Research projects

Ovarian cancer stem cells

The main objective of this project is the discovery and the functional characterization of the pathways that underlie the pathogenic function of OCSC, aimed at identifying vulnerabilities that can be harnessed for therapeutic purposes.

We have obtained the molecular portrait of primary cells derived from either OC or its healthy counterparts (ovarian surface and fallopian tube epithelium). Both the bulk cell populations and their stem cell subsets were profiled, which revealed a series of genes and networks specifically deregulated in OCSC.

Among these, we identified the cell surface molecule CD73 as a novel driver of OCSC function. In particular, our data implicated CD73 in the epithelial-to-mesenchymal transition (EMT) of OCSC and in the expression of CSC-related genes.

CD73 is endowed with enzymatic activity (it is a 5’-ectonucleotidase that converts extracellular AMP into adenosine), thus representing a potential therapeutic target. Indeed, interfering with the ectonucleotidase activity of CD73 reduced dramatically not only the stemness-related properties of OCSC, but also tumor initiation and dissemination in vivo. Ongoing efforts aim at defining the mechanism of action of CD73 in OCSC, focusing on CD73-regulated genetic and biochemical pathways and on their impact on OC stemness.

CD73 also plays an important role in tumor immune escape, a key property of cancer cells that enable them to evade different types of antitumor immune responses. Therefore, besides driving stemness, CD73 might also exerts a protective effect on OCSC against the immune system, thus supporting their long-term quiescence and survival. Taken together, these observations make CD73 an attractive target for innovative, OCSC-directed treatments that may hopefully lead to OC eradication.

Current studies also entail other molecular pathways that we found specifically altered in OCSC. Both the clinical relevance and the functional outcome of such pathways are under investigation. Besides shedding light on the elusive biology of OCSC, this approach is expected to lay the ground for innovative therapeutic strategies towards the eradication of ovarian cancer.

The role of L1CAM in tumor vasculature

L1CAM is a cell-surface adhesion molecule originally identified and characterized in the central nervous system. We and other have subsequently documented the expression of L1CAM also in other non-neural tissues. Moreover, L1CAM is aberrantly expressed in several tumor types, where it contributes to invasion and metastasis. We have also discovered that L1CAM is frequently detected in the vasculature of various solid tumors, but not in normal vessels. Through the integration of conditional knockout mouse models of tumorigenesis with cell biological assays and “omics” approaches, we implicated endothelial L1CAM in the aberrant pathophysiology that characterize tumor-associated vessels. Targeting L1CAM resulted in vascular normalization, suggesting that it might represent a suitable approach to improve drug delivery and distribution into solid tumors. Mechanistically, L1CAM was found to exert a pleiotropic role in endothelial cells, including a global gene expression reprogramming and the induction of STAT3 activation and other major signaling pathways.

Current studies focus on the regulation and function of L1CAM in ovarian cancer vasculature and on its therapeutic implications. In addition, our group is exploring the role of L1CAM in the crosstalk between tumor vessels and ovarian cancer stem cells.