Patrizia Agostinis Lab

Research focus

“We are studying cell death and resistance pathways in tumors, how they impact the interface between cancer cells and stromal cells, modify the tumor microenvironment and anticancer therapy responses. Our ultimate goal is to contribute to combating cancer by translating molecular/cellular knowledge into therapeutic possibilities”

Regulated cell death (RCD) is an essential, genetically controlled, process used to eliminate damaged, defective or excessive cells, to support life. However, both RCD and the mechanisms governing the removal of dying cells are dysregulated during carcinogenesis and contribute to the establishment of a tumor promoting and immune-suppressive microenvironment that fosters metastatic dissemination and contributes to the development of resistance to anticancer therapies. In the last years it is emerging that the mechanisms of cancer cell death and the nature of the tumor microenvironment (e.g. intratumoral amount and composition of immune cells, hypoxic and metabolic status of the tumor) shape and dictate the efficacy of conventional or targeted anticancer regimens and immunotherapies. Accordingly, recent advances in the field of anticancer therapy illustrate that increasing the capacity of cancer cell to elicit an immune response (immunogenicity) and/or inactivating immunosuppressive signals designed by developing tumors to boycott tumor-targeting immune responses (e.g. immune-checkpoints) or favoring dissemination (e.g. tumor angiogenesis), represent most valuable therapeutic avenues. In particular, the induction of cancer cell death able to reinstate, rather than suppressing, anticancer immune responses (i.e. immunosurveillance) mechanisms is a highly desirable therapeutic effect. 

The goal of our research is thus several fold; first is to reach a better understanding of the major mechanisms that control (deranged) cancer cell death at the molecular/cellular and signaling levels. Second is to unravel the immunological consequences of dying cancer cells and exploit this knowledge to design novel therapies, with particular focus on the next generation anticancer vaccines.  Third, is to unravel how vital stress pathways predominantly regulated by ER stress and autophagy, impact the tumor-stroma dialogue, in order to harness these mechanisms for therapeutic benefits. 
 
Current projects at the CDRT
Regulated Cancer Cell Death; molecular and immunological consequences:  Innate immune-sensing of dying cells (apoptosis, necroptosis, ferroptosis) is modulated by several signals including damage-associated molecular patterns (DAMPs), cytokines and chemokines. Our lab focusses on the identification and immunological functions of key immunomodulatory molecules regulating the intersection between dying cells and innate immune cells and how the innate immune cells decode these signals, in response to cancer cell death elicited by various anticancer therapies, including immunotherapies. We study immunogenic cell death (ICD) as a cornerstone of therapy-induced antitumor immunity and the pathways responsible of the anticancer vaccination potential of ICD in vivo.  (Garg et al, Sci Transl Med 2016; Garg et al, Trends Immunol 2017). We are currently interested in translating ICD-based anti-cancer vaccines clinically for glioma treatment.  Recently, we also geared our focus on the molecular underpinnings and immunological impact of a new form of iron-dependent RCD, driven by lipid peroxides, called ferroptosis as an alternative killing modality in drug-resistant cancer cells. We are currently studying the in vivo consequences of ferroptosis vulnerability in melanoma.

Membrane contact sites; shaping cancer cell and T cell responses: The large membranous structures of the ER allow this organelle to come in contact and communicate with virtually all components of the cell, through specialized membrane subdomains called membrane contact sites (MCS). MCS regulate an increasing number of vital cellular processes from Ca2+ signaling, migration, trafficking, metabolism and cell death. The dynamic rearrangement of these communicating channels involves various tethering and lipid transfer proteins at the interface between two organelles. Our lab focusses on i) unravelling vital processes, including Ca2+ fluxes, governed by the ER-mitochondria and ER-PM juxtapositions in stressed or dying cancer cells (Verfaille et al, Cell Death & Differ, 2012; Van Vliet et al, Mol Cell, 2017) and ii) deciphering how MCS modulate T cell activation and effector functions.

Autophagy in cancer growth and angiogenesis: Alterations of main mechanisms controlling proteostasis, including the autophagy endo-/lysosomal network, are increasingly linked to cancer biology. Although aberrations in these proteostasis pathways may not be themselves the drivers of tumorigenesis, they can be harnessed by the cancer cell to support tumorigenesis, on ‘demand’, to meet their increased metabolic and biosynthetic needs by the recycling of cytoplasmic materials, to foster trafficking and secretion of pro-tumorigenic factors (both soluble and vesicle-encapsulated) and to endow the cancer cell with the metabolic plasticity required to interface and co-evolve with its stroma. Ultimately, deranged autophagy may not only detrimentally affect therapeutic responses but also provide an Achilles heel to induce lethal proteotoxic or organellar stress, causing cancer cell death. Research in our lab addresses how selective degradation pathways for the removal of mitochondria (mitophagy), lipid droplets (lipophagy) and ferritin (ferritinophagy) enable cancer cell-stromal cell dialogue and anti-tumor immunity.   Beyond cancer cell autonomous and non-autonomous mechanisms regulated by autophagy, we are particularly interested in understanding how endothelial cell-associated autophagy impacts tumor-driven (lymph)angiogenesis, immunosurvelliance mechanisms and shapes (immuno)therapeutic responses (Maes et al, Cancer Cell 2014; Schaaf et al, Cell Death & Diff 2019). 
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Patrizia Agostinis

Patrizia Agostinis

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Bio

Function: PhD KU Leuven, Belgium 1989-1993 FWO-Postdoctoral Fellow at KU Leuven and EMBO-fellow, University of Padova Italy; 1993-2000 FWO-Group Leader; 2000-present KU Leuven, Group Leader Cell Death Research & Therapy lab, Department of Cellular and Molecular Medicine; 2008-present Full Professor KU Leuven; March 2019, Group Leader VIB-Center for Cancer Biology (CCB)​

Contact Info

VIB-KU Leuven Center for Cancer BiologyO&N 4, 9e verdCampus GasthuisbergHerestraat 49, bus 912 3000 LEUVENRoute description