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

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.

• 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
• Journal: Journal of experimental & clinical cancer research : CR (J Exp Clin Cancer Res) Vol. 40 Issue 1 Pg. 319 (Oct 13 2021) ISSN: 1756-9966 [Electronic] England
• PMID: 34645505 (Publication Type: Journal Article)
• Copyright: © 2021. The Author(s).

Chemical References

• L1CAM protein, human
• Neural Cell Adhesion Molecule L1
• STAT3 Transcription Factor
• STAT3 protein, human
• FGFR1 protein, human
• Receptor, Fibroblast Growth Factor, Type 1

Topics

• Animals
• Cell Line, Tumor
• Female
• HEK293 Cells
• Heterografts
• Humans
• Mice
• Mice, Inbred NOD
• Neoplastic Stem Cells (metabolism, pathology)
• Neural Cell Adhesion Molecule L1 (metabolism)
• Ovarian Neoplasms (metabolism, pathology)
• Receptor, Fibroblast Growth Factor, Type 1 (metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction