Laboratory of Tumor Inflammation and Angiogenesis
Solid tumors are not simply clones of malignant cells. Instead, they can be considered dysfunctional organs, end-product of the altered interplay, within the tumor microenvironment (TME), among cancer cells and stromal cells (e.g. endothelial cells, macrophages, neutrophils, T cells, etc.). This concept has thrown a spotlight on the 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 tumor and inflammation, focusing on functional characterization of the hypoxia-response, a key environmental cue of the TME, on the consequent involvement of tumor metabolism in dictating the immune landscape, and on how immune cell positioning within the tumor impacts on function and phenotypic skewing of immune cells. To address these points, we take advantage of tissue-specific gene targeting and pharmacologic 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 following (meta)-analysis of human and mouse datasets (i.e. transcriptomic and metabolomics data). Our investigations will increase the knowledge on the molecular and cellular partners controlling inflammatory cell skewing in the TME and its significance in cancer and those conditions where imbalanced immune response contributes to the pathogenesis of life-threatening disorders (i.e. chronic infections and autoimmunity).
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 hydroxylase 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 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 immunosuppressive 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 stressors) 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 promotes vessels stabilization, restores oxygenation and prevents metastasis indicating that mTOR activation is antitumoral in hypoxic TAMs (Wenes et al., Cell Metab, 2016). Another example comes from glutamine metabolism.
We have recently shown that the glutamine restricted TME enhances glutamine-synthetase (GS) expression in TAMs and supports their immunosuppressive and proangiogenic function. Conversely, its inhibition fosters their immunostimulatory and antiangiogenic functions through specific metabolic rewiring involving succinate and HIF accumulation. This promotes vascular normalization, oxygenation, infiltration of cytotoxic T cells, 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 factor inhibiting HIF1 (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 shown 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 the 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 stressors present in the TME is more controversial. However, our recent data helped to define a dual role for PHD2 in cancer. On one hand, we showed that under hypoxic conditions, the mTOR pathway is inhibited and PHD2 dephosphorylation by the PP2A/B55a complex prevail leading to HIF accumulation and colorectal 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-ketoglutarate (a-KG) at the expense of the PHD2 inhibitor fumarate, overall resulting in enhanced PHD2 activity. Active PHD2 hydroxylates and degrades B55a and promotes breast cancer cell death under glucose starvation (Di Conza et al., Cell Rep, 2017b).
Mutations or amplification of proto-oncogenes are involved in the pathogenesis of several tumors, which rely on the constitutive engagement of this pathway for their growth and survival. However, they are expressed not only by cancer cells but also by stromal cells, although its precise role in this compartment is not well characterized. Our lab has recently characterized the role of the MET proto-oncogene in stromal cells. We showed that MET is required for neutrophil chemoattraction and cytotoxicity in response to its ligand hepatocyte growth factor (HGF). Met deletion in mouse neutrophils enhances tumor growth and metastasis. This phenotype correlates with reduced neutrophil infiltration to both the primary tumor and metastatic sites. Similarly, Met is necessary for neutrophil transudation during colitis, skin rash or peritonitis. After systemic administration of a MET kinase inhibitor, we demonstrated that the therapeutic benefit of MET targeting in cancer cells is partly countered by the pro-tumoral effect arising from MET blockade in neutrophils. Our work, has uncovered the role of MET in neutrophils, suggesting a potential ‘Achilles’ heel’ of MET-targeted therapies in cancer, and supports the rationale for evaluating anti-MET drugs in certain inflammatory diseases (Finisguerra et al., Nature, 2015).
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