Projects – Cancer metabolism and the immune response

Fellow ESR1. Project: Metabolic induced-essentialities required for tumor maintenance under hypoxia
Host institution: Technion, Israel Institute of Technology; Haifa, Israel
PI: Eyal Gottlieb. http://ticc.web3.technion.ac.il/labs/cancer-metabolism/
Aim and Background: Cancer cells have increased bioenergetic demands and proliferation rates, and have defense mechanisms that are selected for under conditions of stress. Identifying and targeting these survival mechanisms may help eliminate cancer growth and specifically induce cancer cell death. Since hypoxia is not common in normal tissues, genes that are specifically essential for the survival of hypoxic cells can be considered potential targets for preferentially killing cancer cells. We aim to identify specific vulnerabilities cancer cells under hypoxia.
Research: We will study triple negative breast cancer (TNBC) cell lines as this breast tumor subtype is very difficult to treat and associated with poor patient outcome. The research will combine several comprehensive approaches. We will conduct transcriptomic (RNA-Seq) analyses to identify genes that are up-regulated in hypoxic conditions focusing on metabolic genes (enzymes and metabolite transporters). These results will be integrated with data from primary tumours using systems biology and network analysis to try and model a metabolic gene profile with hypoxic signatures, stage of the disease and prognosis. Candidate genes that are potentially essential for hypoxia survival will be tested in vitro utilising RNAi and CRISPR technologies. This will be followed by tumor xenograft animal models utilizing inducible shRNA systems.
Planned secondment: Secondment to IBM Research, Israel to use their expertise in data analysis.
Outputs: i) identification of enzymes and metabolite transporters modulated upon hypoxia, ii) model a metabolic gene profile, iii) list of potential new targets for validation studies.

Fellow ESR2. Project: Metabolic signature of cerebrospinal fluid (CSF) infiltrated with leukemic cells
Host institute: IBM Research – Haifa
Team: Machine Learning for Healthcare and Life Sciences https://www.research.ibm.com/haifa/dept/vst/mldm.shtml
Objectives: Analyze comprehensive transcriptomic and metabolomic data using statistics, machine learning, and systems biology algorithms, to study the potential metabolic adaptations of cancer cell to the central nervous system niche.
Expected results: We aim to identify the differences in CSF metabolic profiles between patients with leukemia, patients without detectable CNS leukemia, and normal controls. Our goal is to develop a diagnostic tool that identifies CNS involvement of leukemia in early stages of the disease or during relapse after treatment.
Planned secondment(s): Technion Integrated Cancer Center
Required technical and professional expertise: Relevant background and research experience in machine learning; good programming skills, preferably in Python or R.

ESR3 – EGFR and tumor cell metabolism
Institute of Cancer Research, Medical University of Vienna, Austria.
PI: Maria Sibilia. https://krebsforschung.meduniwien.ac.at/forschung-research/research-focus/cellular-and-molecular-tumorbiology/maria-sibilia/?L=1
Project: EGFR inhibitors have been shown to lead to reversion of the Warburg phenotype in tumor cells. However, we have recently demonstrated in colorectal cancer (CRC) that EGFR inhibition in tumor cells does not lead to tumor regression which is a very surprising and unexpected finding. In contrast, EGFR inhibition in myeloid cells reduced CRC growth indicating that EGFR is tumorigenic when expressed in tumor-associated myeloid cells. It is presently unknown how EGFR expression is upregulated in tumor-associated myeloid cells and whether factors secreted by tumor cells are important in this process.
Objectives: We aim to investigate the metabolic changes induced by EGFR inhibition in tumor cells and whether these changes can modulate myeloid cells in the tumor stroma. We also intend to validate metabolic phenotypes in human cancer material.
Expected Results: We expect to gain information on the metabolic state of EGFR inhibited CRC and how this affects the immune infiltrate in CRC.
Planned secondment(s): Technion (Haifa, Israel) and Boehringer Ingelheim.

ESR4 – Metabolic vulnerabilities in rhabdomyosarcoma
Institute: IDIBELL. PI: Oscar Martinez-Tirado, http://www.idibell.cat/modul/sarcoma-research-group/en
Project: Alveolar rhabdomyosarcoma is a rare childhood tumor. In this project we aim to identify new possibilities for short circuiting cancer metabolism, based on the genotype of these tumors, which may lead to novel drug combinations.
Expected Results: To identify metabolic factors and pathways important for fusion protein-associated pediatric sarcomas progression.
Candidate requirements: Degree in any Life Sciences discipline. Previous experience in metabolomics would be a plus.
Planned secondments: TICC (Haifa, Israel), Hospital Sant Joan de Deu (Barcelona). PhD registration at the University of Barcelona, Biomedicine program.

