The overall goal of my research is to uncover the tumor microenvironmental dynamics driving cancer progression to provide novel effective therapies to cancer patients.

During my PhD at the University of Bologna I gained extensive knowledge on bone biology and contributed to unravel the properties and function of mesenchymal stem cells (MSCs) in regenerative medicine and cancer. Eager to better understand the biology of these multifaceted stem cells and improve my molecular biology skills, I spent part of my PhD in the lab of Reuven Agami (NKI, Amsterdam), focusing on MSC gene regulation by non-coding RNAs.

Supported by multiple fellowships (including a L’Oréal-UNESCO For Women in Science and a Marie Curie Individual Fellowship), I relocated to the Netherlands as a PostDoc (Michiel Pegtel’s lab, VUmc) to resolve the mechanisms of intercellular communication via extracellular vesicles (EVs) in autoimmunity and cancer (Baglio et al., PNAS 2016; Baglio et al., Clin Cancer Res 2017). Here I developed a strong curiosity for the mechanisms by which tumor cells shape a tumor supporting microenvironment and a high motivation to make a real contribution to the development of novel effective combination immunotherapy strategies.

To identify druggable microenvironmental components driving bone cancer progression, through collaborations with research groups at AmsterdamUMC, LUmc, the Rizzoli Orthopaedic Institute and the UH Cleveland Medical Center, I developed a bioluminescent orthotopic model of osteosarcoma, which enabled precise dissection of the interactions between tumor cells and MSCs in the bone marrow environment in vivo. I demonstrated that bone cancer cells are prolific producers of EVs of endosomal origin (i.e. exosomes) that carry and strongly enhance the activity of TGFβ. Intriguingly, EV-bound TGFβ dramatically alters the immunomodulatory properties of bone marrow MSCs fostering metastasis formation (Baglio et al., Clin Cancer Res 2017).

Based on these studies and supported by a KWF grant selected by the Maarten van der Wijden Foundation, my team is currently investigating the mechanisms by which tumor EVs suppress the bone marrow immune environment leading to immune evasion, and whether TGFβ inhibition alone or in combination with cytokine/chemokine receptor (collaboration with Dompe’ Pharmaceutical) and immune checkpoint inhibitors, prevents bone cancer progression in immunocompetent mouse models.

To this purpose we developed an advanced, highly parametric, spectral flow cytometry strategy that allows to detailly address tumor-associated immune alterations and evaluate treatment effects. With this methodology, we discovered that tumor cells growing in the bone drastically alter the bone marrow immune environment, resulting in the accumulation of myeloid derived suppressor cells, PDL1⁺ monocytes, PD1⁺ T cells and regulatory T cells, likely impacting cancer progression and response to immunotherapy.

Based on these exciting results, supported by an internal Cancer Center Amsterdam funding, we are currently developing an eighty-marker spectral flow cytometry methodology that can be applied in a liquid biopsy setting as a step towards personalized medicine. This method is unique in that it addresses not only the phenotype, but also the metabolic status of cancer patients’ immune cells, an increasingly recognized indicator of effector function that is completely ignored when relying on traditional flow cytometry methods. For its potential clinical applications this technology has already attracted wide interest not only from surrounding scientist and clinicians, but also from pharmaceutical companies, being instrumental for the identification of novel therapeutic strategies and potential companion diagnostics tools.

Finally, apart from EV-bound immunomodulatory proteins, we were among the first to show molecular and mechanistic proof that EVs carry a unique repertoire of non-coding RNAs that functionally impact recipient cells (Baglio et al., PNAS 2016; Baglio et al, Stem Cell Res & Ther 2015). In particular we explored the mechanisms underlying sorting of specific RNA and protein cargo into exosomes, and how delivery to specific subcellular compartments influences their functionality. Based this knowledge, we are currently designing an efficient and safe method for the exosome-mediated delivery of CRISPR-Cas9 for cancer gene therapy.