Individual Research Projects

At a metastatic stage, human cancers are typically incurable. Targeting disseminated cancer cells before they become clinically detectable could provide significant patient benefit. However, the biology of early metastatic lesions is poorly understood, hampering the development of new therapeutic approaches. The objectives of this project are: (1) to characterise cellular states associated with early metastatic lesions using high-resolution molecular profiling (scRNA-seq and scATAC-seq) in experimental systems of metastatic cancer, (2) to identify clinically relevant markers of early stage metastases by integrating data sets from model systems and clinical tumour cohorts, (3) to utilise state-of-the art functional genomics with genetic perturbation (pooled CRISPR/Cas9-based genetic screens) to identify functional drivers of early metastatic tumours, and (4) to dissect the biological mechanisms through which these drivers facilitate metastatic dissemination (targeted loss-of-function and gain-of-function genetic experiments). The overall goal of this project is to characterise adaptive mechanisms that support cancer cell survival upon arrival at the distant metastatic site, and in doing so identify new molecular targets for therapeutic development.

The estimated annual gross salary for the fellow will be €43.043,04.

To apply for this position, please go to https://phd2.irbbarcelona.org/

To form metastasis, tumour cells need to leave the primary tumour, reach the blood flow, colonise distant tissues, and establish secondary tumours. Using state of the art lineage tracing in mouse models of skin squamous cell carcinoma (SCC) presenting spontaneous lung and lymph node metastasis and epithelial-mesenchymal transition (EMT), we will assess the importance of EMT and adaptive plasticity in regulating the development of metastasis. By combining genome-wide CRISPR-Cas9 loss of function studies and single-cell RNA sequencing (scRNA-seq) or single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq), it is possible to define the different metastatic tumour states and their associated enhancers as well as the genes controlling these different adaptive states and the activity of the enhancers specific for each cell states in a single experiment. By combining these new single-cell sequencing analyses, we will decipher the gene regulatory networks (GRN) that control the different EMT states in metastasis in a novel and unbiased manner. Then, we will assess the role of the most significant TF identified by CRISPR-KO to further define the adaptive mechanisms that regulate their functions during EMT, which will be important to define new tumour vulnerabilities and therapeutic opportunities.

CRISPR-Cas9 screen to identify the transcription regulators and the enhancer logic of the different EMT states in metastasis; 2. Validation of the newly discovered TF regulating EMT in metastasis in mouse cancer model; 3. Defining the role and the prognosis relevance of these new TF in human cancers.

The estimated annual gross salary for the fellow will be €39.617,52.

To apply for this position, please go to https://phd2.irbbarcelona.org/

Most disseminated tumour cells are unable to establish primary or secondary metastatic lesions, suggesting that target site microenvironments are hostile. Nonetheless, some disseminated tumour cells are able to resist treatment and to persist. This implies that metastatic cells must adapt to the new organ for survival(1). Of note, this process is inefficient and requires cellular rewiring(2). Identification of the initial cellular populations, their potential interconversions, and the potential for plasticity may lead to unravelling previously unappreciated metastasis gene drivers, and to identifying how they evolve upon treatment selection and metastasis. Mapping this complexity within a drug-resistant metastatic disease (including information about transcriptional, epigenomic, mutational, and genomic aberration patterns) has a high clinical potential. An HER2-enriched (HER2-E) phenotype drives the metastasis expansion gene program and is associated with loss of differentiation in HR+ tumours, even though these are also classified as luminal and express ER. We hypothesise that: FGFR-like expression imposes a metastatic HER2-E phenotype that disables the metastasis suppressor functions of the persister phenotype supporting metastasis adaptation; In this context, we will explore the role of FGFRs in sensitivity to treatment of BCa cells. We will compare control versus FGFR-depleted cells during relapse after chemotherapy, and scRNA-seq to investigate the fate of the FGFR-deficient cells during treatment. We devise a strategy based on the consolidation of this evidence with that previously established through lineage-tracing analysis. We aim to understand the relevance of these populations in treatment of perturbed or unperturbed tumours and its contribution to resume metastasis. We will validate the role of the newly identified marker for cell expansion/therapeutic targeting.

i) To dissect and integrate the FGFR-like BCa tumour treatment resistant adaptive signatures. ii) To unravel FGFR-like HER2-E BCa cellular hierarchies and changes in metastasis and drug resistance through cell fate mapping. iii) To mechanistically analyse FGFR-actionability in HER2-E founding clones.

