Massimiliano Mazzone Lab

Research focus

Solid tumors are not simply clones of malignant cells. Instead, they are dysfunctional organs, end-product of the altered interplay, within the tumor milieu, among cancer cells and stromal cells (e.g. endothelial cells, macrophages, neutrophils, T cells, etc.). This concept has thrown a spotlight on the tumor microenvironment (TME) as the central unit governing tumor progression, metastasis and resistance to antitumor therapies. Our mission is to bridge the current gap between cancer cell biology - autonomous traits of malignant cells -  and tumor biology - non-autonomous traits where, the unique features of the TME along with its cellular cross-talks are the main drivers of malignancy. We believe that only a comprehensive understanding of the environmental cues and molecular pathways that participate in the interaction between cancer cells and stromal cells within the harsh TME (at the primary site and metastatic niche) will enable us to conceive brand new and specific therapeutic strategies.

De facto, the research topics of the lab span the fields of cancer and inflammation, focusing on functional characterization of the hypoxia-response, a key environmental cue of the TME, in differentiation and metabolism of stromal cells, tumor progression and response to chemotherapy. To better understand how the molecular specification of the hypoxia-driven response is orchestrated in different tumor microenvironments and cellular compartments, we take advantage of tissue-specific gene targeting approaches in mice and combine the phenotype discovery with an extensive phenotypic characterization. In particular, we are using state-of-the-art genetic, cell biological, biochemical and structural methods, all complemented by specific multi-omics profiling and bioinformatics (Meta)-analysis of human and mouse transcriptomics and metabolomics datasets.  At the molecular level, we are interested in dissecting the oxygen-dependent and independent stimuli and molecular partners participating in the hypoxia response and determining how and what is conferring the specificity of this response in different cell types.  Our investigations will increase the knowledge on the molecular and cellular partners controlling inflammatory cell skewing and its significance in cancer and those conditions where imbalanced or insufficient growth of blood vessels contributes to the pathogenesis of life-threatening disorders such as ischemic diseases.

Overview of the current research topics

Oxygen shortage, a condition known as hypoxia, can elicit complex and sometimes opposing responses in cancer cells and different stromal tumor compartments. We have previously shown that genetic inactivation of oxygen-sensing prolyl hudroxylase PHD2 in stromal cells, induces tumor vessel normalization, thus reducing metastasis and improving chemotherapeutic drug delivery (Mazzone et al., Cell, 2009; Leite de Oliveira et al., Cancer Cell, 2012). In addition, besides negatively regulating HIF accumulation, PHDs have functions that extend beyond oxygen sensing as observed by our lab in macrophages wherein PHD2 can control the activity of NF-kB, a key signaling molecule for inflammation, which lead macrophage skewing towards a proarteriogenic phenotype (Takeda et al., Nature, 20011; Hamm et al., EMBO Mol Med, 2013). The control of NF-kB by PHDs can be both dependent and independent of the hydroxylase activity and therefore the presence of oxygen. In addition, cytokine driven downregulation of PHD expression levels also results in their reduced enzymatic activity independently of oxygen availability and thus triggers a “hypoxia-like” response.


Much less attention has been paid on how oxygen tension shapes the inflammatory response of inflammatory cells and modulates specific differentiation states. Recently we described a Neuropilin-1-dependent guidance mechanism by which tumor associated macrophages (TAMs) enter hypoxic tumor areas where they elicit their proangiogenic and immune suppressive functions. Thus, blocking Neuropilin-1 was sufficient to entrap macrophages in vascularized normoxic tumor areas and thus restore their anti-tumor capacity and prevent angiogenesis (Casazza et al., Cancer Cell, 2013).  Yet it remains unknown if metabolic changes can alter the pro-tumoral function of hypoxic TAMs.  We recently showed that REDD1 deletion (a gene induced by hypoxia and other environmental stresses) enhances glucose uptake and glycolysis in hypoxic TAMs via mTOR activation thus leading to glucose competition with endothelial cells in the nutrient-poor TME. This promote vessels stabilization, restore oxygenation and prevent metastasis indicating that mTOR activation is antitumoral in hypoxic TAMs (Wenes et al., Cell Metab, 2016). Another example comes from the glutamine metabolism. We have recently shown that the glutamine restrictive TME enhances glutamine-synthetase (GS) expression in TAMs and supports their immunosuppressive and proangiogenic function. Conversely, it’s inhibition fosters their immunostimulatory and antiangiogenic functions through a specific metabolic rewiring involving succinate and HIF accumulation. This promote vascular normalization, oxygenation, infiltration of cytotoxic T cell, and metastasis inhibition (Palmieri et al., Cell Rep, 2017).