ESR5 – Cell-cell effects of starvation of cancer cells on the immune system
Institute: IDIBELL (Bellvitge Biomedical Research Institute). Barcelona, Spain
Team: Cell Death Regulation Group.
PI Cristina Muñoz-Pinedo, http://www.idibell.cat/modul/cell-death-regulation/en
Project: Anti-metabolic drugs promote of tumor cells, but they also induce effects on the tumor stroma and the immune system. The candidate will characterize cell-cell effects of a group of proteins secreted by tumor cells that may play a role in cancer response to anti-metabolic drugs. Experiments will include in vitro analysis of responses of different tumor microenvironment populations to experimental starvation, and in vivo effects of selected proteins during lung cancer and sarcoma development and treatment with anti-metabolites.
Candidate requirements: Degree in Life Sciences. Qualifications for work with murine models are desirable.
Planned secondments: AMC (Amsterdam), AROMICS (Barcelona). PhD registration at the University of Barcelona Biomedicine program.

ESR6 – Cancer-Immunometabolism. How do cancer cells affect the metabolism of normal immune cells in their environment
Institution: AMC (Academic Medical Center), Amsterdam
https://www.amc.nl/web/Research/Overview/Departments/Experimental-Immunology/Experimental-Immunology/Current-research-1.htm
Team: Immuno-hematology group AMC, PI Eric Eldering.
Objectives: Understand and be able to influence metabolic changes induced by malignant cells that subvert T cell function.
Summary: Malignant cells alter the metabolic state and function of surrounding normal T cells. The candidate will investigate this in various B cell malignancies (FL, DLBCL, MM). Healthy donor T cells and patient T cells will be compared for metabolic parameters and in immune function, using cutting edge techniques and co-culture assays (Sea-horse metabolic analyser, metabolomics, candidate gene and drug screens)
Planned secondment(s): IDIBELL (Barcelona), Evotec (Toulouse)
Candidate requirements: degree in life sciences, proven experience with (primary co-)cultures and cellular biochemistry, knowledge of metabolism, immunology and/or hematology strongly preferred, experience with molecular biology, immune- or metabolic assays desirable.

ESR7Identification of metabolic pathways in TAMs and cancer cells that cause immune paralysis
Institution: VIB (Center for Cancer Biology). Leuven, Belgium
Team: Laboratory of Tumor Inflammation and Angiogenesis. PI: Massimiliano Mazzone, https://www.vibcancer.be/massimiliano-mazzone
Objectives: Metabolic competition within the tumor microenvironment is a key hallmark of cancer progression and it can influence the growth and the survival of both cancer cells and tumor stromal cells. We studied Glutamate dehydrogenase 1 (GLUD1), an enzyme that catalyzes the oxidative deamination of glutamate to α-ketoglutarate, and we demonstrated that upon the inhibition of GLUD1 in macrophages we could observe an increase in glutamine level. In a context of immune checkpoint treatments, the increase in glutamine availability can lead to T cell activation and, thus, boost the immune response.
Expected Results: the goal of the project is to reprogram the tumor microenvironment via metabolic editing of cancer cells and/or TAMS in order to improve the efficacy of cancer immunotherapies, both adoptive cell transfer and immune checkpoint inhibition.
Specific requirement of the candidate: The candidate should hold a master in cell biology or related disciplines. Certificate to work with murine models and experience in cellular and molecular biology techniques would be appreciated.
Planned secondment(s): IDIBELL (Barcelona, Spain), AMC (Amsterdam, Netherlands), TICC (Haifa, Israel).

ESR8 – Integrated control of metabolism in TAMs
Institution: VIB (Center for Cancer Biology). Leuven, Belgium
Team: Laboratory of Tumor Inflammation and Angiogenesis. PI: Massimiliano Mazzone, https://www.vibcancer.be/massimiliano-mazzone
Objectives: Fatty acid oxidation is a hallmark of M2-like macrophages in both infectious diseases and the tumor microenvironment. The NAD-dependent deacetylase sirtuin-1, Sirt1, which is induced by hypoxia and a downstream target of AMPK, is a regulator of fatty acid metabolism and regulates HIF pathway. The role of Sirt1 in tumor-associated macrophages is unexplored. We aim to study how Sirt1 integrates TAM metabolism and the immune response orchestrated by TAMs. By looking at the regulation of HIFs by acetylation, we will focus on the metabolic and phenotypic rewiring of hypoxic TAMs, hoping to control their immunosuppressive, pro-metastatic, and pro-angiogenic phenotype.
Expected Results: we aim to re-educate TAMs metabolically and functionally by targeting Sirt1 genetically and pharmacologically. Eventually, downstream targets to HIF regulation by Sirt1 will be functionally validated for targeted therapies in mouse models of cancer.
Specific requirement of the candidate: The candidate should hold a master in cell biology or related disciplines. Certificate to work with murine models and experience in cellular and molecular biology techniques would be appreciated.
Planned secondment(s): IDIBELL (Barcelona, Spain), AMC (Amsterdam, Netherlands), TICC (Haifa, Israel).

