Lung cancer is the leading cause of cancer deaths largely due to late detection and the development of rapid resistance to current therapies. Identifying the cell-of-origin of different cancer subtypes and defining the genetic and molecular alterations that accompany their transformation is of critical importance. This knowledge will help focus intervention strategies on eliminating the cancer propagating cells that most likely retain many of the characteristics of its cell-of-origin.
To determine whether a specific cellular compartment in the lung exhibits cancer-initiating properties, we have established a new strategy of inducing mouse lung cancer in a small, well-defined population of cells. We have constructed a series of Adeno-Cre viruses that permit cell type-restricted switching of oncogenes and/or tumour suppressor genes in Clara cells (CC10+), alveolar type 2 cells (SPC+) and neuroendocrine cells (CGRP+) in the adult mouse lung. Using Rosa26R-LacZ and mT/mG reporter mice, we show that these viruses exhibit a high level of selectivity to the distinct target cell populations.
To gain insight in the cell-of-origin of lung cancer, we have used these Adeno-Cre viruses in well-characterised mouse models of human small cell and non-small cell lung cancer. Recent results from these experiments demonstrate that the cell-of-origin and the initiating genetic lesions strongly influence tumour development. Moreover, we have preliminary evidence to suggest that the cell-of-origin also influences the characteristics of the resulting tumour. Markers identifying the cell-of-origin are therefore likely to have prognostic and predictive value.