The main executors of the cellular response to hypoxia are the hypoxia-inducible factors (HIFs) HIF1 and HIF2, which are negatively regulated by the HIF prolyl hydroxylase (PHD) family members PHD1, PHD2, and PHD3 and by FIH-1. Besides controlling cellular adaptation to hypoxic conditions, it is now clear that prolyl hydroxylases are also involved during cell damage and metabolic stress. For instance, we have showed that PHD1 can cause resistance to chemotherapy through the regulation of P53-mediated DNA repair thus highlighting PHD1 inhibition as a novel approach to increase the therapeutic efficacy of standard chemotherapy (Deschoemaeker  et al., EMBO Mol Med, 2015). Another example comes from the regulation of endothelial apoptosis where we showed that FIH-1 can regulate Notch signaling pathway and affect endothelial cell survival and apoptosis (Kiriakidis  et al., FASEB J, 2015). The role of PHD2 in controlling cancer cell adaptation to the environmental stresses present in TME is more controversial. However, our recent data helped to define a dual role for PHD2 in cancer. On one hand, we showed that in hypoxic condition, the mTOR pathway is inhibited and PHD2 dephosphorylation by the PP2A/B55alpha complex prevail leading to HIF accumulation and cancer cell survival through autophagy (Di Conza et al., Cell Rep, 2017a). On the other hand, glucose shortage tilts the balance toward an excess of alpha-KG at the expense of the PHD2 inhibitor fumarate, overall resulting in enhanced PHD2 activity. Active PHD2 hydroxylates and degrades B55a and promote cancer cell death under glucose starvation (Di Conza et al., Cell Rep, 2017b).

 

> video on basic research on collaboration between immune system & cancer - Massimiliano Mazzone 
- ©VIB, 2015​

Publications

Pharmacologic or Genetic Targeting of Glutamine Synthetase Skews Macrophages toward an M1-like Phenotype and Inhibits Tumor MetastasisPalmieri E* Menga A* Martin Perez R* Quinto A Riera Domingo C De Tullio G Hooper D Lamers W Ghesquière B Mcvicar D Guarini A Mazzone M* Castegna A*Cell Reports, 20, 1654-1666, 2017* These authors contributed equally
Macrophage Metabolism Controls Tumor Blood Vessel Morphogenesis and MetastasisWenes M, Shang M, di Matteo M, Goveia J, Martin Perez R, Serneels J, Prenen H, Ghesquière B, Carmeliet P, Mazzone MCell Metabolism, 24, 701-715, 2016
Tumour-educated circulating monocytes are powerful candidate biomarkers for diagnosis and disease follow-up of colorectal cancerHamm A* Prenen H* Van Delm W* Di Matteo M Wenes M Delamarre E Schmidt T Weitz J Sarmiento R Dezi A Gasparini G Rothé F Schmitz R D'hoore A Iserentant H Hendlisz A Mazzone MGUT, 65, 990-1000, 2016* These authors contributed equally
MET is required for the recruitment of anti-tumoural neutrophilsFinisguerra V, Di Conza G, di Matteo M, Serneels J, Costa S, Thompson A, Wauters E, Walmsley S, Prenen H, Granot Z, Casazza A, Mazzone MNATURE, 522, 349-53, 2015
Impeding Macrophage Entry into Hypoxic Tumor Areas by Sema3A/Nrp1 Signaling Blockade Inhibits Angiogenesis and Restores Antitumor ImmunityCasazza A, Laoui D, Wenes M, Rizzolio S, Bassani N, Mambretti M, Deschoemaeker S, Van Ginderachter J, Tamagnone L, Mazzone MCANCER CELL, 24, 695-709, 2013

Job openings

News

ONCURIOUS NV acquires unique portfolio of next-generation immuno-oncology assets from VIB

01/09/2017 - ​ONCURIOUS NV, a biotech company focusing on the development of innovative oncology treatments, announces that it has reached principle agreement with VIB to acquire exclusive licences to a portfolio of five unique next generation immuno-oncology assets.

Scientists unravel role of glutamine synthetase in the spread of cancer

17/08/2017 - A team led by Massimiliano Mazzone (VIB-KU Leuven) and Alessandra Castegna (University of Bari) has demonstrated a way to alter the metabolism of macrophages, a particular type of white blood cell often responsible for supporting tumor growth.

