NFIB overexpression cooperates with Rb/p53 deletion to promote small cell lung cancer.

Nan Wu,Cindy J Bachurski,David Macpherson,Deshui Jia,Richard M Gronostajski,Ali H Ibrahim

doi:10.18632/oncotarget.11583

Abstract

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor type that is typically metastatic upon diagnosis. We have a poor understanding of the factors that control SCLC progression and metastasis. TheNFIB transcription factor is frequently amplified in mouse models of SCLC, but clear evidence that NFIB promotes SCLC in vivo is lacking. We report that in mouse models, Nfib amplifications are far more frequent in liver metastases over primary SCLC, suggesting roles in tumor progression/metastasis. Overexpression of Nfib in a sensitized mouse model led to acceleration of SCLC, indicating that Nfib functions as a bona fide oncogene. Suppression of Nfib expression in cell lines derived from the doxycycline-inducible Rb/p53/TET-Nfib model led to increased apoptosis and suppression of proliferation. Transcriptional analysis revealed that Nfib regulates the expression of genes related to axon guidance, focal adhesion and extracellular matrix-receptor interactions. These data indicate that Nfib is a potent oncogene in SCLC, and the enrichment of Nfib amplifications in liver metastases over primary SCLC points to Nfib as a candidate driver of SCLC metastasis.

Highlights

The most metastatic form of lung cancer is Small cell lung cancer (SCLC), a highly aggressive neuroendocrine cancer [1]
The use of neuroendocrine specific Ad-Calcitonin Gene Related Peptide (CGRP)-Cre is necessary in the Rblox/lox;p53lox/lox;Ptenlox/ lox model, as this dramatically reduces the incidence of adenocarcinoma that otherwise occurs with Ad-CMV-Cre infection in these mice [6, 7, 9]
Multiple chromosome 4 amplifications, including Nfib were present in the liver metastasis but not the matched lung tumor. Across another Rb/p53 model pair that was clearly clonally related (H6210), Mycl amplification was present in the lung SCLC, and the liver metastasis exhibited Nfib amplification but lacked Mycl amplification (Supplemental Figure 1B)

Summary

Introduction

The most metastatic form of lung cancer is SCLC, a highly aggressive neuroendocrine cancer [1]. The high frequency of metastasis at diagnosis raises the possibility that SCLC may acquire many of the genetic lesions needed for metastasis early, but there has been little work to compare primary SCLC to metastases using human samples. This is likely owing to the difficulty in accessing samples from a tumor type that rarely undergoes surgical resection. Tumors in the Rb/p53 mouse model undergo spontaneous secondary genetic alterations that occur in human SCLC such as amplification of Mycl or deletion of Pten [6]. We need a better understanding of which genetic changes occur very early in tumor initiation and which subsequent mutations contribute to tumor progression and metastasis

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Conclusion