European Research Council (ERC) transitional measures
The European Research Council (ERC) is the premier European funding organisation for excellent frontier research. The ERC offers four core grant schemes: Starting Grants, Consolidator Grants, Advanced Grants and Synergy Grants.
To compensate for Switzerland's current third-country status in the Horizon package 2021-2027, these schemes have been replaced by transitional measures for the 2021, 2022 and 2023 calls for proposals by the Swiss National Science Foundation (SNSF).
STARTING GRANTS:
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2023-2028: Oncogenic Competence at the Cellular and Multicellular Level in Melanoma
Grantee:
Arianna Baggiolini
Funding Scheme:
SNSF-2022-StG
Duration:
April 2023 – March 2028
Title:
Oncogenic Competence at the Cellular and Multicellular Level in Melanoma
Acronym/ID:
211664
Abstract
Oncogenes cause malignant transformation only in certain cellular contexts, a phenomenon called oncogenic competence. In melanoma, tumour initiation upon oncogene expression activates a neural crest lineage program. My work has shed some light on why a neural crest-like state is required and particularly susceptible to oncogenic transformation and shown that an epigenetic developmental program regulates such a state. My lab will take a multidisciplinary approach using my expertise in mouse biology, cellular engineering, and human pluripotent stem cell (hPSC)-based technologies to study the epigenetic regulation of oncogenic competence during melanoma initiation and progression. Finally, we will define how oncogenic competence is regulated at the cell-intrinsic and multicellular levels depending on the microenvironment.
Oncogenic competent progenitor cells express a distinct profile of epigenetic-related factors. Among those, ATAD2, an ATPase- and bromodomain-containing protein, regulates oncogenic competence in melanoma, activates a developmental signature typical of the neural crest and regulates the MAPK pathway. ATAD2 is necessary and sufficient for tumor initiation and confers invasive properties to hPSC-derived melanoma cells. Furthermore, ATAD2 induces the expression of many epigenetic factors known to play a role in melanoma, and many of those factors are direct targets. My lab will investigate the developmental chromatin programs and the role of ATAD2 in the epigenetic regulation of both melanoma initiation and progression.
A progenitor cell-related signature is often related to melanoma invasion to distant organs, and the brain is one of the most frequent sites affected by metastatic melanoma cells. My lab will use a cutting-edge hPSC-based brain organoid model, that I have developed, to study oncogenic competence in the human brain microenvironment, the cellular cross-talk between melanoma cells and the brain cells, cancer cell adaptation and niche remodelling. The brain microenvironment imposes a distinct selective pressure on the cancer cell. The 3 cell types – neurons, astrocytes, and microglia – build the neuroinflammatory axis, which involves complex cellular cross-talk that promotes homeostasis and neuronal function during health but can play a pro-metastatic role in the context of brain metastases. Challenging access to brain cells, especially in the human context, and difficulties maintaining those cells in culture, have hampered the study of melanoma cells in the human brain microenvironment. Studies using genetically engineered mouse models have been proven to be very efficacious and instructive. However, some aspects of the neuroinflammatory axis are unique to humans reflecting the species-specific differences in the cell types of the brain. Using both melanoma mouse models and the hPSC-derived brain organoid platform, we will investigate cellular cross-talk and melanoma cell adaption to the brain microenvironment and highlight the mechanisms responsible for the instruction and the remodeling of the brain niche.
Aim A) Investigation of the developmental chromatin programs controlling oncogenic competence during melanoma initiation and progression. We will investigate the epigenetic regulatory landscape and the role of ATAD2 in the epigenetic regulation of oncogenic competence during melanoma initiation and progression. We will define the upstream mechanisms that regulate the expression of ATAD2 and the acquisition of an oncogenic competent state and, finally, build a melanoma mouse model to study the role of Atad2 in vivo.
Aim B) Study of oncogenic competence at the multicellular level in the brain. We will identify the mechanisms that regulate melanoma cell adaptation to the brain microenvironment and niche remodeling. We will investigate the role of developmental chromatin programs in the formation of brain metastasis, and how the niche might select and/or regulate those programs. To this aim, that lab will use both the hPSC-derived brain organoid platform and mouse models of melanoma brain metastasis.
