Abstract 3678: Ovarian cancer stemness is driven by a novel L1/Stat3/Src axis

Abstract

Abstract Introduction Ovarian cancer (OC) is the most lethal gynaecological malignancy due to the lack of peculiar symptoms in its early phase (Bowtell, 2010). OC often relapses as a chemoresistant disease within 3 years after surgical debulking (Lengyel, 2010; Sun et al, 2007). These pathological hallmarks raised the hypothesis that OC is a cancer-stem cell (CSC)-driven disease. Indeed, a “stem-like” chemoresistant subset of OC cells is more tumorigenic than the bulk tumor cell population and is able to form spheroids in vitro (Bapat et al, 2005; Pan et al 2012). This pointed to ovarian CSC (OCSC) as an attractive target for OC-eradicating therapies. The cell adhesion molecule L1 has been implicated in OC progression (Zecchini et al, 2008). While a few reports implicated L1 in stemness, its role in OCSC has not been investigated. Based on these observations, we aimed to investigate the functional role of L1 in the physiopathology of OCSC. Experimental procedures OVCAR3 and Ov90, two OC cell lines with high and low endogenous L1 levels, respectively, were employed for loss- and gain-of-function studies. Sphere-forming efficiency (SFE) was determined as the fraction cells within the bulk population able to overcome anoikis and proliferate in suspension cultures, and used as an in vitroproxy for CSC frequency. Tumorigenesis in NSG mice was employed as in vivo assays for cancer stemness. BBI608 and SU6656 were used as STAT3 and SRC activity inhibitor, respectively. Results L1 was both required and sufficient for self-renewal in OC. Indeed, L1 silencing prevented tumor formation while its forced expression in OCSC-enriched sphere cultures promoted tumor initiation in vivo. Mechanistically, L1 increased dramatically the expression and the activation of STAT3 in OCSC and promoted its nuclear localization. L1 per se was sufficient for OC sphere formation even under very stringent culture conditions in which, once again, STAT3 was activated in L1-expressing OCSC only. Moreover, STAT3 activity was required for L1-induced clonogenic advantage, which occurred in a JAK-independent manner. Alternatively, L1-induced SFE was mediated by SRC-dependent STAT3 activation. SRC inhibition, in turn, reduced FAK activation in L1-expressing OCSC. Thus, a novel L1/STAT3/SRC axis appears to sustain OCSC pathophysiology. L1 is also an optimal target for OC eradication since it confers chemoresistance to OCSC while its targeting reduces OCSC frequency. On these premises, L1 targeting should be explored in combined treatments with chemotherapeutic agents. Conclusion L1 can be considered as a new player and potential target in the context of OCSC, and the L1/STAT3/SRC interplay emerges as a novel mechanism in OC initiation and progression. Therefore, this work might pave the way to novel therapeutic strategies for the eradication of such a devastating disease. Citation Format: Marco Giordano, Alessandra Villa, Giovanni Bertalot, Fabrizio Bianchi, Stefano Freddi, Ugo Cavallaro. Ovarian cancer stemness is driven by a novel L1/Stat3/Src axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3678.