The estimated annual gross salary for the fellow will range between €30,000 and €33,000.

To apply for this position, please go to https://www.irbbarcelona.org/en/careers/young-scientists/adaptmet-2025-call

We subscribe to the view that a tumour should be considered as a communicating organ in its own right, comprising multiple cell types that collectively evolve into a clinically manifested and deadly disease. Our overarching aim is to functionally define the cellular elements of a tumour. In the current project, microniches orchestrated by cancer-associated fibroblasts (CAFs) will be divulged and interrogated for function during metastatic dissemination. By a refinement of current state-of-the-art technologies, our studies enable inferences about molecular interactions between specialised cell types in confined cellular niches. With a unique map of microenvironmental niches as a backdrop, the project will confront previously unresolved questions in tumour biology by: 1) Defining the dynamic changes in the tumour architecture manifested in the composition of CAF microniches at different phases of tumorigenesis, from initiation to distant spread, and in the face of treatment, 2) Identifying precision drug targets based on CAF microniches to prevent cancer dissemination and drug resistance and 3) Discovering biomarkers from CAF microniches for improved diagnostication of cancer.

Taken together, the objectives will define a sustainable framework for exploring and implementing CAF microniches as drug targets and tools for the development of precision cancer medicines targeting metastatic dissemination. Specifically, we expect to 1) Provide a map of dynamic changes in paracrine signalling in a stage- and organ-specific manner leading up to metastatic dissemination; 2) Identify and validate 1-3 actionable drug targets for precision targeting of CAF microniches; and 3) Identify and validate 1-3 prognostic and/or predictive biomarkers for diagnostication or targeting of metastatic dissemination.

The estimated annual gross salary for the fellow will be €34.272.

To apply for this position, please go to https://phd2.irbbarcelona.org/ (Adaptmet recruitment) and Lund University’s recruitment system Varbi- https://lu.varbi.com/en/what:job/jobID:770662/
Only applications received in both systems will be considered.

The immune system plays a pivotal role in limiting tumour proliferation at all stages of the metastatic cascade. A particularly puzzling phase is early organ colonisation, during which the majority of tumour cells are eliminated, while some go into dormancy only to reappear later, often leading to lethal metastases. The intricacies of the role of the immune system during the phase of early organ colonisation and the immune evasion adaptive strategies employed by cancer cells remain poorly understood and may open new therapeutic avenues. This project aims to: (1) Delineate the cellular adaptive states and immune-contexture of early metastatic lesions in lung cancer that are either eliminated by the immune system or evade immunity, and investigate whether cellular states associated with immune-evasion are innate or evolve in the organ setting, by examining pre- and post-metastatic clones using advanced molecular profiling and our novel lineage tracing methods in experimental models (CaTCHseq paired with novel high-resolution spatial technologies); (2) use state-of-the-art functional genomics (through targeted CRISPR/Cas9 screens) to identify key drivers of immune evasion during early organ colonisation and cross-reference with clinical datasets; (3) dissect the biological mechanisms through which these drivers promote immune evasion during organ colonisation (targeted loss-of-function and gain-of-function genetic experiments). Through this concerted effort, we aim to provide the basis for the development of innovative strategies to enhance the immune response against metastatic tumour cells.

1. We will define clinically benchmarked gene expression states that characterise tumour clones with defined metastatic competence and immune-phenotypes and gain insights into the origin and evolution of these states within the organ site (Objective 1). 2. We will identify new genes and pathways that functionally mediate sensitivity or resistance to immunity (Objective 1-2). 3. We will establish biological mechanisms through which these genes support immune evasion and metastasis formation, and thereby, identify potential new targets for therapy (Objective 3).

The estimated annual gross salary for the fellow will be €41.797.