VIB pushes the boundaries of science to develop new diagnostic tools

27/07/2017 - With their world-leading strengths in molecular research and biotechnology, various VIB labs are paving the way for novel diagnostic tools that will reduce disease burden and save lives by making disease diagnosis better, faster and more flexible.

VIB and DNAlytics team up to develop non-invasive Colorectal Cancer screening test

24/03/2017 - Based on a research program from VIB, KU Leuven and UZ Leuven, with the support of the Fournier Majoie Foundation, DNAlytics will develop the ColonoKit which should make it possible to detect colorectal cancer in an early stage using a simple blood test.

PHD2 targeting overcomes breast cancer cell death upon glucose starvation

21/03/2017 - The Massimiliano Mazzone group (VIB-KU Leuven) has recently demonstrated that PP2A/B55α promotes the growth of colorectal cancer, by dephosphorylating PHD2 and modifying its enzymatic properties.

Researchers identify phosphorylation process vital to cancer growth

14/02/2017 - ​Scientists at VIB-KU Leuven have identified a new mechanism that impacts tumor growth. The typical lack of oxygen in tumors doesn’t only stimulate proliferation, but also offsets the important role of the protein PHD2 as ‘cancer cell killer’.

Scientists reveal link between cell metabolism and the spread of cancer

20/10/2016 - Scientists at VIB and KU Leuven discovered a crucial factor in the spread of cancer. A team led by Massimiliano Mazzone has demonstrated that the metabolism of macrophages can be attuned to prevent the spread of cancer.

Reducing resistance to chemotherapy in colorectal cancer by inhibition of PHD1

19/08/2015 - ​Scientists at VIB and KU Leuven have shown that blocking the PHD1 oxygen sensor hinders the activation of p53, a transcription factor that aids colorectal cancer (CRC) cells in repairing themselves and thus resisting chemotherapy.

Circulating immune cells and cancer, novel insights might lead the way to optimizing diagnosis and treatment

25/06/2015 - One of the things Max Mazzone (Vesalius Research Center) focuses on is the role of our immune system in cancer. And this has recently lead to two important breakthroughs published in Nature and Gut.

Novel insights in MET-proto-oncogene might lead to optimizing cancer treatment

18/05/2015 - The MET-proto-oncogene is involved in the pathogenesis of several tumors and therefore represents an interesting target for future therapies currently tested in dozens of clinical trials.

Bio-marker set forms the basis for new blood test to detect colorectal cancer

27/03/2015 - Researchers from VIB and KU Leuven have identified bio-markers that can be incorporated in a new diagnostic test. This should make it possible to detect colorectal cancer in an early stage using a simple blood test.

Scientists shed new light on the fight against cancer

10/12/2013 - The Leuven-based VIB researchers have revealed a mechanism that explains why the anti-tumor activity of specific immune cells called macrophages is suppressed during tumor growth.

Possible new venues for the treatment of ischemic disorders

26/09/2013 - ​Occlusion of the main arterial route redirects blood flow to the collateral circulation. Max Mazzone, VIB Vesalius Research Center, KU Leuven, investigates the genetic and molecular mechanisms that are responsible for reestablishing the blood flow.

Scientists uncover strategy able to dramatically reduce chemotherapy’s side effects

14/08/2012 - Researchers in Leuven (VIB/KU Leuven) have confirmed their hypothesis that normalizing blood vessels by blocking oxygen sensor PHD2 would make chemotherapy more effective.

New strategy to accelerate blood vessel maturation has therapeutic potentials for ischemic diseases

10/10/2011 - In Nature, VIB-K.U.Leuven researchers describe a new mechanism to enhance the restoration of the blood flow in ischemic diseases, which are among the leading causes of death worldwide.

White blood cells as a new diagnostic technique for intestinal cancer

03/02/2011 - The Fournier-Majoie Foundation for Innovation (FFMI) has awarded Max Mazzone of VIB-K.U.Leuven a grant for research into a new method of early detection of colon cancer.

New strategy to combat cancer - Streamlining blood vessel walls

12/02/2009 - Our blood vessels have a built-in rescue-mechanism that springs into action when there is insufficient oxygen in our tissues. VIB scientists at K.U.Leuven have now discovered that this mechanism can be mobilized in the battle against cancer.

Massimiliano Mazzone

Massimiliano Mazzone

Research area(s)

Model organism(s)

Bio

​PhD: Univ. of Torino, Torino, Italy, 2007
Postdoc Fellow at VIB, Vesalius Research Center, Univ. of Leuven, Leuven, Belgium, 2006-09
VIB Group leader since February 2009

Contact Info

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