Our work will provide mechanistic insights into the process of oncogenic competence and its regulation both at the cell-intrinsic and extrinsic levels, depending on the microenvironment. We will investigate the role played by developmental chromatin factors in the regulation of oncogenic competence during melanoma initiation and metastasis formation. Furthermore, we will define novel approaches to target oncogenic competence, exploit susceptibilities of melanoma brain metastasis and promote an anti-metastatic niche.
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2024-2028: Dissecting the role of intracellular bacteria and neutrophil heterogeneity in cancer susceptibility and progression
Grantee:
Arianna Calcinotto
Funding Scheme:
SNSF-2023-StG
Duration:
January 2024 – December 2028
Title:
Dissecting the role of intracellular bacteria and neutrophil heterogeneity in cancer susceptibility and progression
Acronym/ID:
218488
Abstract
Neutrophils have recently gained increased attention in cancer. We have recently demonstrated that neutrophils support the growth of hormone-driven cancers such as breast and prostate cancer. We have found that during tumorigenesis, neutrophils are mobilized from the bone marrow and recruited to tumors by the tumor secretome. We have also shown that once in the tumor microenvironment, these cells persist alive, acquiring features of cellular senescence. This finding has reverted a previous notion in the field, considering these immune cells of a short half-life. Recent results from my lab identified a subset of immature neutrophils named Neutrophil Precursors (PreNeu) that can proliferate in the tumors of Luminal B breast cancer patients, an aggressive tumor type characterized by poor prognosis. As demonstrated, these immune cells can promote genetic instability by releasing into the tumor microenvironment an oncometabolite. The intratumoral microbiota has also recently raised increased attention in cancer. Previous studies demonstrate that bacteria highly colonize breast tissues and that microbes are located mostly intracellularly in cancer cells and immune cells.
Whether the intracellular cancer bacteria regulate neutrophil heterogeneity in the tumor microenvironment, or may contribute to cancer susceptibility in BRCA-mutated germline females is a black hole in the field.
The main objectives of this application are to assess whether intracellular bacteria can promote breast cancer aggressiveness through the regulation of the tumor secretome and tumor immune response, using innovative state-of-the-art methodologies and different in vivo mouse models of breast cancer and cancer susceptibility.
CONSOLIDATOR GRANTS:
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2016-2021: Dual targeting of senescence and tumor immunity for cancer therapy
Grantee:
Andrea Alimonti
Funding Scheme:
ERC-2015-COG
Duration:
July 2016 – June 2021
Title:
Dual targeting of senescence and tumor immunity for cancer therapy
Acronym/ID:
Immune-senescence - 683136
Abstract
We have previously demonstrated that cellular senescence opposes tumorigenesis thereby opening up new potential opportunities for cancer treatment. Senescence and tumor immunity in cancer are tightly interconnected. Tumor-infiltrating immune cells promote the clearance of senescent tumor cells thereby contributing to the tumor suppressive function of senescence. Moreover, T lymphocytes can drive senescence in cancers by secreting different cytokines in the tumor microenvironment. We have also recently reported that GR1+ myeloid cells antagonize treatment-induced senescence (TIS) and that compounds that block the tumor recruitment of GR1+ cells enhance TIS. Major objective of this proposal is to characterize the immune landscape of different prostate cancer mouse models in order to develop novel treatment modalities that combine pro-senescence compounds with immunotherapy. Using proteomics and bioinformatics approaches, we will assess how the genetic background of prostate tumors, shapes the tumor microenvironment and immune response during TIS. Next, we will define the mechanisms that regulate the recruitment and activation of myeloid derived suppressive cells, macrophages and B-lymphocytes in Pten deficient prostate tumors by focusing on a novel class of secreted factors identified in these tumors. We will also assess in vivo whether the secretome of tumor cells can transmit senescence to TILs and compounds that interfere with the secretome can prevent immunosenescence. Finally, we will develop monoclonal antibodies directed towards senescent tumors cells that we will use as diagnostic and therapeutic tools. These antibodies will be used as biomarkers to detect senescent tumor cells in prostate cancers and will be tested in pre-clinical trials to assess whether they improve tumor clearance during TIS. Our findings will form the basis for future clinical trials in prostate cancer patients.
