Castillón
Objective:
Despite significant efforts, genetic alterations that specifically promote metastatic phenotypes have not been identified. However, cancers with high propensity to metastasize have distinct transcriptional profiles. This suggests that metastatic programming in primary tumours is largely caused by aberrations in transcriptional control. Nevertheless, how metastatic transcriptional programs arise has remained elusive. We will use experimental metastasis models to identify critical transcriptional control mechanisms of metastatic progression. First, we will use established clones of varying metastatic potential to perform chromatin and transcriptional profiling (ATAC-seq, RNA-seq and ChIP-seq). Using computational methods with clinical validation, we will identify candidate gene regulatory regions and their regulators underlying metastasis. We will then use experimental genetics (gene and gene regulatory element loss-of-function and gain-of-function) to identify functional drivers of metastatic transcriptional programs.
Originally from Spain, Leticia graduated in Biotechnology at the University of Zaragoza in 2017. During her bachelor, she completed her thesis work in Evolutionary Genomics in the laboratory of Dr. Jonas Warringer at the University of Gothenburg in Sweden. As a graduate, she remained in Gothenburg to further develop her research expertise at the laboratory of Sebastian Westenhoff. In 2021, she completed her Master in Biotechnology at Chalmers University of Technology, where she used in silico approaches to study the role of alterations in the spliceosome and the splicing process in cancer progression and response to therapy.
Now, Leticia is joining the Evomet network as part of Sakari Vanharanta´s lab at the University of Helsinki to unravel the genetic mechanisms underlying metastasis. Since metastasis is the leader cause of cancer deaths worldwide, a better understanding of the drivers of metastatic progression is key to bring more effective therapies to cancer patients.
As part of this network, Leticia is looking forward to being part of a multicultural and cutting-edge consortium that bridges academia and industry, to hone her skills as a researcher and professional, and to connect with her fellow students. Most of all, she is excited for the valuable contribution Evomet will be making, pushing the boundaries of our understanding of metastasis.
WP1: Cell Fate / ESR2
Project title: Tumour transition states and metastasis (Brussels)
Andrea Pérez
Objective:
To form metastasis, tumour cells need to leave the primary tumour, reach the blood flow, colonize distant tissues, and establish secondary tumours. Using state of the art lineage tracing in mouse models of skin SCCs presenting spontaneous lung and lymph node metastasis and epithelial to mesenchymal transition (EMT), we will assess the importance of EMT and mesenchymal to epithelial transition (MET) in regulating the development of metastasis. Using single cell RNA and ATAC sequencing, we will unravel the tumour states present in the primary tumours, circulating tumour cells (CTCs) and at the metastatic sites. We will define the functional role of these different tumour states and the molecular mechanisms regulating their transition using genetic gain and loss of function and pharmacological inhibition of the pathways uncovered by these analyses. This study will provide key insights into the molecular mechanisms that regulate tumour transition states controlling metastasis.
Andrea Pérez González obtained her BSc in Biotechnology in 2019 and she subsequently received her Degree in Pharmacy (BPharm/MPharm) in 2021, both from Universidad Francisco de Vitoria (Spain).
She has conducted research in several institutions so far. In 2017, she was awarded the prestigious Amgen European Scholarship to join the University of Cambridge and study the electrophysiological properties of Small Cell Lung Cancer. In 2018, she received a CiQUS summer scholarship to join a molecular biology laboratory in Santiago de Compostela University. And in 2019, she studied stem cell-based models for personalized cancer research in the New York Stem Cell Foundation (NYSCF) for six months.
Andrea’s major motivation is to increase cancer patient’s survival. Thus, in August 2021, she moved to Brussels to start her PhD in the laboratory of Prof. Cédric Blanpain, aiming to better understand metastasis-initiating cells. Metastasis is the leading cause of death among cancer patients and tumor heterogeneity has been suggested to be the main driver of metastasis. Therefore, understanding which cells within a primary tumor present the capability to lead to metastasis will be key for the therapy of the cancer patient.
By being part of Evomet, Andrea is not only conducting her PhD in a cutting-edge laboratory, but also benefiting from a leading scientific atmosphere and an incomparable networking environment.