To apply for this position, please go to https://phd2.irbbarcelona.org/

For successful dissemination and outgrowth into metastases, cancer cells must evade detection and destruction by the immune system and adapt to a foreign tissue environment. Increasingly, it is recognized that cancer cell-intrinsic features, particularly altered genetics, play a pivotal role in determining the secretome and subsequent immunoregulatory capacity of cancer cells. This research proposal seeks to unravel the impact of diverse genetic compositions in mammary tumours on the immune milieu within pre-metastatic and metastatic niches across various organs, and how this impacts organ-specific metastasis formation. Building on these insights, we aim to provide preclinical proof-of-principle for anti-metastatic immune intervention strategies that are tailored to the genetic makeup of breast cancer. Leveraging cutting-edge models and technologies, including multiple (genetically engineered) mouse mammary tumour models, scRNA sequencing, multiplex IHC, high dimensional flow cytometry, and secretome analysis, we intend to address three objectives: 1) to comprehensively map the cellular and molecular heterogeneity of the immune landscape of (pre-)metastatic niches in lymph nodes and lungs of mice with mammary tumours with differing genetic makeup; 2) to identify paracrine communication networks between breast cancer cells with genetic variations and host cells that shape the immune contexture of the (pre-)metastatic niches; 3) to explore pre-clinical interventions that disrupt the (pre-)metastatic niche, tailored to the genetic makeup of the cancer cells.

1) We will identify how diverse genetic compositions in breast cancer impact the immune composition of the premetastatic and metastatic niche in lymph nodes and lungs. 2) We will identify the paracrine mediators with which breast cancer cells with varying genetic composition communicate with host cells in the (pre-)metastatic niche. 3) We will provide preclinical proof-of-principle for personalised (pre-)metastatic niche targeting strategies.

The estimated annual gross salary for the fellow will be €49.322.

To apply for this position, please go to https://phd2.irbbarcelona.org/

Hormone receptor-positive (HR+) BCa cells exposed to a suboptimal niche environment acquire a latent phenotype and gain intrinsic resistance to chemotherapy. We hypothesise that transcriptional and epigenetic plasticity are key to the adaptive drug-tolerant persister (DTP) cell metastasis phenotype. We believe that this plasticity is a prerequisite for a) latent metastasis; b) developing acquired drug resistance; and c) colonising distant sites. To decode the molecular underpinnings of the adaptive plasticity of DTP metastatic cells, we will elucidate and integrate the mechanisms through which signalling pathways, chromatin remodelling factors, and transcriptional networks contribute to DTP and metastasis expansion, samples analyses will be done by bulk and scRNA-seq. We will integrate data from all omic approaches, to define pathway deregulation and transcriptional gene adaptive programs. Potential proteins from genes described above will be characterised in a metastasis spatio-temporal manner using IHC multiplexing. We will use the CATCH system to isolate founding clones alive before and during selection, allowing functional experiments. We will preferentially focus on those molecular changes that control luminal differentiation, impose indolent metastasis, and are related to secreted factors or receptors.

i) Define the ER+BCa chromatin and transcriptional landscape in DTP latent metastatic cells. ii) Connect the initial BCa cell adaptive transcriptome states, with the clone outcomes at relapse. Pathway analysis and differential expression profiling of pre-treatment and post-treatment relapses will allow us to identify surface receptors or other means to purify and isolate those cell states prospectively. iii) confirm potential mechanisms of resistance as well as biomarkers of non-responders.

The estimated annual gross salary for the fellow will range between €30,000 and €33,000.

To apply for this position, please go to https://www.irbbarcelona.org/en/careers/young-scientists/adaptmet-2025-call

Breast cancer (BCa) is the most common cause of cancer-related death in women worldwide. The survival rate of localised BCa is 98%; however, this falls to 28% for distant metastatic BCa. Endothelial cells (ECs) line the inner part of blood vessels and regulate tissue pathophysiology through paracrine signals. Yet, the paracrine response of bone ECs in the presence of metastasis remains unknown. We will use a mouse model of bone metastasis in combination with transgenic mouse models that allow us to trace distinct endothelial cells subpopulations to identify the endothelial paracrine signals which promote metastatic growth in the bone. To address our questions, we will combine scRNAseq and 3D multiplexing in vivo, with proteomic screening in vitro.

