CROSSTALK BETWEEN TUMOUR VASCULATURE AND OVARIAN CANCER STEM CELLS: THE ROLE OF L1CAM.

Ovarian cancer is the most lethal gynaecologic tumour, mainly due to relapse and chemoresistance, two events fuelled by ovarian cancer stem cells (OCSC). The tumour microenvironment (TME) is thought to act as a niche for OCSC, preserving stem cells properties and sustaining tumour recurrence. The crosstalk between TME and OCSC, therefore, offers a source of new targets and mechanisms to overcome the limitations of current treatments. We identified L1CAM, an adhesion glycoprotein, expressed both in tumour endothelium and epithelial cancer cells, as a mediator of the interaction between the vascular TME (vTME) and OCSC. L1CAM expression correlates with metastatic spread and poor outcome, because of its ability to induce cancer proliferation and chemoresistance, together with the increase of vessels permeability and neo-angiogenesis. Notably, endothelial cells express a new isoform of L1CAM (L1-ΔTM), that is released as a soluble factor. We found that endothelial L1-ΔTM enhances stem-like properties in OCSC, a process mediated by IL6/JAK2/STAT3 signalling axis. Furthermore, the RNA-sequencing analysis revealed that L1-ΔTM confers a proinflammatory phenotype on OCSC, able to support cancer initiation, proliferation and progression. Moreover, I have setup a perivascular niche-on-chip confirming the capability of L1-ΔTM-expressing vessels to foster proliferation and spreading in the tumoral compartment. Our approach highlights L1-ΔTM as a druggable target in the crosstalk between vTME and OCSC. Indeed, our findings could provide the rationale for exploring novel L1CAM-based therapeutic approaches aimed at the eradication of OC through the elimination of its stem cell compartment.

Grantor dc:publisher

Università degli Studi di Milano

Year dc:date

2024

Author dc:creator

• BARONIO, MICOL

Contributors dc:contributor

• supervisor: U. Cavallaro ; internal advisor: G. Scita ; phd coordinator: S. Minucci
• Cavallaro
• Ugo
• M. Baronio
• DI FIORE, PIER PAOLO
• SCITA, GIORGIO
• MINUCCI, SAVERIO

• ovarian cancer
• tumour microenvironment
• L1CAM
• endothelium
• cancer stem cell
• STAT3.
• Settore MED/04 - Patologia Generale

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

http://dx.doi.org/10.13130/baronio-micol_phd2024-04-11
10.13130/baronio-micol_phd2024-04-11

OAI identifier oai:identifier

oai:air.unimi.it:2434/1038194