Investigating the initiation and progression of small cell lung cancer

Abstract

Small cell lung cancer (SCLC) comprises 18% of all lung cancer cases and is an aggressive disease with a five-year survival rate of less than 5%, mainly due to the advanced nature of the disease at the time of diagnosis. Despite the need to better understand this disease, the genetic lesions that contribute to SCLC remain poorly characterized. To investigate the genetic aberrations that occur in SCLC, we analyzed the copy number alterations in tumors and metastases arising in a mouse model of SCLC (mSCLC), driven by conditional inactivation alleles of two tumor suppressor genes, Trp53 and Rbl. We identified frequent, high-level amplification of a novel, protooncogenic transcription factor Nuclear Factor I/B (Nfib in mouse, NFIB in human), which frequently occurred coincident with amplification of a previously characterized oncogene, L-myc (Mycl). Functional studies revealed cooperation between Nfib and Lmyc in cellular transformation. Comparative genomics identified NFIB amplifications in human SCLC and uncovered a role for NFIB in regulating cell viability and proliferation. We also examined the effect of lung injury on SCLC initiation and progression utilizing naphthalene, a chemical that ablates the cells that line the bronchioles of the lung. The pulmonary neuroendocrine cells, the putative cell of origin of SCLC, are refractory to naphthalene-mediated injury. We demonstrated that naphthalene-mediated injury prior to tumor initiation in the mouse model of SCLC induced more advanced mSCLC lesions and decreased tumor latency. Throughout the course of this thesis work, we successfully utilized a mouse model of SCLC to interrogate the initiation of SCLC as well as to define the genetic alterations that occur in SCLC tumors and metastases. This work has led to the identification of candidate genes that promote tumor progression and to a better understanding of the process of tumor initiation. We anticipate that these findings will not only enhance our understanding of SCLC, but may lead to the development of therapeutics used to treat this aggressive disease.