WP1: Cell Fate / ESR3
Project title: Integrating genomics and multiplexed pathology to predict outcome in patients with metastatic breast cancer (Paris)
Jomar Sangalang
Objective:
Outcome of patients with HR+/Her2- metastatic breast cancer is highly heterogeneous, with a subset of patients who are long term survivors, and at the other extreme, a group of patients who die within two years. The objective of this project is to characterise this group with very poor outcome. Specific Aim 1: to identify a genomic profile associated with poor outcome. We have already performed whole exome sequencing of 617 metastatic breast cancer patients (Bertucci, Nature, 2019). We will have sequenced overall 1500 patients by the end of 2020. We believe this cohort will represent patient heterogeneity sufficiently well to develop useful statistical models of patient outcomes. Genomic data are often characterized by complex interactions, so we plan to use graph-based genomic data analysis to model these interactions (Pirayre 2017). Specific Aim 2: to identify a proteomic profile associated with poor outcome. In order to address this question, we will profile the same samples mentioned in specific aim 1 in a proteomic facility (Liquid chromatography-mass spectrometry, n=6 000 prot, Astra Zeneca). We plan to profile 1 000 samples with a high degree of precision. From the statistical point of view, using so many variables to characterize a relatively low number of patients may incur bias. We will specifically use bias-reduction techniques from AI techniques, such as bagging and boosting methods (Bühlman 2012), to produce more reliable models and profiles. Specific Aim 3: to integrate data from genomic and proteomics with methods of representation learning for multi-modal data and to develop a predictor of patients outcome with artificial intelligence models. A special focus will be devoted to the identification of biological markers with a strong influence on patient outcomes thanks to techniques of explainable AI. Combining data from these two very different sources is a challenge from the data analytics point of view. We plan to leverage the power of graph-based neural-networks to this end (Kipf 2017). Specific Aim 4: to validate the predictor in an independent dataset (PADA1 trial, n=300 for the validation set).
Jomar completed his Bachelor of Chemical Engineering with Biomedical Engineering Specialization at the University of Calgary in Canada, and completed his thesis research on the biomechanics of colorectal cancer cells in a tumor microenvironment in the laboratory of Dr. Amir Sanati-Nezhad.
Now a Canadian expat since 2019, he completed his Master in Biomedical Engineering at FH Aachen University of Applied Sciences in Germany. In his Master studies, he gained practical work experience at Ecolab Deutschland and Emma—The Sleep Company, where he honed his skill in programming and data automation. He also completed his Master thesis in the laboratory of Dr. Kristen Kozielski at the Karlsruhe Institute of Technology, in the field of magnetoelectric nanoparticle research. Jomar now joins the Doctoral School of Oncology in Université Paris-Saclay, through the lab of Fabrice André at Institut Gustave Roussy.
Cancer research has always been a dream for Jomar. His motivation for undertaking the Master degree was to eventually do cancer research. His big dream: to see a world where cancer is obsolete. Because metastasis plays a huge role in cancer progression, understanding the mechanisms of metastasis is key in helping millions of people.
As an ESR of Evomet, Jomar is delighted to be connected within both academia and industry in this field. In this network, Jomar hopes to learn from the expertise of the experts, expand his connections, and develop his skills as a researcher and professional. An exciting road ahead!
WP1: Cell Fate / ESR4
Project title: Cell fate mapping (Barcelona)
Diogo Soares
Objective:
Luminal cells (LCs) act as the cancer cell of origin in the most common BCa, the luminal subtype. It remains unclear whether the heterogeneity found in luminal-derived tumours and metastasis post treatment arises from a pre-existing heterogeneity within LCs. Recently developed technology allows for primary and metastasis BCa human/mouse organoid lines, which broadly recapitulate the diversity of the disease (Morphology, Histopathology, ER status, etc.) and are consistent with in vivo xeno- transplantations and patient responses. These will be used to identify in vitro drug resistance and clonal selection mechanisms and its relationship with LC heterogeneity. In this context, we will genetically define the various multipotent and differentiated populations using luminal markers and use lineage tracing to assess whether lineage-restricted tumor-initiating cells (TIC) maintain the ER+ lineage. We have devised a strategy based on editing the genomes of patient-derived tumor organoids using CRISPR/Cas9 technology to integrate reporter cassettes at desired marker genes. We aim to describe the gene programs that define these populations, and how they evolved upon treatment selection and metastasis. Lineage-tracing experiments will confirm the capacity of the distinct populations to self-renew and generate progeny over periods of metastasis and drug treatment selection.
Diogo is originally from Lisbon, Portugal. For his undergraduate degree, Diogo moved to the United States on a full scholarship and completed a BSc degree in Biology from Eastern Kentucky University. He then returned to Lisbon and obtained his MSc degree in Neuroscience at the Faculty of Medicine of the University of Lisbon and Institute for Molecular Medicine. At the iMM Diogo fermented his interest in mechanism that regulate cell fate decisions in pathological vs non-pathological contexts. Diogo proceeded to carry out his MSc thesis work, and dedicated two years, at the Gulbenkian Institute of Science with Dr. Diogo Castro. His work involved studying how proneural bHLH transcription factors regulate neural stem cell fate during cell-cycle exit. This work lead to several publications that elucidated on the mechanism by which the proneural factor Ascl1 functions as a master regulator of neurogenesis in the mammalian brain. Diogo then proceeded to acquire advanced microscopy training at the Institute for Interdisciplinary Science in Bordeaux, as well as experience in bioinformatics.
