ERC FUNDED PROJECTS

Brown adipocytes can dissipate energy in a process called adaptive thermogenesis. Whilst the classical brown adipose tissue (BAT) depots disappear during early life in humans, cold exposure can promote the appearance of brown-like adipocytes within the white adipose tissue (WAT), termed brite (brown-in-white). Increased BAT activity results in increased energy expenditure and has been correlated with leanness in humans. Hence, recruitment of brite adipocytes may constitute a promising therapeutic strategy to treat obesity and its associated metabolic diseases. Despite the beneficial metabolic properties of brown and brite adipocytes, little is known about the molecular mechanisms underlying their specification and activation in vivo. This proposal focuses on understanding the complex biology of thermogenic adipocyte biology by studying the epigenetic and transcriptional aspects of WAT britening and BAT recruitment in vivo to identify pathways of therapeutic relevance and to better define the brite precursor cells. Specific aims are to 1) investigate epigenetic and transcriptional states and heterogeneity in human and mouse adipose tissue; 2) develop a novel time-resolved method to correlate preceding chromatin states and cell fate decisions during adipose tissue remodelling; 3) identify and validate key (drugable) epigenetic and transcriptional regulators involved in brite adipocyte specification. Experimentally, I will use adipose tissue samples from human donors and mouse models, to asses at the single-cell level cellular heterogeneity, transcriptional and epigenetic states, to identify subpopulations, and to define the adaptive responses to cold or β-adrenergic stimulation. Using computational methods and in vitro and in vivo validation experiments, I will define epigenetic and transcriptional networks that control WAT britening, and develop a model of the molecular events underlying adipocyte tissue plasticity.

1 552 620 €

Start date: 2019-03-01, End date: 2024-02-29

Acquisition of the hallmark capability for invasion and in turn metastasis is for most human cancers the defining event in progression to life threatening disease. Its determinants are remarkably complex. Genetically engineered mice can model human cancers, with tumors arising in specific organs, reflecting onco-genomic and histopathological features of particular tumor types. This project will use four mouse models to characterize newly implicated determinants of invasive tumor growth. We have observed that genetic polymorphisms can govern predisposition to invasive cancer. Additionally, therapeutic targeting of another hallmark capability – tumor angiogenesis – has revealed adaptive resistance, whereby late-stage tumors, faced with the inability to grow en masse supported by angiogenesis, switch instead to grow diffusively, by invading adjacent tissue; this phenomenon may underlay the limited benefit seen with anti-angiogenic therapies in the clinic. There are three interconnected goals: (1) Polymorphic regulation of tumor invasion. We will investigate the mechanisms and functional importance of candidate genes resident within a genetic modifier locus on mouse Chr 17 that can alternatively suppress or facilitate invasive tumor growth dependent on constitutional genetic background. (2) Adaptive induction of invasion. We will elucidate the determinants of the invasive growth capability that is induced in response to potent inhibition of angiogenesis. (3) Testing mechanism-based therapeutic co-targeting of the capabilities for invasion and angiogenesis. We will use functional genetic, genomic profiling, and pharmacological approaches to assess these two new modes of regulating invasive growth, and then apply the knowledge in preclinical trials aiming to lay the groundwork for future clinical trials in which these intersecting hallmark capabilities are coordinately disrupted, with promise for more enduring therapeutic responses and benefit to cancer patients.

2 500 000 €

Start date: 2013-09-01, End date: 2018-08-31

Breast cancer is the most common cancer in women, resulting in as many as 500000 deaths per year worldwide. Patients with breast cancer die unequivocally because of the development of incurable distant metastases and not because of symptoms related to the primary site. Understanding the complex, yet fundamental mechanisms driving breast cancer metastasis is critical to develop therapies tailored to this disease. The current understanding of how metastasis occurs is derived primarily from mouse models and largely dominated by the notion that single migratory cancer cells within the primary tumor can actively disseminate to distant sites and develop as metastatic deposits. Unexpectedly, our very recent study on patient blood samples has shown that cancer cell groupings, held together through strong cell-cell junctions, can break off the primary tumor and form a metastatic lesion up to 50 times more efficiently than single migratory cancer cells (Aceto et al, Cell, 2014). These findings lead to new open questions, yet highlight a previously unappreciated and targetable mechanism of cancer dissemination. Our preliminary data suggest that, among all types of cell-cell junctions, desmosomes and tight junctions are involved in this process, and therefore represent unprecedented options for developing a metastasis-tailored therapy for breast cancer. The two predominant goals of this proposal are: first, to define the role of specific desmosome (DSG2) and tight junction (CLDN3 and TJP2) components in the development of metastasis. Second, to address their involvement in cellular signaling and response to therapy. These studies will not only use our first-of-a-kind in vivo models developed from patients with breast cancer metastases, but also cross the boundaries between basic science and clinical applications. Our research has the long-term ambition to lead to a novel class of therapeutic agents tailored to block cell-cell junctions and prevent metastatic spread of cancer.

1 744 921 €

Start date: 2016-03-01, End date: 2021-02-28

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.

2 000 000 €

Start date: 2016-07-01, End date: 2021-06-30