With the combination of models and techniques that we have at our disposal, we aim to decipher (i) how the metastasis process in the bone occurs; (ii) which are the EC signals that promote metastasis growth; and (iii) new targetable paracrine signals which block metastasis growth.

The estimated annual gross salary for the fellow will range between €30,000 and €33,000.

To apply for this position, please go to https://phd2.irbbarcelona.org/

The 3 members of the NR2F nuclear receptor family have been linked to crucial functions in cancer progression and metastasis. Shortly, NR2F1 has been linked to metastasis dormancy, NR2F2 can act on tumour growth and metastasis by modulating angiogenesis, and NR2F6 overexpression has been linked to tumour aggressiveness, metastasis adaptation and relapse as well as to tumour immune environment. We will use gain and loss of function cancer cell line models as well as transgenic mice models to decipher the role of NR2F1, NR2F2 and NR2F6 in metastasis formation and dormancy. Their role will be studied in cancer types in which they are overexpressed, like in skin squamous cell carcinoma, breast cancer and ovarian cancer. The effects of gene deletion or gain of function will be studied on invasion, migration, differentiation, proliferation, apoptosis, number, size and dormancy status of metastasis. In vivo tumours and metastasis will be isolated and cells profiled, to identify the adaptive gene regulatory networks associated with the loss or gain of NR2F members and the observed phenotype.  This study will provide key insights into the molecular mechanisms implicating the NR2F family members in metastasis.

Define the i) phenotype of NR2F1, NR2F2 and NR2F6 gain and loss of function in several cancer models in metastasis formation, ii) in metastasis dormancy, iii) as well as the associated gene regulatory networks, iv) and identify potential therapeutic targets to decrease metastasis burden.

The estimated annual gross salary for the fellow will be €48.000.

To apply for this position, please go to https://phd2.irbbarcelona.org/

Oncogene inhibition by targeted therapies can lead to very significant reduction in metastatic burden. However, minimal residual disease often persists as latent metastases, some of which eventually relapse and cause a difficult-to-treat metastatic disease. Novel approaches are thus needed to target latent metastatic disease after successful systemic therapy. To understand molecular mechanisms that facilitate the survival of latent metastatic disease after successful therapy, work under this project has the following aims: (1) To characterize cellular states associated with residual disease after oncogene inhibition using high-resolution molecular profiling (RNA-seq, ATAC-seq) in experimental systems that model oncogene-dependent cancer growth in vivo. With a focus on HIF2A, a central driver of kidney cancer and a validated clinical drug target, we will use both genetic tools and clinically approved small molecules for oncogene inhibition. (2) Building on the molecular profiles from Aim 1, to use state-of-the-art genetic perturbation by CRISPR/Cas9 to identify molecular dependencies in residual cells after prolonged oncogene inhibition. (3) To combine the new biological insight derived from Aims 1-2 with detailed mechanistic analyses to test and validate novel targets that could be exploited to reduce the probability of eventual metastatic relapse after initially successful oncogene targeted therapy (targeted loss-of-function and gain-of-function genetic experiments).

1. Molecular profiles associated with latent metastatic cells after successful oncogene inhibition (Objective 1).

2. Identification of genes that support the survival of latent metastatic disease after oncogene targeted therapy (Objective 2).
3. Biological mechanisms that support metastasis formation by latent disseminated cells after oncogene targeted therapy, i.e. identification of potential new targets for therapies against latent metastatic cells (Objective 3).

The estimated annual gross salary for the fellow will be €43.043,04.

To apply for this position, please go to https://phd2.irbbarcelona.org/

The main objective of the project is to identify novel ctDNA-based biomarkers for predicting response to treatment in metastatic HER2-positive (HER2+) and triple-negative breast cancer (TNBC). To do so, the DC will gather all clinicopathological data from patients with metastatic HER2+ and TNBC for which liquid biopsies have been obtained at baseline, cycle 2 day 1, and end of treatment/progressive disease of any given treatment. The DC will also isolate ctDNA from all liquid biopsies which will be analysed using shallow whole genome sequencing and a next generation sequencing panel for the detection of mutations. Finally, the DC will perform correlative analyses to identify associations of ctDNA alterations with adaptive response to treatment, survival, and other clinicopathological variables, as well as with tumour tissue-based biomarkers.

