Overview of the group

Our group investigates the cellular and molecular mechanisms involved in the inflammatory response, with particular interest in its resolution and its role in tumor progression and metastasis. In this scenario, the laboratory is actively engaged in the study of genetic and epigenetic mechanisms regulating leukocyte traffick and their recruitment and activation during the inflammatory response.

 

Research themes

A first research area is focused on the chemokine system, a large family of cytokines with chemotactic activity that acts through specific receptors to control leukocyte recruitment during immune responses. In particular, the laboratory has been involved in the identification and functional characterization of chemokine scavenger receptors, an emerging subset of receptors with regulatory functions and a significant role in various pathological conditions. The laboratory has identified the first receptor of this subgroup, characterized the structural aspects that support its biological function (scavenging of the ligand, intracellular trafficking, signaling properties), and has demonstrated its non-redundant role in vivo in several models of inflammation (sterile inflammation, fetal loss, colitis), infection (mycobacteria), immune-mediated diseases (GvHD) and cancer (colon cancer, Kaposi's sarcoma). In recent years, the laboratory has also been putting efforts in the development of new inhibitors of this molecular system, providing a significant contribution to the understanding of the mechanism of action of allosteric modulators of chemokine receptors. More recently, it has been involved in the functional characterization of molecules that can block the production of chemokines.

A second research area focuses on the biology of macrophages, which play a central role in the inflammatory response, representing a bridge between  innate and adaptive immunity and also coordinate tissue remodeling. Macrophages exert a wide range of biological activities that contribute to the resolution of the inflammatory response, but also have a protumoral role when exposed to specific signals from the tumor microenvironment. These pleiotropic functions result from macrophage response to microenvironmental signals, which lead to different types of polarized macrophage activation. The laboratory first described the complete transcriptional profile of human macrophages activated by the classical (M1) or alternative (M2) pathway and has identified several molecular markers currently under study. Finally, the laboratory is actively involved in the study of genetic and epigenetic mechanisms underlying resolution of inflammation and its protumor role. In particular, the laboratory has recently provided evidence of a role of iron metabolism and new transcription factors in the biology of tumor-associated macrophages. Finally we have identified several microRNAs associated with macrophage activation in response to pro and anti-inflammatory signals and we are currently investigating the complex interaction between microRNA and transcription factors in the regulation of resolution of inflammation.

Another research line, coordinated by Federica Marchesi, is focused on the analysis of leukocytes (macrophages, lymphocytes, B cells) infiltrating solid tumors (adenocarcinoma of the pancreas, lung and colorectal). The dual role of immune cells in cancer has long been known, and the advancement of our knowledge on the molecular mechanisms that regulate their activity in tumors has important clinical and therapeutic implications. Our research is aimed at testing specific immune variables as biomarkers of prognosis or response to therapy in cancer patients. In parallel, identified immune variables are evaluated in preclinical models as potential therapeutic targets of chemo-immunotherapeutic strategies.

 

Contacts

massimo.locati@unimi.it
http://scholar.google.it/citations?user=UbWBTBsAAAAJ

federica.marchesi@unimi.it
http://orcid.org/0000-0002-7212-5721