Our laboratory is situated at the health sciences campus of Gasthuisberg in research building O&N1



Design SAVANT

Research

Our lab uses several molecular and biochemical approaches to generate fundamental knowledge on the biology of ER stress and autophagy/vesicle trafficking regulating cancer cell death and to assess the immunological impact of dying cancer cells (e.g. emission of damage-associated molecular patterns, cytokines/chemokines), both in vitro as well as in vivo (mouse and zebrafish models). Our ultimate goal is to contribute to combating cancer, by developing new anticancer strategies, such as next-generation of anticancer vaccines, based on the activation of immunogenic cell death, by translating molecular/cellular knowledge into therapeutic possibilities.

CDRT's Main Research Lines Include

1. ER Stress and the regulation of cell death pathways

ER-mitochondria and ER-PM cross-talk during ER stress

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ER-mitochondria and ER-PM cross-talk during ER stress


The plastic membranous structures of the ER allow this organelle to come in contact and communicate with virtually all components of the cell, through specialized membrane contact sites. Inter-organellar contact sites regulate an increasingly important number of cellular processes, from migration to trafficking or cell death. Dynamic rearrangement of these communicating channels involves ER proteins interfacing between organelles, but their identification in vertebrates remains elusive. ER homeostasis and calcium signaling are emerging processes crucially regulated by ER-PM juxtapositions. Our previous work revealed that ER stress sensor PERK, with a known function during the unfolded protein response (UPR), enables tethering of the ER to the mitochondria by its localization at the Mitochondria Associated Membranes (MAMs) (Verfaillie et alVan Vliet et al). Moreover, our research has shown that during immunogenic cell death PERK drives the trafficking/mobilization of key danger signals (like extracellular ATP and ecto-calreticulin) to the extracellular environment, favoring the elicitation of anti-tumor immunity (Garg et al. 2012). By using state-of the art molecular/cellular biology tools, life imaging and TIRF microscopy, and a set of important cellular/in vivo models we are currently defining the relevance of novel PERK-regulated complexes at the ER-PM interface in calcium fluxes, migration and danger signal export. Considering the implication of PERK also in diabetes and neurodegeneration this study may help developing new therapeutic modulators of this kinase.


2. Altered proteostasis and vesicle trafficking in tumor-stroma interaction

Altered proteostasis networks in cancer cells and tumor-stroma interaction

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Altered proteostasis networks in cancer cells and tumor-stroma interaction



Alterations of main proteostasis mechanisms, like the autophagy/ endo-/lysosomal network, are increasingly linked to cancer biology (Maes et al. 2015). Although aberrations in proteostasis pathways may not be themselves the drivers of tumorigenesis, they can act as mediators and be utilized by the cancer cell on ‘demand’ to support oncogene-driven proliferation, to meet the increased demand from cancer cells to secrete protumorigenic factors (both soluble and vesicle-encapsulated) in order to facilitate their invasion and seeding to other organs as well as to increase the plasticity of the interface with other stromal cells. Ultimately, deranged proteostasis may not only detrimentally affect therapeutic responses but also provide an Achilles heel to induce proteotoxic stress and promote eventual cancer cell death. Research in our lab focuses on key mediators of trafficking and lysosomal degradative pathways, like autophagy, which play a pivotal role in the etiology of both neurodegenerative disorders and cancer. In this context, we are currently addressing, using a combination of state-of the art omics approaches, cellular and mouse models of melanoma and glioblastoma, how deletion of key autophagy (like ATG5 or BNIP3) or endo-lysosomal modulators (ATP13A2) support cancer cell progression as well as its microenvironment, ultimately aiming to develop new therapeutic approaches harnessing the endo-lyososomal sytem. Recently, using unique genetic mouse models (e.g. conditional KO mice harboring specific deletion of ATG5 or NOTCH1 in the vasculature), we have uncovered that key components of autophagy/lysosomal degradation pathways in tumor-associated endothelial cells regulate important processes assisting the metastatic cascade and revealed that one of the main in vivo mechanism of action of the first autophagy inhibitor chloroquine is the induction of vessel normalization (Maes et al. 2014). We are currently investigating how autophagy in the melanoma stroma influences the tumor microenvironment and progression and how we can take advantage of this to improve antitumor therapy.


3. Immunology of Cancer cell death

Molecular signaling and system biology of immunogenic cell death

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Molecular signaling and system biology of immunogenic cell death


Innate immune-sensing of dying cells (apoptosis, necrosis or necroptosis) is modulated by several signals including damage-associated molecular patterns (DAMPs), cytokines and chemokines ( Garg et al. 2015). Our lab is actively involved in identifying the immunological functions of key immunomodulatory molecules regulating the interaction between dying cells and innate immune cells (Krysko DV et al. 2012), in response to cancer cell death elicited by various chemotherapies (Dudek-Peric et al. 2015), physicochemical therapies (e.g., radiotherapy or photodynamic therapy/PDT) (Garg et al. 2012), and oncolytic viruses. In particular, we focus on immunogenic cell death (ICD) as a cornerstone of therapy-induced antitumor immunity and have unraveled danger signaling and phagocytic (Garg et al. 2015) pathways responsible of the anticancer vaccination potential of ICD both in vitro and in vivo. We are also studying on distinguishing ICD-associated signalling network at the system levels and carrying out in silico prognostic biomarker assessment through large-scale meta-analysis to show that ICD can be used as a platform for discovery of robust, and novel predictive/prognostic biomarkers (Garg et al. 2015).

Next-generation DC-vaccines based on the concept of ICD

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Next-generation DC-vaccines based on the concept of ICD


Cancer-induced immunosuppression is a roadblock to immunotherapy. Using an orthoptopic high-grade glioma (HGG) mouse model and both prophylactic/curative setups, our group has recently provided evidence for the powerful in vivo tumor-rejecting effectiveness of next generation dendritic cell (DC)-vaccines based on the concept of ICD (induced by hypericin-based photodynamic therapy) (Garg et al. 2016). At the molecular/signaling levels, we found that the ability of DC vaccines to elicit HGG rejection was significantly blunted if cancer cell-associated reactive oxygen species and emanating danger signals were blocked either singly or concomitantly, or if DC-associated MyD88 signal, or the adaptive immune system (especially CD8(+) T cells) were depleted. In vivo ICD-based DC vaccines synergized with standard-of-care chemotherapy (temozolomide) to increase survival of HGG-bearing mice resulting in ~50% long-term survivors. Additionally, DC vaccines induced an immunostimulatory shift in the brain immune contexture that was associated with good patient prognosis. We are currently interested in translating ICD-based vaccines clinically for glioma treatment (and if possible, also for other cancer-types like melanoma, lung cancer, ovarian cancer).

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Where to find us:

Useful links to reach Leuven:
Official tourist page: Link
Transfer by train: Leuven is about 30min away by train from Brussels airport. Trains to Leuven leave Brussels airport approx. every 15min.
To reach Campus Gasthuisberg see this link

Contact:

To contact the lab, please send an email to: 
Patrizia Agostinis
Cell Death Research and Therapy Lab, Department of Cellular & Molecular Medicine
Faculty of Medicine
Campus Gasthuisberg, O&N I Herestraat 49 - bus 802
3000 Leuven, Belgium
Tel 003216330650,
Email: 
patrizia.agostinis@kuleuven.be