Abstract A08: A new driver pathway in ovarian cancer stem cells
Authors: Giordano Marco , Villa Alessandra , Beralot Giovanni , Bianchi Fabrizio , Cavallaro Ugo 
Published: September 2020

Ovarian cancer stem cells (OCSC) are believed to fuel tumor metastasis, recurrence, and chemoresistance. Therefore, understanding the molecular players involved in OCSC function represents an urgent need towards the design of innovative and more efficacious treatments of this neoplasm. Our molecular profiling of primary OCSC isolated from high-grade serous ovarian cancer patients revealed a series of novel genes and pathways specifically associated with this cell subpopulation. Among these, we initially focused on CD73, a cell-surface 5’-ectonucleotidase that catalyzes the production of extracellular adenosine. Our data revealed the new role of CD73 as a driver of OC stemness and a potential target for OCSC-eradicating treatments. More recently, we investigated the functional role in OCSC of the immunoglobulin-like cell adhesion molecule L1 (L1CAM), a transmembrane protein that we have previously implicated in OC malignancy (Zecchini et al., 2008). Loss- and gain-of-function studies were performed by manipulating the expression of L1CAM in OC cells. These experiments revealed the causal role of L1CAM not only in stemness-related properties such as anoikis resistance, clonogenic proliferation under low-attachment conditions and self-renewal, but also in OCSC-driven tumor initiation. Mechanistically, L1CAM appeared to act through the induction, activation, and nuclear translocation of STAT3, all events that occurred predominantly in the OCSC compartment rather than in the bulk tumor cell population. Indeed, the inhibition of STAT3 activity abolished L1-induced OC stemness. Of note, L1-dependent activation of STAT3 was not mediated by the canonical JAK pathway, but rather by the nonreceptor tyrosine kinase SRC. Accordingly, SRC inhibition prevented the induction of stemness-related features by L1CAM. Finally, to identify the molecular mechanisms that link L1CAM with SRC, we built on our previous findings that the L1CAM-related molecule NCAM activates FGFR1 signaling. This enabled us to find a crosstalk between L1CAM and FGFR1 which, in turn, accounts for the stimulation of SRC-mediated activation of STAT3 and, ultimately, OCSC function. Finally, we provide evidence that the inactivation of L1CAM enhances the sensitivity of OCSC to chemotherapeutics, implicating L1CAM as a potential target to overcome chemoresistance. In conclusion, our results uncovered a novel L1/FGFR1/SRC/STAT3 pathway that acts as a driver in OC stemness, shedding light on the pathophysiology of OCSC and opening new therapeutic perspectives for the eradication of such a devastating disease.

References: Lupia M, …Cavallaro U. CD73 regulates stemness and epithelial-mesenchymal transition in ovarian cancer-initiating cells. Stem Cell Reports 2018;10:1412-25. Francavilla C.*, Lupia M.*, …Cavallaro U*, Olsen JV.* Phosphoproteomics of primary cells reveals druggable kinase signatures in ovarian cancer. Cell Rep 2017;18:3242-56 (*equal contribution).

Citation Format: Marco Giordano, Alessandra Villa, Giovanni Beralot, Fabrizio Bianchi, Ugo Cavallaro. A new driver pathway in ovarian cancer stem cells [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A08.