Oncogenic FGFR Fusions Produce Centrosome and Cilia Defects by Ectopic Signaling

Area of Science:

• Cell Biology
• Molecular Oncology
• Genetics

Background:

• Primary cilia are crucial for cell fate decisions and signaling.
• Fibroblast growth factor receptors (FGFR) regulate cilia function, and their aberrant activity is linked to genetic disorders and cancer.
• FGFR gene fusions are implicated as oncogenic drivers, with potential roles in cilia involvement.

Purpose of the Study:

• To investigate the role of FGFR gene fusions in cancer, focusing on their mechanisms as oncogenic drivers.
• To explore the potential involvement of primary cilia in FGFR-mediated oncogenesis.

Main Methods:

• Analysis of FGFR gene fusions and their fusion partners.
• Examination of centrosome cycle proteins and their association with FGFR fusions.
• Assessment of ciliogenesis and cell division in the context of FGFR fusions.

Main Results:

• A significant number of FGFR fusion partners are centrosome cycle proteins involved in mitotic spindle organization and ciliogenesis.
• Gene fusions often lead to the loss of centrosome protein function, causing haploinsufficiency.
• This haploinsufficiency results in cilia loss and deregulated cell division.

Conclusions:

• FGFR gene fusions contribute to cancer development through mechanisms involving primary cilia.
• The loss of centrosome protein function and subsequent cilia dysfunction, coupled with aberrant FGFR signaling, drives FGFR fusion-driven cancers.
• This highlights a novel pathway for oncogenesis involving cilia dysfunction in FGFR-mediated cancers.