ESR9EGFR and innate cell metabolism
Institute of Cancer Research, Medical University of Vienna, Austria.
PI: Maria Sibilia. https://krebsforschung.meduniwien.ac.at/forschung-research/research-focus/cellular-and-molecular-tumorbiology/maria-sibilia/?L=1
Project: The oncogenic function of the EGFR is not only attributed to its expression in tumor cells, as we recently demonstrated that EGFR is upregulated in tumor-associated macrophages (TAMs) and myeloid cells, where it seems to promote tumor development. It is presently unclear how EGFR expression in TAMs affects their metabolic behavior.
Objectives: We aim to investigate the metabolic signatures of EGFR deficient and proficient myeloid cells, focusing first on myeloid cells isolated from mouse CRCs and validate these findings in human CRC.
Expected Results: We expect to gain information on the metabolic signatures of EGFR proficient and deficient myeloid cells isolated from CRC and how they affect cancer growth.
Specific requirement of the candidate: Applicants should hold a Master degree or equivalent and be knowledgeable in cell biology, molecular biology and immunology. Experience with mouse models would be advantageous
Planned secondment: VIB Leuven, Evotec (Toulouse, France)

ESR10 – Starvation signaling pathways that lead to cytokine production
Institute: IDIBELL (Bellvitge Biomedical Research Institute). Barcelona, Spain
Team: Cell Death Regulation Group.
PI Cristina Muñoz-Pinedo, http://www.idibell.cat/modul/cell-death-regulation/en
Project: Starvation of cancer cells has been shown to promote chemokine secretion. The candidate will employ cellular and molecular biology techniques to investigate intracellular signaling pathways activated in response to nutrient deprivation, and the role of these pathways in death of cancer cells and cell-cell communication upon starvation.
Planned secondment: VIB Leuven, FEBS Journal. PhD registration at the University of Barcelona, Biomedicine program.

ESR11 – Metabolic adaptations and essentialities under hypoxia
Name of partner : Evotec , www.evotec.com (Evotec – Integrated Services, Evotec – In Vivo Services, Evotec – Proteomics Metabolomics Services). Toulouse, France.
Name of leader: Nathalie Alet
Objectives: to identify metabolic genes that are modulated or mutated in acute myeloid leukemia patient samples. Set up in vivo model(s) suitable for validation of their interest.
Expected Results: We will model a metabolic gene profile in acute myeloid leukemia and link this gene profile to patient outcome according to the treatment received. Then drugs/compounds potentially modulating the metabolic profile in a beneficial way may be tested in vivo.
Specific requirement of the candidate: The candidate should hold a master 2 in pharmacology or related disciplines. Practice or knowledge of in vivo animal experimentation techniques as well as in cellular and molecular biology techniques would be appreciated.
Planned secondments: TICC, AMC (Amsterdam)

ESR12. Project: Role of diets on chemotherapies and anti-cancer immune response
Name of the institute: INSERM U1065, Mediterranean Center for Molecular Medicine (C3M).
Name of the team: Metabolism, Cancer and Immune response
Name of the leader: JE RICCI, PhD. ricci@unice.fr
Location: Nice, France.
Web link: http://www.unice.fr/c3m/index.php/research-teams/jean-ehrland-ricci/
Abstract of the project: We recently established that reducing the dietary intake of mice that develop B lymphomas by 25% a week was sufficient to reduce Mcl-1 expression and sensitize those mice to the targeted chemotherapy (Meynet et al Blood 2013, Meynet et al Trends Mol Med 2015). Using cutting edge technologies the PhD student will comprehensively detect the global cellular changes induced by specific diets in RNA, protein, cytokine and immune response. The project will be conducted in cell lines, murine and human primary cells as well as in vivo.
Specific requirement of the candidate: The candidate should hold a master 2 in cell biology, pharmacology or related disciplines. Practice or knowledge of in vivo animal experimentation techniques as well as in cellular and molecular biology techniques would be appreciated.
Planned secondment(s): TICC, Cancéropole.