We expect to identify novel ctDNA-based biomarkers for predicting response to treatments in metastatic HER2-positive (HER2+) and triple-negative breast cancer (TNBC).

The estimated annual gross salary for the fellow will range between €30,000 and €33,000.

To apply for this position, please go to https://phd2.irbbarcelona.org/

The majority of cancer therapies suffer from resistance development, preventing long-term cures. Cancer immunotherapies revolutionised cancer treatment with curative effects. However, this success is currently limited to inflamed tumours. Current therapies mainly induce apoptosis, lacking the capacity to stimulate the immune system. Immunogenic cell death (ICD), on the other hand, can activate an anti-tumour specific immunity against the primary tumour and metastases. Emerging ICD pathways include ferroptosis, necroptosis, and pyroptosis. Studies demonstrated that pyroptosis induction in a subset of cancer cells already leads to the clearance of tumours via the immune system. However, our understanding of how immunogenic cell death pathways alter the tumour microenvironment to contribute to an adaptive antitumor immune response is currently poorly understood, representing a major hindrance for novel ICD therapies in the primary and advanced metastatic setting. Herein we will investigate different forms of cell death and their ability to initiate a systemic de-novo immune response. We have established murine cancer cell lines in which apoptosis, pyroptosis, and necroptosis can be selectively induced. Our preliminary evidence suggests that pyroptosis can lead to a robust antitumor immune response systemically. To improve our understanding of non-immunogenic versus immunogenic cell death, tumour microenvironment changes in all three settings will be compared.

The above-described studies will uncover i) the effects of non-immunogenic and immunogenic cancer cell death on the tumour and metastasis microenvironment, especially on the innate immune system. These results potentially can help us to ii) understand how to (re-)activate the immune system against cancer cells in future therapies.

The estimated annual gross salary for the fellow will be €50.570,40, with possibility for overpayment.

To apply for this position, please go to https://phd2.irbbarcelona.org/

The aim of this project is to characterise the interactions between tumour and metastasis infiltrating immune cells and cancer cells in the context of isoform-level protein-protein interactions. Many cancers are known to have increased rates of isoform switching, which occurs more often in cell membrane proteins compared with intracellular proteins. These may lead to different adaptive cancer states.

Objective 1 is to use publicly available single cell whole transcript sequencing data from different cancers to characterise the interactions between tumour and metastasis infiltrating immune cells and cancer cells. We will quantify isoform-specific expression of receptors, ligands, and cytokines in individual immune cells and cancer cells in the tumour microenvironment (TME) and elucidate interactions. We theorise that subclonal isoform switching in the immunological synapse of cancer cells is an immune escape adaptive mechanism.

Objective 2 is to use bulk transcriptomics data from several cancers. We will deconvolute bulk transcript expression to metastasis and immune cell population level expression to validate the findings from Objective 1, and to broaden the analysis to various cancer types for which single cell whole transcript sequencing is not yet available.

We expect to gain insights into the impact of subclonal isoform-switching on tumour-immune cell interaction, and its role in immune escape. If relevant, we will form testable hypotheses about whether these sub gene-level changes are actionable for concomitant therapy of immune “cold” tumour microenvironments.

The estimated annual gross salary for the fellow will be €61.056.

To apply for this position, please go to https://phd2.irbbarcelona.org/

Abnormal cell migration is characteristic of cancer cells and is driven by cytoskeletal remodelling. Epithelial cells become motile by undergoing epithelial-to-mesenchymal transition (EMT), while mesenchymal cells increase migration speed by adopting amoeboid features. We have described how amoeboid behaviour is not merely a migration mode but a cellular state—within the EMT continuum—by which cancer cells survive, invade, adapt, and colonise challenging microenvironments. We found an enrichment in amoeboid cells at the border of primary tumours and at the border of metastatic lesions in several tumour types. The tumour edge represents a unique structure in which cancer cells are more exposed to matrix, stromal cells, and immune infiltrate. Invading and disseminating cells must overcome immune cell attack on their way to a secondary site, so they develop immunosuppressive strategies. In this project, we will focus on studying the adaptive interactions that amoeboid cancer cells establish with the metastatic niche, with a particular focus on TNBC metastasizing to lung and brain and the specific interactions with immune cells in those organs. 3D co-culture systems and organoids, mouse models, and patient samples will be used to dissect the specific crosstalk between amoeboid cancer cells and the TME supporting their metastatic abilities.

