PO-287 A novel L1/STAT3 crosstalk drives ovarian cancer stem cell function

Introduction Ovarian cancer (OC) is the most lethal gynaecological malignancy due to the lack of peculiar symptoms during its onset. Moreover, OC often relapses as a chemoresistant disease within 1–2 years after surgical debulking. These pathological hallmarks raised the hypothesis that OC is a cancer-stem cell (CSC)-driven disease. Indeed, a ‘stem-like’ chemoresistant subset in OC is able to form spheroids in suspension cultures and is more tumorigenic respect to the bulk population. This pointed to ovarian CSC (OCSC) as an intriguing target for OC-eradicating therapies. The cell adhesion molecule L1 (hereafter referred to as L1) has been implicated in OC progression. Furthermore, L1 function has been causally linked to stemness in both embryonic and stem-like cells from different tumours. Finally, a strong correlation exists between L1 expression and shorter 5 year overall and progression-free survival in Stage I/II OC, a subgroup of patients that normally has a relatively good prognosis. This confirms the potential clinical value of L1 in OC. Based on these observations, we aimed to investigate the functional role of L1 in the physiopathology of OCSC. Material and methods OVCAR3 and Ov90, two OC cell lines with high and low L1 levels, respectively, were employed for loss- and gain-of-function studies. Sphere-forming efficiency (SFE) and tumorigenesis in NSG mice were employed as in vitro and in vivo assays for cancer stemness, respectively. BBI608 was used as STAT3 activity inhibitor. Results and discussions L1 was both required and sufficient for self-renewal in OC in vitro . Moreover, L1 silencing prevented tumour formation while its forced expression in OCSC-enriched sphere cultures promoted tumour initiation in vivo. L1 per se was sufficient for OC sphere formation even under very stringent conditions. Mechanistically, L1 dramatically increased the expression and the activation of STAT3 in OCSC. Moreover, STAT3 activity was required for L1-induced OCSC function and, interestingly, L1-induced activation of STAT3 occurred in a JAK-independent manner. Thus, a novel L1/STAT3 axis appears to sustain OCSC pathophysiology. Conclusion L1 can be considered as a new player and potential target in the context of OCSC, and the L1/STAT3 cross-talk emerges as a novel driver in OC initiation and progression. Therefore, this work might pave the way to novel therapeutic strategies for the eradication of such a devastating disease.