ESR13. Project: L-Asparaginase as an alternative option to lymphoma patients not responding to current treatments
Name of the institute: INSERM U1065, Mediterranean Center for Molecular Medicine (C3M).
Name of the team: Metabolism, Cancer and Immune response
Name of the leader: JE RICCI, PhD. ricci@unice.fr
Location: Nice, France.
Web link: http://www.unice.fr/c3m/index.php/research-teams/jean-ehrland-ricci/
Abstract of the project: Diffuse large B-cell lymphoma (DLBCL) are very common and aggressive tumors with exacerbated metabolism. Despite the breakthrough treatments with anti-CD20 immunotherapy (Rituximab, R), associated with the conventional treatment CHOP (referred as R-CHOP), 40% of patients with DLBCL are ultimately in treatment failure. Interestingly, 80% of DLBCL do not express asparagine synthase (ASNs) that catalyzes the conversion of glutamine and aspartate into asparagine, a nonessential amino acid that participates in the synthesis of DNA and protein synthesis. Therefore, the PhD student, will analyze if L-Asparaginase (a drug that depletes Asn from the circulation) could be proposed as a complementary treatment to R-CHOP refractory patients. The project will be conducted in cell lines, murine and human primary cells as well as in vivo.
Specific requirement of the candidate: The candidate should hold a master 2 in cell biology, pharmacology or related disciplines. Practice or knowledge of in vivo animal experimentation techniques as well as in cellular and molecular biology techniques would be appreciated.
Planned secondment(s): HSL and TICC

ESR14 – Identify the impact of drugs targeting metabolism on immune checkpoints in lymphoma
Name of the institute: Université Paris Descartes, Faculté de Pharmacie
Name of the team: NF-kB, Differentiation and Cancer
Name of the leader: Catherine Thieblemont M.D., Ph.D./Véronique Baud, Ph.D.
Location: Paris, France.
Abstract of the project: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive non-Hodgkin lymphoma. Up to 40% of DLBCL patients will ultimately relapse or progress and die, highlighting the crucial need for novel therapeutic strategies. Remarkably, we have recently demonstrated that metabolic inhibition is of great clinical benefit for refractory/relapsed DLBCL patients. Further, growing understanding of the complex dialog between tumor cells and their microenvironment contributed to the development of immune checkpoint inhibitors. The proposed PhD program aims at studying the interplay between anti-metabolic drugs and (i) immune checkpoints (e.g. PDL-1, CTLA-4) and (ii) NF-kB activation, a master control of immune response, in aggressive relapsed/refractory DLBCL to improve clinical efficacy. The project will be conducted in DLBCL patient samples, cell lines using co-culture systems, and in vivo animal models.
Specific requirement of the candidate: Applicants should hold a Master in cell biology, immunology or related disciplines. Direct experience on onco-hematology research is not necessary. Background in cellular and molecular biology techniques as well as in vivo animal experimentation would be an advantage.
Planned secondment: INSERM (Nice).

ESR15 – Preclinical development of novel chemical entities as antitumour agents
Team: Applied research using Omic Sciences, S.L. (AROMICS)
PI Dr. Carmen Plasencia, http://www.aromics.es
Project: We recently patented a family of new chemical entities, derivatives of berberine, with activity as antitumor agents. First lead compound is advancing up to clinics to treat malignant mesothelioma. The PhD student will comprehensively contribute to the selection and optimization of a lead candidate, and to test it in pre-clinical models. Selection will be based on the in vitro and in vivo activity, modulation of specific targets and metabolic pathways, physicochemical and pharmacological aspects, with the objective of completing the preclinical development stage for the selected candidate(s).. The candidate will employ cellular and molecular biology techniques as well as pharmaocological aspects (ADMET) to elucidate the efficacy of the compounds and their properties to advance into further development stages.
Specific requirement of the candidate: The candidate should hold a master in pharmacology, molecular biology, biomedicine or related disciplines. Practice or knowledge of drug development experimentation techniques, including cellular and molecular biology techniques as well as pharmacokinetic aspects would be appreciated. Also some experience in research laboratories of pharma companies will be welcomed.
Planned secondment(s): MUW (Vienna). Purpose: To expand the knowledge about the efficacy of the drugs in different mouse models, including evaluation over specific targets relevant for the tumorogenesis in these models. PhD registration at the University of Barcelona Biomedicine program.