i) We will characterise how Myosin driven cytoskeletal dynamics blockade generates a less supportive TME in metastasis and ii) how these adaptive mechanisms operate during metastatic organ colonisation and outgrowth; iii) we will use this gained knowledge to identify therapeutic vulnerabilities of amoeboid metastatic TNBC cells that could be clinically targeted.

The estimated monthly gross salary for the fellow will be £4574.

For this position, please see:

https://www.icr.ac.uk/media/docs/default-source/studying-at-the-icr/2023-phd-recruitment/sanitised-phd-proposal-template-icr-vsm.pdf

The recruitment for this position is now closed:

https://www.icr.ac.uk/studying-and-training/phds-for-science-graduates/phd-studentship-projects

Metastases to the brain can develop in up to 40% of patients with cancer in extracranial organs, thus representing a major clinical challenge. Our lab has investigated in depth the tumour microenvironment (TME) in brain metastasis (BrM) in recent years, and we have revealed critical tumour-promoting roles for immune cells. Intriguingly, we often find immune cells clustered in the perivascular niche surrounding the blood vessels in the brain. Therefore, in this new project, we will explore the intricate interplay between immune cells and the blood vasculature in the brain—to ask how blood vessels control the entry of immune cells into the TME and subsequently modulate their functions. To address these questions, we will use a comprehensive strategy to integrate existing data from our analyses of patient samples (e.g., scRNAseq of endothelial cells, pericytes, and different immune cells), coupled with ex vivo functional assays (including blood-brain barrier (BBB), angiogenesis, and brain slice assays) and mouse BrM models. This will allow us to uncover the adaptive cellular and molecular mechanisms driving the complex interplay of cells in the brain TME. This gained knowledge will be critical for the ultimate development and evaluation of improved therapies for these diseases.

We expect the following outcome from this proposed research: i) to determine the adaptive cellular and molecular mechanisms by which immune cells selectively cross the BBB to enter the brain TME; ii) to understand how the blood vasculature (focusing on endothelial cells and pericytes) alters the functions of neighbouring immune cells; iii) to use this gained knowledge to identify therapeutic targets which can then be evaluated in our preclinical BrM models.

The estimated annual gross salary for the fellow will be CHF 55.000.

The recruitment for this position is now closed: https://joycelab.org/positions

Until recently, the standard of care treatment for ER+ breast cancer has focused on ablating ER signalling using various endocrine therapies, including Fulvestrant, a selective ER antagonist and degrading compound. Given the cell cycle dysregulation in luminal breast tumours, it is not a surprise that the very recent development of novel cell cycle inhibitors such as Ribociclib, a CDK4/6 inhibitor, has revolutionised the standard of care for advanced, metastatic breast cancer. However, metastatic breast cancer is mostly incurable. Although promising new treatment options such as the combination of Fulvestrant plus Ribociclib improve overall survival in metastatic breast cancer patients, mechanisms of adaptation to treatment, its evasion, and resistance pose a major hurdle in finding a cure for patients. Identifying clinically relevant mechanisms of resistance is of paramount importance to better understand and treat metastatic ER+ breast cancer. We will use a combination of cell lines in vitro and in vivo, patient material, and the CaTCH system.

i) Elucidate how resistance to Fulvestrant plus Ribociclib emerges in breast cancer metastasis. ii) Address how the therapy shapes the clonal landscape of the primary tumour and the metastatic lesions of in vivo ER+ breast cancer models. iii) Identify, validate and characterise what transcriptomic changes arise upon resistance to Fulvestrant plus Ribociclib in the metastatic setting.

The estimated annual gross salary for the fellow will be CHF 51.267.

To apply for this position, please go to https://phd2.irbbarcelona.org/