Now he joins the lab of Dr. Roger Gomis as a PhD student at IRB Barcelona. His work aims to use lineage tracing and single-cell sequencing techniques to identify key gene signatures that define and structure luminal breast cancer cellular hierarchies, as well as those that drive tumor initiation and differentiation.
Diogo’s work is ultimately driven by an unwavering curiosity of complex biological processes, and the motivation to translate knowledge acquired to real word solutions. He seeks to contribute with excellent research that can potentially shed light on the mechanisms regulating cancer metastasis.
WP2: Environment / ESR5
Project title: Mechanisms of immune evasion in metastatic cancer (Vienna)
Guillem Estivill
Objective:
Understanding how the immune system affects cancer progression remains one of the fundamental questions in cancer biology and is crucial for the development of effective therapies. To dissect the molecular mechanisms of immune evasion and their emergence during tumour dormancy and metastatic colonization, we will use established metastasis models combined with a novel technique we have developed, utilizing CRISPRa to trace clones in heterogeneous cell populations (CaTCH; Umkehrer et al. submitted). CaTCH enables lineage tracing of millions of cells with stably integrated DNA barcodes (BCs). Importantly, activation of a reporter allows FACS-based isolation of clones with distinct phenotypes of interest (i.e. tumour cells that stay dormant or escape dormancy in an immune-competent or -deficient background), enabling their mechanistic workup. We will assess the immune-contexture, mutational load and the transcriptional programs in the selected cancer cell clones and their pre-selection counterparts. By integrating clinical data, we will identify candidate mediators of these phenotypes, probe their role in functional metastasis assays (gain/loss of function) and dissect the underlying mechanisms.
Guillem was born and raised in Barcelona, and completed his Bachelor degree in Biomedicine from University of Barcelona, where his interest for cancer biology originated. This drove him to pursue different projects in cancer research during summer breaks in his undergraduate years, both in Barcelona and abroad, and then his Bachelor thesis in the laboratory of Prof. Vincenzo Cerullo in University of Helsinki. There he worked on the design of adenoviral vector-based cancer vaccines as a novel immunotherapy approach against melanoma. This deep dive into the immunotherapy field made him become very passionate about the intricacies of the immune system, cancer vaccines and immuno-oncology. That is why he then completed an Erasmus Mundus International Master in Immunology and Vaccinology, and moved to Boston to pursue his Master Thesis research in the laboratory of Dr. Judith Agudo, in the Dana-Farber Cancer Institute, where he worked on mechanisms of immune evasion by cancer stem cells in murine models of triple-negative breast cancer, with a specific focus on the function of dendritic cells within the tumour microenvironment.
Now, for his PhD, Guillem joins the laboratory of Dr. Anna Obenauf in the Institute of Molecular Pathology in Vienna. There, he works towards unraveling new mechanisms of immune evasion in metastatic cancer by applying CaTCH, a novel tool that allows to perform lineage tracing of single clones throughout a biological selection process, such as the string of events underlying metastasis.
Guillem has a profound admiration for the workings of the immune system and believes that there is a big gap to fill in the understanding of how metastatic cells evade immune surveillance in different steps of the dissemination and seeding processes. He is very happy to be part of the Evomet network, which he believes brings together an outstanding group of expert scientists and motivated students to tackle metastasis from very different optics. He is convinced that this collaborative effort will speed up the discovery process and the translational availability of therapies for cancer patients.
WP2: Environment / ESR6
Project title: Role of vascular cells in castration naïve metastatic prostate cancer (Barcelona)
Hielke van Splunder
Objective:
We will study the contribution of the vascular compartment in the castration-naïve metastatic PCa, encompassing a tumour type that is metastatic at the time of first diagnosis. Specifically, we aim to: 1) identify critical molecular changes in the stroma of metastatic prostate cancer through computational and clinical analysis; and 2) conduct co-culture analysis with modify stroma and transformed epithelium, as well as in vivo modification of the stroma in murine models of prostate cancer. The nature of the stromal contribution to the progression of the disease will be mechanistically deconstructed and exploited for the development of therapies.
