Although smoking is a major risk factor in developing lung cancer, in people who have never smoked, lung cancer is still the 7th most prevalent cancer worldwide. This may be partly explained by exposure to air pollution, another risk factor for lung cancer, but recent studies have failed to detect signatures of pollution-induced mutations in non-smokers with lung cancer. Moreover, it is now well appreciated that many of the same driver mutations found in tumors, such as mutated epidermal growth factor receptor (EGFR) are often found in people who will never go on to develop lung cancer. These results complicate the model that chemical carcinogens cause cancer solely by mutating cancer-driving genes, and suggest that they may have other effects which promote tumor formation and growth.
In this ASPIRE award, Charles Swanton and his team will test the hypothesis that while oncogenic EGFR mutations can and do occur in normal tissue, they are not sufficient for cancer growth alone. The team posits that tissue and cells with such mutations must also be triggered in some way by carcinogenic environmental factors to promote remodeling of the cellular microenvironment which activates tumor formation. Swanton’s team will measure the presence and expansion of cells with mutant EGFR in normal tissues and assess whether these correlate with various parameters, including air pollution, cigarette smoke exposure, and gender. They then plan to characterize alterations in the lung microenvironment that may initiate cancer development and functionally validate candidates that drive selection of mutant clones in normal tissues. Understanding how environmental factors can trigger cancer in the absence of a mutagenic signature may provide alternative therapeutic approaches and novel risk factors for cancer prevention, diagnosis, and treatments.