FGFR1 Oncogenic Activation Reveals an Alternative Cell of Origin of SCLC in Rb1/p53 Mice

Giustina Ferone; Ji-Ying Song; Oscar Krijgsman; Jan van der Vliet; Miranda Cozijnsen; Ekaterina A Semenova; David J Adams; Daniel Peeper; Anton Berns

doi:10.1016/j.celrep.2020.02.052

FGFR1 Oncogenic Activation Reveals an Alternative Cell of Origin of SCLC in Rb1/p53 Mice

Cell Rep. 2020 Mar 17;30(11):3837-3850.e3. doi: 10.1016/j.celrep.2020.02.052.

Authors

Giustina Ferone¹, Ji-Ying Song², Oscar Krijgsman³, Jan van der Vliet¹, Miranda Cozijnsen¹, Ekaterina A Semenova¹, David J Adams⁴, Daniel Peeper³, Anton Berns⁵

Affiliations

¹ Oncode Institute, Division of Molecular Genetics, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
² Division of Molecular Oncology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
³ Oncode Institute, Department of Experimental Animal Pathology, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
⁴ Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
⁵ Oncode Institute, Division of Molecular Genetics, the Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Electronic address: [email protected].

Abstract

Fibroblast growth factor receptor 1 (FGFR1) is frequently amplified in human small-cell lung cancer (SCLC), but its contribution to SCLC and other lung tumors has remained elusive. Here, we assess the tumorigenic capacity of constitutive-active FGFR1 (FGFR1^K656E) with concomitant RB and P53 depletion in mouse lung. Our results reveal a context-dependent effect of FGFR1^K656E: it impairs SCLC development from CGRP^POS neuroendocrine (NE) cells, which are considered the major cell of origin of SCLC, whereas it promotes SCLC and low-grade NE bronchial lesions from tracheobronchial-basal cells. Moreover, FGFR1^K656E induces lung adenocarcinoma (LADC) from most lung cell compartments. However, its expression is not sustained in LADC originating from CGRP^POS cells. Therefore, cell context and tumor stage should be taken into account when considering FGFR1 inhibition as a therapeutic option.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma of Lung / genetics
Adenocarcinoma of Lung / metabolism
Adenocarcinoma of Lung / pathology
Animals
Bronchi / pathology
Cell Transformation, Neoplastic / drug effects
Cell Transformation, Neoplastic / pathology
Cisplatin / pharmacology
Drug Resistance, Neoplasm / drug effects
Gene Expression Regulation, Neoplastic
Humans
Integrases / metabolism
Keratins / metabolism
Lung Neoplasms / genetics
Lung Neoplasms / metabolism*
Lung Neoplasms / pathology*
Mice
Mutation / genetics
Nasal Cavity / pathology
Neurosecretory Systems / pathology
Oncogenes*
Pulmonary Alveoli / drug effects
Pulmonary Alveoli / pathology
Receptor, Fibroblast Growth Factor, Type 1 / genetics*
Receptor, Fibroblast Growth Factor, Type 1 / metabolism
Retinoblastoma Protein / metabolism*
Small Cell Lung Carcinoma / genetics
Small Cell Lung Carcinoma / metabolism*
Small Cell Lung Carcinoma / pathology*
Tumor Suppressor Protein p53 / metabolism*

Substances

Retinoblastoma Protein
Tumor Suppressor Protein p53
Keratins
Receptor, Fibroblast Growth Factor, Type 1
Cre recombinase
Integrases
Cisplatin