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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2021

Open Access 01-12-2021 | Ovarian Cancer | Research

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

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

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

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Abstract

Background

Cancer 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.

Methods

The 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.

Results

We 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.

Conclusions

Our 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.
Appendix
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Metadata
Title
L1CAM promotes ovarian cancer stemness and tumor initiation via FGFR1/SRC/STAT3 signaling
Authors
Marco Giordano
Alessandra Decio
Chiara Battistini
Micol Baronio
Fabrizio Bianchi
Alessandra Villa
Giovanni Bertalot
Stefano Freddi
Michela Lupia
Maria Giovanna Jodice
Paolo Ubezio
Nicoletta Colombo
Raffaella Giavazzi
Ugo Cavallaro
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-021-02117-z

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