L1CAM promotes ovarian cancer stemness and tumor initiation via FGFR1/SRC/STAT3 signaling

Marco Giordano,Fabrizio Bianchi,Michela Lupia,Maria Giovanna Jodice,Alessandra Decio,Alessandra Villa,Nicoletta Colombo,Micol Baronio,Ugo Cavallaro,Raffaella Giavazzi,Stefano Freddi,Giovanni Bertalot,Paolo Ubezio,Chiara Battistini

doi:10.1186/s13046-021-02117-z

Abstract

BackgroundCancer stem cells (CSC) have been implicated in tumor progression. In ovarian carcinoma (OC), CSC drive tumor formation, dissemination and recurrence, as well as drug resistance, thus contributing to the high death-to-incidence ratio of this disease. However, the molecular basis of such a pathogenic role of ovarian CSC (OCSC) has been elucidated only to a limited extent. In this context, the functional contribution of the L1 cell adhesion molecule (L1CAM) to OC stemness remains elusive.MethodsThe expression of L1CAM was investigated in patient-derived OCSC. The genetic manipulation of L1CAM in OC cells provided gain and loss-of-function models that were then employed in cell biological assays as well as in vivo tumorigenesis experiments to assess the role of L1CAM in OC cell stemness and in OCSC-driven tumor initiation. We applied antibody-mediated neutralization to investigate L1CAM druggability. Biochemical approaches were then combined with functional in vitro assays to study the molecular mechanisms underlying the functional role of L1CAM in OCSC.ResultsWe report that L1CAM is upregulated in patient-derived OCSC. Functional studies showed that L1CAM promotes several stemness-related properties in OC cells, including sphere formation, tumor initiation and chemoresistance. These activities were repressed by an L1CAM-neutralizing antibody, pointing to L1CAM as a druggable target. Mechanistically, L1CAM interacted with and activated fibroblast growth factor receptor-1 (FGFR1), which in turn induced the SRC-mediated activation of STAT3. The inhibition of STAT3 prevented L1CAM-dependent OC stemness and tumor initiation.ConclusionsOur study implicate L1CAM in the tumorigenic function of OCSC and point to the L1CAM/FGFR1/SRC/STAT3 signaling pathway as a novel driver of OC stemness. We also provide evidence that targeting this pathway can contribute to OC eradication.

Highlights

Cancer stem cells (CSC) have been implicated in tumor progression
L1 cell adhesion molecule (L1CAM) is upregulated in ovarian CSC (OCSC) and promotes clonogenicity and self‐renewal L1CAM is expressed at higher level in ovarian carcinoma (OC) in respect to normal ovary (Supplementary Fig. S1A and [57])
Given that ovarian cancer stem cells (OCSC) are viewed as main players in these events [37], we asked whether L1CAM plays a role in OC stemness and in OCSC-driven tumor progression

Summary

Introduction

In ovarian carcinoma (OC), CSC drive tumor formation, dissemination and recurrence, as well as drug resistance, contributing to the high deathto-incidence ratio of this disease. The molecular basis of such a pathogenic role of ovarian CSC (OCSC) has been elucidated only to a limited extent. In this context, the functional contribution of the L1 cell adhesion molecule (L1CAM) to OC stemness remains elusive. The lack of specific symptoms associated to the early phases of the disease, which results in the diagnosis being done at late stages in nearly 70% of cases [23]. Unlike the primary tumor, recurrent OC often develops chemoresistance and becomes unresponsive to standard treatments [37]

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Conclusion