Modulating the Tumor Microenvironment

We specialize in the isolation, characterization and gene modification of mesenchymal stromal/stem cells (MSC) to create a targeted delivery platforms for anticancer molecules. In recent years, we have focused our attention particularly on TNF-relateded inducing ligand (TRAIL) a pro-apoptotic molecule physiologically expressed by leukocytes but not by MSCs, which is capable of inducing apoptosis in tumor cells while sparing healthy tissues. In our laboratory, using lentiviral and retroviral vectors, we have genetically modified MSC to induce the expression of a soluble (s) variant of TRAIL. MSCs expressing sTRAIL have been shown to kill a wide variety of cancers, including cervical adenocarcinoma, lung cancer, neuroblastoma, osteosarcoma, rhabdomyosarcoma, Ewing sarcoma, glioblastoma, and pancreatic cancer. Through the use of preclinical, physiologically relevant in vitro 3D models (including matrices, bioreactors, and bioprinting platforms) and in vivo models, we have demonstrated the efficacy of our cell-based therapeutic approach, leading to AIFA authorization for the treatment of patients affected by pancreatic cancer. 

It is now widely demonstrated that the non-malignant cellular component that constitutes the tumor stroma plays a fundamental role in disease progression and in the response to therapy. Stromal cells mediate signals essential for tumor cell survival and growth, promote metastasis, and protect cancer cells from the cytotoxic effects of chemotherapeutic agents. Consequently, the study of the interactions between stromal and tumor cells represents a crucial aspect for the identification of new molecular targets underlying this cellular crosstalk, with the aim of developing novel therapeutic strategies designed to make the tumor more susceptible to treatment. In this context, we are investigating the mechanisms governing tumor–stroma interactions, particularly in pancreatic cancer, which, due to its biological features, represents the paradigm of tumor–stroma interplay. Through transcriptomic studies and gene editing approaches, we have identified a key protein involved in the tumor–stroma axis in pancreatic cancer. Blocking the biological activity of this protein may increase tumor sensitivity to pharmacological therapies, thereby improving therapeutic response.

Combinatorial therapeutic approaches represent a central strategy in our research, integrating sTRAIL MSC-based therapies with conventional treatments to overcome apoptosis resistance mechanisms within the tumor. In particular, our group has demonstrated that sTRAIL MSCs, in combination with standard chemotherapeutic regimens, achieve synergistic and more durable antitumor effects. This concept has been supported by our previous study, demonstrating that Paclitaxel preconditioning can revert TRAL resistance in pancreatic cancer improving the tumor cell killing mediated by sTRAL MSC. More recently, we have further demonstrated the relevance of combinatorial strategy based on Gemcitabine and sTRAIL MSC to overcome intrinsic drug resistance of tumor stromal compartment and profoundly influence the extracellular matrix deposition. By integrating gene therapy, 3D culture systems, and in vivo models, these combinatorial strategies provide a robust platform for the development of next-generation cancer therapies with strong translational potential and the aim of improving clinical outcomes.