Gerard Evan, Ph.D.
Our laboratory is interested in the molecular processes that underlie tumorigenesis, tumor progression and tumor maintenance. Cancers appear very different from the normal tissues from which they are presumably derived, and this has engendered the widely held contemporary view that cancers are the protracted end result of a bewildering complexity of molecular lesions that between them drive the formation of the equally complex neoplastic phenotype. However, appearances can be deceiving. We know that many oncogenes are highly pleiotropic "master" switches that modulate a wide variety of mechanistically diverse processes. Consequently, the apparent complexity of cancers may be instructed by a relatively simple, and hence therapeutically tractable, set of molecular lesions. Our overarching aim is to establish what such molecular lesions might be, what effects they have on specific cell types, alone and in combination, and how critical such lesions are not only to drive tumor formation but also to maintain an established tumor.Some years ago we noted an unexpected link between the processes that drive cell proliferation and those that promote programmed cell death (apoptosis). We showed that the ubiquitous Myc oncoprotein was a potent trigger of apoptosis in cells deprived of survival factors or subjected to any of a diverse range of insults including DNA damage, interferon and death receptor signaling, hypoxia and nutrient privation. On the basis of such observations, we proposed the now generally accepted notion that the coupling of cell proliferation with cell death represents an innate tumor suppressive mechanism that efficiently restrains the emergence of autonomous clones within the soma. Thus, no cancer can arise without concomitant suppression of cell death. This, in turn, raises some critical questions. First, how does cell death become suppressed during tumorigenesis? Second, besides deregulated cell proliferation and suppressed cell death, what else (if anything) is needed for a cancer to arise? Third, how important is suppression of cell death for the maintenance of established cancers? In particular, might reconstitution of cell death offer an effective and tumor-specific general therapeutic strategy for treating cancer? Much of the work in our laboratory addresses these key questions using a variety of novel experimental systems and technologies. In particular, we are developing a number of new types of reversibly switchable mouse transgenic, knock-in, knock-out and gene replacement models with which to explore when, where, how and why specific oncogenes and tumor suppressors exert their effects in the development of normal and neoplastic tissues.