Hielke started his Bachelor of Biotechnology at Wageningen University & Research in 2014. During his undergraduate studies, he particularly enjoyed a half-year exchange at Ryerson University in Toronto, and an industrial placement at Synthon Biopharmaceuticals in the Netherlands. There, he used structural biology to better understand a novel antibody-drug conjugate technology. After his Bachelor’s, he continued to study Medical & Process Biotechnology, and Hielke´s interest in biotechnology matured into a fully-fledged passion for biomedical research and therapeutic innovation. Hielke conducted his Master thesis at the Antibody Research & Technology department of Genmab A/S, located in Utrecht. At Genmab, he studied the process of antibody-induced receptor co-localization on the cancer cell surface, using the complement system as ultimate read-out.
A few months ago, Hielke joined the lab of Dr. Mariona Graupera at the Josep Carreras Leukaemia research institute in Barcelona. Here, Hielke strives to understand the role of vascular cells in castration naïve metastatic prostate cancer (PCa) as part of the EVOMET innovative training network.
Hielke is excited to work on a project that aims to unravel the complex heterogeneity of the tumour stroma in metastatic PCa, which could provide an innovate perspective on therapeutic strategies and may ultimately improve the lives of patients. Hielke is delighted to work closely with the best academic, clinical and industrial entities that are part of the EVOMET consortium. He looks forward to expanding his network and skills, and is grateful to be on a solid track for his scientific career.
WP2: Environment / ESR7
Project title: Investigating the contributions of non-cancerous immune and stromal cells to metastasis progression (Lausanne)
Rui Santalla
Objective:
Emerging evidence indicates that immune cells are mobilized and activated in the tumour microenvironment (TME) during metastatic cancer progression. The TME is also altered following various anticancer therapies, which can paradoxically contribute to a lack of response/acquired resistance to treatment. In particular, inflammation can promote metastatic progression. We will systematically focus on different immune cell types whose levels vary across systemic inflammation, in specific tissues – including the brain, and whose variations are further exacerbated by the presence of a primary tumour. We will determine whether this translates to increased cancer metastasis to this site, and the potential dependency on specific cytokines or factors. Subsequent genetic, chemical or biological studies will follow to confirm the causality of these mechanisms to the metastatic phenotype. The underlying mechanistic contribution of the microenvironment to metastasis and therapeutic resistance will be based on a range of complementary techniques including mouse models of cancer, 3D co-culture systems, computational approaches, and analysis of patient samples in collaboration with our clinical colleagues.
Rui is originally from Galicia, a region in north-west Spain. In 2019, he received a BSc degree in Biomedical Sciences at University of Barcelona. Through the Erasmus program, Rui performed his BSc thesis research project at the Radboud Institute for Molecular Life Sciences (Nijmegen, the Netherlands), in the lab of Prof. Annemiek van Spriel. He then moved to Trinity College Dublin, Ireland, to do a MSc in Immunology, and did his MSc thesis research in the lab of Prof. Luke O’Neill. Rui has recently joined the Evomet ITN in the lab of Prof. Johanna Joyce, University of Lausanne, Switzerland, where he studies the brain metastasis microenvironment.
Metastatic disease represents a major challenge in treating cancer patients. Rui thinks that exploiting the immune system will be critical to treat metastasis, and he will dedicate all his enthusiasm towards the development of next-generation cancer immunotherapies.
For Rui, being part of the Evomet and the Joyce lab represents a fantastic opportunity where he can learn from diverse fields including metastasis, cancer biology, immunology, and neuroscience. He views Evomet as a unique collaborative structure to generate knowledge in a synergistic manner, enriching the projects of all ESRs and potentiating team building among the labs.
WP2: Environment / ESR8
Project title: Biology of breast cancer metastasis (London)
Georgios Skiadas
Objective:
Invasive lobular breast cancer (ILC) represents 10-15% of all newly diagnosed breast cancers and has a distinct pattern of metastatic spread, with a greater propensity to develop ovarian, GI and leptomeningeal metastasis where the tumour spread is typically over the serosal surfaces rather than infiltrating into the parenchyma. In addition, lobular breast cancers have poor long-term outcome indicative of a latent metastatic phenotype. The genetics of ILC have been well studied, however the biology of ILC is poorly understood due to the paucity of clinically relevant models. To identify therapeutic vulnerabilities associated with ILC, we will develop improved in vitro, ex vivo and in vivo models and interrogate the biology of ILC metastatic colonisation – focusing on the pattern of metastatic spread in the peritoneum and leptomeninges. In parallel we will collect liquid biopsies (ascitic fluid and cerebrospinal fluid) from ILC patients for ultra-low-pass and whole exome sequencing to identify potential drivers of metastatic spread, determine the clonal evolution of ILC metastasis and for the development of diagnostic and disease monitoring biomarkers.
Georgios completed his bachelor’s in chemistry at the University of Patras in Greece. During his undergraduate studies, he was impressed by the intricate mechanisms that cancers take advantage of to develop and spread, so he decided to join the lab of Prof. Achilleas Theocharis to investigate how the extracellular matrix components can influence the development of glioblastoma. He subsequently joined the master’s programme in Biomedical Sciences at the Medical School of the University of Patras and the lab of Dr. Georgios Stathopoulos, where he gained experience with mouse models of lung adenocarcinoma and malignant pleural effusion. Before completing his master’s degree, he moved to Barcelona to carry out an Erasmus+ internship in the lab of Dr. Luis Serrano at the Centre for Genomic Regulation, where he became familiar with bacterial engineering techniques. Georgios is now part of the Breast Cancer Now charity at the Institute of Cancer Research in London, working under the supervision of Profs. Clare Isacke and Andrew Tutt.
Georgios is interested in investigating how our normal cells can be stratified by cancers to help them promote their growth in distant sites of the body. He is determined to see his work translated into new therapeutic approaches to tame metastatic cancer, so as to improve the quality of life of millions of cancer patients the world over.
He is delighted to be part of EVOMET, which is comprised of a heterogeneous network of excellent investigators and students from around the world, working across different sectors and in different aspects of metastasis. He is certain that the network will provide him with the necessary tools to excel in the field of metastasis research, as well as with unforgettable experiences and wonderful friendships.
Supervisor
Secondments
ZS, IJC
Doctoral programme
The Institute of Cancer Research, University of London
WP3: Latency / ESR9
Project title: The role of MSK1 and NK cells in breast cancer latency (Barcelona)
Milos Lazic
Objective:
We build on our previous hypotheses/work to investigate and unravel how MSK1 contributes to BCa dormancy. We will determine how chromatin is organized within dormant tumour cells (DTCs), focusing on histone H3 to map genomic and transcription changes associated with metastatic escape from non-adaptive, anti-tumor immune activities. We will test the metastasis cascade of events to pinpoint how to therapeutically intervene in crosstalk between signalling pathways and/or the epigenetic regulations that support metastatic escape. We will characterize, at the genetic, biochemical, and cellular levels, whether MSK1 in DTC cells controls mediators of the non-adaptive immune response. To establish the contribution of MSK1 in attenuating the NK functions in metastatic cells, we will use both stable gain-of-function (gene overexpression) and loss-of-function (gene knockdown/knockout via shRNA and CRISPR/Cas9). We will test the metastatic activities of these transfectants with in vitro experiments as well as inoculation into immunocompromised mice of various backgrounds with immune deficiencies, including Balb/c Nude athymic mice (FOXN1nu) that retain functional innate system, and the more immune compromised NOD/SCID gamma mice with neither adaptive nor innate immunity.
Miloš completed his Medical Degree in 2019 at the Faculty of Medicine, University of Belgrade, with a research thesis focusing on the immunohistochemical profiling of Snail transcription factor in renal cell carcinoma under the supervision of Maja Životić MD Ph.D.
After graduating, he finished a six-month rotation at the University Clinical Centre of Serbia and acquired his medical license. In 2020 he started teaching Pathophysiology at the Faculty of Pharmacy, University of Belgrade. Alongside teaching at the Faculty of Pharmacy, he was also a student on specialist academic studies in pharmacy, and in 2021 he obtained a degree in Biological Medicines, with a thesis focusing on the use of CAR-NK cells in cancer therapy.
Throughout his studies, Miloš has strived to form a complete picture of cancer, from bench to bedside. He has learned and worked with many supervisors like Marija Matić MD Ph.D., Momčilo Ristanović MD Ph.D., Katarina Savić-Vujović MD Ph.D. and David Šmajs MUDr. Ph.D. He now joins the University of Barcelona Doctoral Program in Biomedicine under the mentorship of Roger Gomis, Ph.D. at IRB Barcelona.
Miloš hopes to contribute to the collective war on cancer by improving the understanding of the metastatic immune environment and cancer dormancy. As Sun Tzu wrote in the Art of War, “If you know your enemies and know yourself, you will not be imperiled in a hundred battles.”.
As an ESR of Evomet, Miloš is excited for the opportunity to follow an academic career and hopes to bring knowledge of clinical practice into the laboratory and later transfer the knowledge of laboratory research back into the clinic, thereby using it to help cancer patients directly.
