The laboratory of Tumor Microenvironment is part of the Mario Negri Institute laboratories in Bergamo, in Anna Maria Astori Centre, within the “Kilometro Rosso Science and Technology Park”.
The laboratory studies the interaction between tumor cells and the surrounding microenvironment, focusing on factors involved in extracellular matrix remodeling, blood vessels formation and functioning and the desmoplastic reaction, in order to understand how the microenvironment influences tumor growth, invasion, metastasis, and response to chemotherapy. The final aim is to identify tumor markers and molecular targets for the development of new therapies. Furthermore, the laboratory aims at developing approaches to modify the structure and properties of the extracellular matrix and the tumor microenvironment in order to improve the efficacy of antineoplastic drugs.
Matricellular proteins in the tumor microenvironment: thrombospondin-1
Thrombospondin-1 (TSP-1) is a structurally and functionally complex matricellular protein that, in tumors, mediates the interaction between tumor cells and the microenvironment. Acting as a link between tumor cells, normal cells, soluble factors and the extracellular matrix, TSP-1 is able to influence the growth and malignant behavior of tumors. The laboratory analyzes the role of specific TSP-1 domains in regulating tumor vascularization, growth, metastasis and response to antineoplastic drugs. The identified relevant sites of TSP-1 are then analyzed in terms of interaction with other molecules, mechanisms of action and biological activity on different cell types. Active sequences, able to inhibit tumor malignancy, are then used as a model for the design of new therapeutic molecules.
Proteases and their physiological inhibitors in the tumor-microenvironment interaction in pancreatic cancer
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal tumors, characterized by a prominent extracellular matrix remodeling, altered balance between proteases and their physiological inhibitors, and fibrosis, that foster tumor progression. We aim to identify the mechanisms by which proteases and their inhibitors regulate the progression of pancreatic carcinoma, analyzing the release or degradation of growth factors, cytokines, and angiogenic factors, the generation of biologically active matrix fragments and the direct activation of specific molecular pathways. The results will provide indications for the development of therapies aimed at “re-educating” the tumor microenvironment, restoring its capacity to restrain tumor growth.
Organ-specificity of tumor metastasis
The interaction between tumor cells and the microenvironment determines the particular ability of different tumor types to metastasize preferentially to specific organs. The laboratory studies the cellular and molecular mechanisms through which the primary tumor microenvironment, particularly matricellular proteins and molecules associated with the extracellular matrix, influences the invasive and metastatic properties of tumor cells. Moreover, we study how changes in the microenvironment of distant organs create a fertile soil for metastasis (‘premetastatic niche’). We focus in particular on mammary tumors, that develop bone and lung metastasis, and on pancreatic and colon tumors, that develop liver metastasis.
Preclinical studies on new agents acting on the extracellular matrix to normalize the tumor microenvironment
Targeting the extracellular matrix to improve the efficacy of chemotherapeutic drugs is a promising therapeutic strategy. The extracellular matrix of tumors, which differs from that of normal tissues in quantity, composition and mechanical properties, can contrast the distribution and the activity of anticancer drugs. We analyze different therapeutic approaches to normalize the extracellular matrix in terms of biochemical, physical and functional properties, with the aim to increase drug concentration inside the tumor and the therapeutic efficacy of chemotherapy.
International Consensus on Cardiopulmonary Resuscitation.