Gene Expression Laboratory
Daniel and Martina Lewis Chair
Geoffrey M. Wahl, a professor in the Gene Expression Laboratory, is studying the genetic basis of the origin and progression of cancer and why tumors become resistant to drugs.
Wahl has been involved in various aspects of cancer research for his entire 40 year career, first as a graduate student of Dr. Mario Capecchi, then as a post-doctoral fellow with Dr. George Stark. Since that time, Wahl's own lab has focused on identifying the molecules and mechanisms involved in the genetic and phenotypic heterogeneity common to most human cancers. Their work has involved uncovering the mechanisms that lead to the most common forms of genetic instability in human cancers. This led them to investigate the mechanisms that prevent normal cells from acquiring the large-scale chromosomal changes that fuel the progression of many cancers. This work revealed that one function of the p53 tumor suppressor, one of the most commonly mutated genes in human cancer, is to prevent the emergence and proliferation of cells with genome instability. However, Wahl and his colleagues have also recognized that in some cancers, such as pancreatic cancer, there is substantial proliferation of an abnormal stroma that augments the growth of the associated epithelial cancer cells, and that this stroma has normal p53 that can be activated. They are currently working on strategies to activate the p53 in the abnormal stroma to see whether this also impedes growth of co-cultured pancreatic cancer cells or decreases the stromal response in vivo. More recently, they showed that p53 can also limit the ability of normal cells to de-differentiate into pluripotent stem cells, and that its mutation in cancer correlates with the acquisition of a de-differentiated stem-like state associated with some of the most aggressive forms of breast cancer. Most recently, they have become interested in the nature of the stem-like cells in a dangerous form of very aggressive breast cancers referred to as "triple negative" because they lack or have low expression of estrogen and progesterone receptors and the Her2 protein, which encodes an epidermal growth factor related receptor. The Wahl lab has also identified, isolated and characterized the stem cells that are formed in the fetus. The genes expressed in these fetal mammary stem cells show significant similarities to those expressed in the triple negative breast cancers. They are now characterizing these cells further in an attempt to identify molecular targets for which non-genotoxic therapeutics can be developed to provide an alternative, or addition, to the chemotherapy currently used to treat patients whose cancers show an enrichment for the fetal mammary stem cell signature.
Significant advances in breast cancer prevention and treatment have come from strategies based on knowledge of mammary cell biology and the unique molecular fingerprints of individual tumors. Despite such advances, however, more than 40,000 patients in the United States and about 500,000 worldwide will die of breast cancer in the next 12 months. In too many cases, treatment failures resulting from emergence of drug-resistant cells and metastases will shorten lifespan and reduce quality of life. The overarching issue the Wahl lab addresses is whether a better understanding of the stem-like cells Wahl and others have found in many breast cancers could provide clues to the development of more effective treatment strategies.
During the 1800s pathologists and developmental biologists emphasized that understanding cancer requires deep knowledge of the principles governing the development of the tissue of origin in which the cancer will arise. Thus, even in the 19th century, scientists appreciated that cancer is a caricature of normal development. Wahl's group therefore expended considerable effort studying the development of the mouse mammary gland in the hope that it would provide insight into the types of cells and processes that are perturbed in the generation of human breast cancers.
His team recently reported the first identification, isolation and characterization of mouse fetal mammary stem cells (fMaSCs) and their associated gene expression profiles. Significantly, they found that many growth regulatory pathways present in fMaSCs appear to be enriched in specific patients with aggressive and frequently chemoresistant basal-like and triple-negative cancers. This is important, as these cancers currently lack molecular targets around which to build personalized therapeutic agents, such as Herceptin for those breast cancers that overexpress Her2 (a growth factor receptor that Herceptin inactivates). The researchers tested whether currently available targeted therapeutic agents directed against some fMaSC growth factor pathways would inhibit their growth and found that the agents tested worked well to inhibit fMaSC growth.
Wahl and his group are now doing the work needed to extend these studies to the clinic in the hope that this basic research can be translated to the bedside to help patients with breast cancers that currently lack targeted therapeutic strategies. An implication of the work is that cells that fuel cancer progression may revert to, or acquire, gene expression characteristics initially found in the stem cells of the embryonic tissue of origin.