WP3: Latency / ESR10
Project title: Endothelial cells determining metastatic latency in breast cancer (Barcelona)
Marta Fidalgo
Objective:
We aim to understand the contribution of endothelial cells and the angiogenic switch to support expansion of indolent latent metastatic cells. We will determine how endothelial cells are organized within latent metastasis by focusing on genomic, transcription and translation changes associated with overt metastasis. We will test several functions that support metastasis to identify where, when and how endothelial cells contribute to support exit from latency. To establish the contribution of endothelial cells in attenuating or supporting the expansion of latent metastasis, we will use a series of genetically engineered mouse models with reduced and enhanced angiogenesis through the manipulation of the PI3K pathway specifically in the endothelium. This will be back-crossed in Balb/c Nude athymic mice (FOXN1nu) background to subsequently introduce a series of human breast cancer latent metastasis models. Next, we will screen for communication signals and gene expression patterns among cancer and endothelial populations. Subsequent mechanistic analysis will be performed to understand the molecular dependencies among the cellular populations. Finally, confocal microscopy of in bone events will be performed post intra iliac injection and bone growth in vitro.
Marta Fidalgo completed her bachelor’s degree in Genetics and Biotechnology from the University of Trás-os-Montes e Alto Douro in Portugal. For her final report she moved to Porto to work on the Molecular Microbiology lab at the Institute for Research and Innovation in Health. In this project the aim was to understand how a specific bacteria could adapt to its surroundings and how it interacted with its microenvironment. Then, Marta received a master’s degree in molecular medicine and Oncology from the Faculty of Medicine of Porto’s University. For her master thesis, Marta developed a project in the field of Developmental Biology at Dr. Cláudio Franco‘s lab, the vascular morphogenesis lab, in the Molecular Medicine Institute in Lisbon. The main aim of this project was to understand how blood vessels develop in the lungs, particularly after birth. Again, very much focused on the intrinsic regulations necessary for a cell or tissue to perceive and comply with its environment. Taking the expertise in blood vessels and the interest in cell-cell communication and allying it with the better understanding of cancer metastasis was always the goal, so Marta is extremely excited with being an ESR in Mariona Graupera’s Lab. In her current project she will be able to assess the role of vascular cells and other components of the tumor microenvironment in promoting the exit from latency in breast cancer cells leading to breast cancer metastasis. Currently Marta is enjoying the city of Barcelona and is very eager to know where these new experiences are going to take her!
Supervisor
Secondments
UNIL, IRB, Max Planck
Doctoral programme
University of Barcelona
WP3: Latency / ESR11
Project title: Genes and signalling pathways involved in metastatic cancer dormancy (Brussels)
Monica Jordan
Objective:
Tumour dormancy is characterized by a reversible cell cycle arrest of tumour cells and is thought to be the cause of metastasis relapse years after remission. The mechanisms that regulate tumour dormancy are poorly understood. We will use a model of skin squamous cell carcinoma, in which fluorescently labelled tumour cells (TCs) spontaneously form metastasis in the lung, to decipher the mechanisms that control metastasis dormancy. In this model, we have found that isolated quiescent TCs could be identified. To uncover the mechanisms that control metastasis dormancy, we will micro-dissect overt metastases, FACS isolate fluorescently quiescent and proliferative TCs, and perform single cell RNA seq to identify the gene signature of dormant and proliferative metastatic cells. We will then use pharmacological approaches to assess the function of candidate signalling pathways that are likely to mediate dormancy and the function of these genes or pathways in the regulation of lung metastasis proliferation will be assessed. This study will be important to uncover new regulators of metastasis dormancy with important implications for cancer therapy.
Mónica received her BSc in Biomedical Sciences from the University of Barcelona in 2019. She started getting in touch with the laboratory by an extracurricular internship focused on the oncogene Red at IRB Lleida. She completed her Bachelor thesis on the study of KIT-mutated melanoma and its response to target therapies at the Institut de Recherche Saint Louis in Paris. Cancer field awakened her interest, so she decided to pursue the MSc in Basic and Translational Research in Cancer, also hosted by the University of Barcelona. This master gave her the opportunity to get a solid background in all the main areas of cancer and to specialize in melanoma, neural cancer, and colorectal cancer. For her Master thesis, she went back to Paris to continue with the melanoma project she started during her Bachelor. Once she completed her undergraduate studies, she worked for a year as research assistant at the Neuropathology laboratory of the University of Barcelona and IDIBAPS.
Mónica now joins the Evomet-ITN project as a PhD student at the Laboratory of Stem Cells and Cancer in the Université Libre de Bruxelles. Her project is focused on decipher the Genes and signaling pathways involved in metastatic cancer dormancy.
