Get started
Work

Unravelling Lung Cancer Heterogeneity and Associated Therapeutic Responses using in vivo and ex vivo Model Systems

Year: 2018
Type: dissertation
Abstract: Lung cancer is the major cause of cancer-related deaths worldwide (Ferlay et al., 2015; Siegel et al., 2018). Tobacco smoking is the primary risk factor, contributing to nearly 85% of the lung cancer deaths (Furrukh, 2013). Lung cancer is histologically and genetically a heterogeneous disease (Gridelli et al., 2015). Comprehensive genomic profiling has led to the classification of lung cancer into distinct molecular subtypes, and the development of targeted therapies against specific genetic alterations (Bronte et al., 2010). However, as of yet, no clinically approved therapies available for the treatment of lung cancer patients carrying common driver genes, namely mutations in oncogenic KRAS (Kirsten Rat Sarcoma Viral Oncogene Homolog), and the tumor suppressor STK11 (Serine/Threonine Kinase 11, also known as LKB1). This thesis investigates the role of niche-specific lung progenitor cells in defining NSCLC histotype spectra and immune microenvironment heterogeneity, using a murine model driven by oncogenic Kras and loss of the tumor suppressor Lkb1. In addition, using Kras-driven NSCLC mouse models, this thesis also demonstrates histotype-associated spatial oncogenic signaling heterogeneity and its importance in defining therapeutic responses. Furthermore, it establishes Kras-driven NSCLC tumor tissue slice cultures and shows their utility as ex vivo models in predicting spatial responses to drug combinations. Finally, by performing drug screening on murine NSCLC primary cell cultures coupled with in vivo acute drug response analysis, this thesis identifies tumor subtype-selective therapeutic sensitivity and resistance mechanisms, as well as effective drug combinations.
Language: English
Field: Medicine
Open Access status: green
OpenAlex ID: W2910789489
Cites: 333
Cited by:
Related to: 10