Cholangiocarcinoma Malignant Traits Are Promoted by Schwann Cells through TGFβ Signaling in a Model of Perineural Invasion

Author:

de Franchis Valerio1,Petrungaro Simonetta1ORCID,Pizzichini Elisa1ORCID,Camerini Serena2,Casella Marialuisa2ORCID,Somma Francesca1,Mandolini Enrico1,Carpino Guido1ORCID,Overi Diletta1ORCID,Cardinale Vincenzo3,Facchiano Antonio4ORCID,Filippini Antonio1ORCID,Gaudio Eugenio1,Fabrizi Cinzia1ORCID,Giampietri Claudia1ORCID

Affiliation:

1. Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Sapienza University of Rome, 00161 Rome, Italy

2. Core Facilities, Istituto Superiore di Sanità, 00161 Rome, Italy

3. Department of Medico-Surgical Sciences and Biotechnology, Sapienza University of Rome, 04100 Latina, Italy

4. Laboratory of Molecular Oncology, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, 00167 Rome, Italy

Abstract

The term cholangiocarcinoma (CCA) defines a class of epithelial malignancies originating from bile ducts. Although it has been demonstrated that CCA patients with perineural invasion (PNI) have a worse prognosis, the biological features of this phenomenon are yet unclear. Our data show that in human intrahepatic CCA specimens with documented PNI, nerve-infiltrating CCA cells display positivity of the epithelial marker cytokeratin 7, lower with respect to the rest of the tumor mass. In an in vitro 3D model, CCA cells move towards a peripheral nerve explant allowing contact with Schwann cells (SCs) emerging from the nerve. Here, we show that SCs produce soluble factors that favor the migration, invasion, survival and proliferation of CCA cells in vitro. This effect is accompanied by a cadherin switch, suggestive of an epithelial–mesenchymal transition. The influence of SCs in promoting the ability of CCA cells to migrate and invade the extracellular matrix is hampered by a specific TGFβ receptor 1 (TGFBR1) antagonist. Differential proteomic data indicate that the exposure of CCA cells to SC secreted factors induces the upregulation of key oncogenes and the concomitant downregulation of some tumor suppressors. Taken together, these data concur in identifying SCs as possible promoters of a more aggressive CCA phenotype, ascribing a central role to TGFβ signaling in regulating this process.

Funder

Sapienza University

Ricerca Corrente

Progetto Dipartimentale Sapienza

Publisher

MDPI AG

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