Mónica became passionate about cancer research ever since she started her project on melanoma and decided to dedicate her all career to this endeavour. Although the metastatic process has been extensively studied, much remains to be learned. Mónica wants to contribute with her research to metastasis understanding to have the possibility to provide answers to all these questions that remain unknown, and to maybe have an impact on society and healthcare.
Mónica feels truly privileged to be one of the 15 ESR of Evomet since it is a great opportunity for her scientific training, both in the academic and industrial fields. Without the slightest doubt, the best of being part of Evomet is the amazing and passionate team of PhD students and PIs, with whom you never stop learning!
Supervisor
Cedric Blanpain
Secondments
ICR, IRB
Doctoral programme
Université Libre de Bruxelles
WP4: Expansion / ESR12
Project title: Molecular profiling of HER2-enriched hormone receptor-positive breast cancer metastasis (Barcelona)
Benedetta Conte
Objective:
To identify genomic alterations and signalling pathways associated with treatment failure in patients with metastatic HER2-enriched (HER2-E) hormone receptor-positive (HR+) breast cancer (BC): DNA and RNA of >400 HR+ samples (including 140 HER2-E) from 4 metastatic cohorts will be extracted and analyzed for genomic alterations. Massive parallel sequencing (MPS; MiSeq Illumina platform) will be used to detect somatic mutations on a panel of 60 oncogenes and tumour suppressor genes, covering most frequently mutated exons including PIK3CA, TP53, CDH1, GATA3 and ESR1 as well as tumour mutational burden. The nCounter Breast Cancer 360 Panel (Nanostring Technologies) will be used to determine the expression of 752 genes across 23 key BC pathways and processes. Intrinsic subtypes and biologically relevant gene signatures will be determined using R software. Subsequent phenotypic characterization will take place.
Benedetta completed her Master Degree in Medicine and Surgery at the University of Pavia (Italy), with an experimental thesis on myeloid neoplasm at the laboratory of Prof. Luca Malcovati. From 2016 until 2021, she worked as a resident in Medical Oncology at the Hospital San Martino in Genova (Italy), were she dedicated to the clinical care of patients with cancer. In 2019, she did a research fellowship at the Professor’s Aleix Prat laboratory in the August Pi i Sunyer Biomedical Research Institute (IDIBAPS) in Barcelona. There, she developed a strong interest in cancer research, and she honed her skill in gene expression profiling and data analysis.
In September 2021 Benedetta entered the Doctoral School of Translational Medicine at the University of Barcelona and she re-joined the research group of Professor Aleix Prat at IDIBAPS.
As a medical oncologist who has been seeing and talking to patients with metastatic cancer, Benedetta feels a strong commitment to cancer research. In these years within the Evomet project, she aims to understand how breast cancer metastasis eventually develop resistance to therapies.
Evomet has given Benedetta the opportunity to work closely with top scientists in the field of cancer research and to connect with other brilliant early researchers. She feels to be part of an ambitious, meaningful project which aims to improve the lives of persons with metastatic cancers and their relatives.
WP4: Expansion / ESR13
Project title: Molecular and cellular mechanisms of cigarette smoke-evoked metastasis (Basel)
Juliane Heilig
Objective:
The majority of the world population smokes or has smoked, and a further proportion is or has been exposed to environmental tobacco smoke. Although recent evidence consistently supports an association between smoking and an increased risk of breast cancer development, progression to metastasis and death, the underlying mechanisms are poorly understood. Here we will assess the effects of exposure to cigarette smoke using mouse models of the most frequent gain-of-function mutation in breast cancer (i.e., mutant phosphatidylinositol 3-kinase (PI3K)). We will directly assess how smoking contributes to breast cancer metastasis in a cell-autonomous (i.e., within cancer cells) or non-cell-autonomous (i.e., immune cells within metastatic sites) manner, and identify and validate the oncogenic molecular and cellular mechanisms involved. We will use a battery of cell biological assays, as well as multiphoton intravital imaging to dissect the mechanisms underlying cigarette smoke-evoked metastasis.
Juliane started her scientific career with a bachelor degree in biology at the Humboldt-Universität zu Berlin. In her thesis, she researched about the influence of a long non-coding RNA in Drosophila melanogaster. To discover how science is practiced in a different part of the world, she completed a 6-month exchange program at the University of Kelaniya, Sri Lanka during her Bachelor studies. Expanding her international research experience even further, Juliane accomplished a Master in Immunology and Microbiology at the Uppsala University in Sweden. In her Master Thesis, she examined the efficacy of the therapeutic antibody Rituximab in different isotype forms on B-cell Lymphoma spheroids. Juliane is now part of the doctoral program at the Universität Basel, Switzerland in the lab of Professor Mohamed Bentires-Alj.
To work in the field of Cancer research, especially triple-negative breast cancer, has always been Juliane’s dream job. She feels that her daily work and research might have a direct influence in the future on a patient’s life. As metastasis is the deadliest aspect of cancer, Juliane is proud to be a part of the Evomet network. Together with the other 14 PhD students, she will face the fight against metastasis by combining their knowledge, building a network and broaden their expertise in this field.
WP4: Expansion / ESR14
Project title: Induction of immunogenic cell death in cancer cells via the activation of the STING pathway (Vienna)
Jingyi Shen
Objective:
The nucleic acid sensor STING is an important regulator in innate immune cells to protect the body against invading pathogens and malignant cells. Currently, synthetic STING agonists are tested in clinical trials for their ability to induce a de novo antitumor immune response in metastatic tumour patients. Besides activating immune cells, we discovered that STING agonists can induce cell death in both cancer and immune cells, although at different concentration ranges. In preliminary experiments, we discovered that some cancer cells die via the immunogenic cell death pathway. Understanding if and how STING induces immunogenic cancer cell death and activates immune cells while maintaining their viability will be crucial. For this project, we will investigate which pathways regulate STING induced cell death in cancer and immune cells using CRISPR, proteomics and high throughput drug screening platforms. Determine if the identified cell death pathways are immune activating or immune silent and test which of these pathways are differentially regulated in cancer and immune cells.
Jingyi obtained her B.A. degree in Biology from Pitzer College in the U.S., where she conducted thesis research on proteasomal activity and mitochondrial function in the context of aging. Jingyi then joined the Erasmus International Master in Innovative Medicine and obtained her degrees from Heidelberg University in Germany and Uppsala University in Sweden. During her master, Jingyi studied the role of osteopontin in melanoma therapy resistance and cell invasion with Prof. Jonathan Sleeman’s group at Universitätsmedizin Mannheim. She then worked on the therapeutic impact of a chemokine on the maintenance of chronic myeloid leukemia stem cells in the bone marrow niche with Dr. Hong Qian at Karolinska Institutet. Jingyi now joins Dr. Sebastian Carotta’s group at Boehringer Ingelheim. It is absolutely exciting for her to combine the interests in metastasis, tumor microenvironment, and cancer immunology in her current project.
Although sounds cliché, most people may have lost someone due to cancer. Jingyi’s motivation in cancer research comes from personal experiences. She believes that discoveries originated from benchwork are critical in improving cancer treatments in the future. Jingyi strives to gain relevant knowledge and skills through the Evomet PhD program, which hopefully will allow her to bring benefits to patients someday.
WP4: Expansion / ESR15
Project title: Early detection of silent killer cancers using deep learning and large health care data (Copenhagen)
Laura Degand
Objective:
Today, many cancers are often diagnosed at a late stage resulting in poor treatment options and survival rates. One of the most difficult cancers to detect early on is pancreatic cancer, which has one of the lowest 5-year relative survival rates at only 9%. Symptoms of pancreatic cancer, such as weight loss, abdominal discomfort and occasionally diabetes, are often mistaken for signs of less severe illnesses and overlooked in clinical practice. Other examples of cancer types diagnosed in a late stage are lung, colorectal, ovarian, stomach and liver cancer. Recently, deep learning has demonstrated to be a highly effective methodology to learn complex data structures, such as healthcare data. Danish health registries are some of the largest and most comprehensive healthcare datasets in the world. These comprise disease history, clinical notes, laboratory measurements, drugs and diagnostic images. Due to the linkability by the Central Person Register (CPR) identification number, it is possible to achieve individual-level linking across all data types.
Laura obtained an Engineering degree in Computer Science with a specialisation in Image Processing in 2020 after her studies in France. During her education, she did her first experience in the medical domain by doing a gap year as a research assistant at the VIDA Lab at NYU, supervised by Pr. Guido Gerig. This opportunity has helped her to discover the academic and research world but also to improve her technical skills in programming and in image processing – her main project at NYU was to apply segmentation to brain on MRI and to deal with large datasets. She continues her education in the medical field by doing her end-of-studies internship at General Electric Healthcare, in R&D, where she designed algorithms to improve the image acquisition of mammography.
Continue to use her computer skills for medical research was one of the wishes of Laura after her graduation. Thus, the PhD subject proposed by Evomet and ZS Associates about pancreatic cancer and deep learning decided Laura to move to Copenhague to undertake a doctorate at the University of Copenhague at the Novo Nordisk Foundation Center for Protein Research and at ZS Associates.