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2018-2023: Harnessing clonal evolution in chronic lymphocytic leukemia
Grantee:
Davide Rossi
Funding Scheme:
ERC-2017-COG
Duration:
July 2018 – March 2023
Title:
Harnessing clonal evolution in chronic lymphocytic leukemia
Acronym/ID:
CLLCLONE - 772051
Abstract
Chronic lymphocytic leukemia (CLL), the most common leukemia in adults, is addicted of interactions with the microenvironment. The B-cell receptor (BCR) is one of the most important surface molecules that CLL cells use to gain oncogenic signals from the microenvironment. The critical role of BCR signaling for the pathogenesis of CLL is supported by the therapeutic success of ibrutinib, a targeted agent that disrupts the BCR pathway. Beside microenvironmentpromoted oncogenic signals, the biology of CLL is also driven by molecular lesions and clonal evolution, that mark CLL progression and treatment resistance. The interconnection between microenvironment-promoted oncogenic signals and clonal evolution has been postulated in CLL but never proven because of the lack of suitable ex vivo models. Ibrutinib allows the unprecedented opportunity of assessing the contribution of cell signaling to cancer clonal evolution directly in vivo in patients. The project working hypothesis is that mutation- and selection-driven clonal evolution is promoted by microenvironment-induced signals, including those propagated from the BCR. According to this hypothesis: i) BCR signaling inhibition due to ibrutinib should stop clonal evolution; while ii) acquisition of by-pass mechanisms that keep ongoing signaling should promote mutation and selection despite BCR inhibition, thus favoring CLL clonal evolution and ibrutinib resistance. In this scenario, the combination of ibrutinib with drugs that overcome by-pass mechanisms could prevent clonal evolution, thus improving treatment efficacy and patient outcome. In order to address our working hypothesis, we will take advantage of clinical trial and co-clinical trial samples to monitor signaling and clonal evolution under ibrutinib and ibrutinib-based combination treatments.
ADVANCED GRANTS:
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2023-2028: Microbiota regulation of prostate cancer growth and metastatic dissemination
Grantee:
Andrea Alimonti
Funding Scheme:
SNSF-AdG-2022
Duration:
October 2023 – September 2028
Title:
Microbiota regulation of prostate cancer growth and metastatic dissemination
Acronym/ID:
216062
Microbiota are microorganisms living in symbiosis with the host, being fundamental to homeostasis. Imbalances in these bacterial communities, termed dysbiosis, have been described and are associated with multiple pathologies, including cancer. This proposal is structured with four different Aims, which are tightly interconnected but independent from each other. Aim 1 will assess whether and how the gut or intratumoral microbiota promote metastases formation in prostate cancer (PCa). Preliminary data collected by my team through immunohistochemistry and 10x single-cell analyses demonstrate the presence of intratumoral bacteria in metastatic tumor lesions of patients affected by PCa. We therefore hypothesize that: 1) intratumoral bacteria hijack circulating tumor cells (CTC) to enhance their metastatic capability and/or 2) commensal bacteria are recruited in CTC clusters or in metastatic tumor lesions to support metastatic seeding and growth. In Aim 2, we will develop a drug discovery platform to identify microbiome-derived therapeutics to treat primary and metastatic prostate cancer. We have found that the supernatant of Prevotella Stercorea, a gut commensal bacteria found enriched in the stools of patients associated with a favorable prognosis, can suppress prostate cancer growth without halting normal cell proliferation. Therefore, we aim to assess whether additional bacteria associated with a favorable prognosis in castration resistance prostate cancer (CRPC) patients produce metabolites and/or small molecules that suppress prostate tumor cell proliferation and metastases. Aim 3 will focus on the generation of Live Biotherapeutic Products (LBPs) for the treatment of prostate cancers. We will engineer LBPs with bacterial small molecules identified in Aim 1 to assess whether they can antagonize the development of metastatic PCa. These bacteria will also be used in combination therapies to assess if they can improve the efficacy of the standard of treatments in PCa. Finally, in Aim 4 we will assess the efficacy of available therapies targeting the gut microbiota in CRPC patients and develop a novel fecal biomarker for the detection of the unfavorable microbiota. We have previously demonstrated that antibiotic treatments in different GEMMs and PDX models block CRPC development. I now plan to assess in a clinical trial whether this combined treatment can also affect CRPC development and impact metastasis formation in PCa patients. In this respect, my team has already proved in the past the capability to translate novel pre-clinical findings to the clinic.
