A large fraction of lung cancers contains genetic changes (called mutations) in a tumor promoting gene called KRAS. KRAS-mutant lung cancer, often very aggressive and notoriously difficult to treat, is the most common lung malignancy diagnosed in current or former smokers and the epidemic of this lethal disease will remain long after smoking incidence has dropped. It is widely appreciated that carcinogenic (such as smoking) exposure elicits tumor promoting molecular and inflammatory changes throughout the lung. Notably, the lung is ecologically rich with various cell populations besides the airway lining including diverse immune subsets that may participate in cancer. Yet, for a fatal malign...

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A large fraction of lung cancers contains genetic changes (called mutations) in a tumor promoting gene called KRAS. KRAS-mutant lung cancer, often very aggressive and notoriously difficult to treat, is the most common lung malignancy diagnosed in current or former smokers and the epidemic of this lethal disease will remain long after smoking incidence has dropped. It is widely appreciated that carcinogenic (such as smoking) exposure elicits tumor promoting molecular and inflammatory changes throughout the lung. Notably, the lung is ecologically rich with various cell populations besides the airway lining including diverse immune subsets that may participate in cancer. Yet, for a fatal malignancy like KRAS-mutant lung cancer that is causally related to tobacco, very little, if any, is known about how different cell populations come together and interact to inspire inception of the disease from a specific region in the lung.

Understanding these ecological mechanisms will provide a new compelling view of the evolution of KRAS-mutant lung cancer and, thus, pave the way for design of new therapeutic strategies for this vexing disease. Using a unique cohort of human samples, an experimental mouse model that faithfully recapitulates the disease, as well as cutting edge technology and computation that probe genetic and immune changes in each individual cell, this research proposal seeks to unravel an "atlas" of KRAS-mutant lung cancer evolution in space and in time and of its response to early immune-based treatment. At the conclusion of our project, we will have transformed our understanding of how KRAS-mutant lung cancer evolves from a particular niche in the smoking-exposed lung and provided a foundation for developing new strategies for the interception of this all too common yet morbid malignancy.

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