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Geoffrey M. Wahl, PhD
Daniel and Martina Lewis Chair, Gene Expression Laboratory
Salk Institute of Biological Medicine
La Jolla, California
Goal: To advance the understanding of how obesity contributes to breast cancer.
Impact: Dr. Wahl is conducting laboratory studies to determine the role obesity plays in intra-tumoral heterogeneity, which is a common feature of triple-negative breast cancer (TNBC). His work could lead to improved outcomes in patients with TNBC, an aggressive subtype of breast cancer that has a high risk of metastasis.
What’s next: He and his colleagues will investigate why obesity promotes TNBC at the genetic level.
Breast tumors are made up of a diverse population of cancer cells, a condition referred to as intra-tumor heterogeneity. The wider the variety of cells present, the more difficult the cancer is to treat, since not all of the tumor cells will respond to a given therapy in the same way. Dr. Wahl is investigating why obesity—a well-established risk factor for breast cancer—allows breast cells to change their state, which is a known contributor to intra-tumor heterogeneity.
Full Research Summary
Research area: Understanding the role that obesity plays in breast cancer development and progression.
Impact: Tumors are not a mass of homogeneous cells but are rather comprised of a diverse mix of cancer cells that have evolved down individual paths to develop unique genomic—the make up the tumor cell DNA—profiles. This property is referred to intra-tumoral heterogeneity and is associated with more aggressive tumors that tend to be resistant to multiple anti-cancer drugs. An important question is whether risk factors associated with breast cancer may play a role in the aggressive nature of some breast cancers. Obesity-induced changes to metabolism, hormone production, and chronic inflammation have all been implicated in the increased risk of breast cancer associated with obesity. Understanding the influence of obesity may lead to new breast cancer prevention strategies.
Current investigation: Dr. Wahl is pursuing a new line of research in collaboration with BCRF investigator Dr. Andrew Dannenberg to examine the effects of obesity on intra-tumoral heterogeneity, specifically asking whether obesity changes the breast cells in a way that enables them to change into cancer cells more easily. Their sophisticated laboratory methods will enable them to determine whether these changes involve the DNA of the breast cells, the altered environment surrounding the breast cells, or whether it is a combination of the two.
What he’s learned so far: Dr. Wahl and his group have developed a laboratory model and shown how the breast develops and responds to environmental or cell-intrinsic changes. They have made the critical discovery that post-menopausal obesity increases the proportion of the cell type thought to be the progenitor of TNBC.
What’s next: The team is now assessing the impact of high fat and sugar diets on the molecular landscape of breast cancer cells, how diet affects intra-tumor heterogeneity, and the impact of diet on the trajectory of metastasis.
Dr. Geoffrey M. Wahl is a Professor at the Salk Institute, an Adjunct Professor at the University of California, San Diego in the Department of Biology, and the past President of the American Association for Cancer Research (2006-2007). Dr. Wahl’s research focuses on the cells that originate and perpetuate cancers, the conditions that lead to cancer progression and metastasis, and why tumors become therapy resistant. Dr. Wahl’s early work involved uncovering the mechanisms that lead to the most common forms of genetic instability in human cancers, including those often seen in the highly aggressive, basal-like group of triple negative breast cancers. BCRF funds have been used to discern the nature of the cells that originate or perpetuate basal-like breast cancers. The Wahl laboratory found that mutations in the p53 gene, the most commonly mutated gene in basal-like breast cancer, increases the chances that a fully mature cell can "reprogram" into a more primitive "stem-like" cell. His lab also found that these primitive cells have strong similarities to the earliest stem cells identifiable during breast development, which they call fetal mammary stem cells. BCRF funding is enabling Dr. Wahl’s team to characterize the pathways essential for the growth and survival of these cells, as he expects these pathways will be important for perpetuation of basal-like breast cancers. The Wahl lab is also identifying molecules useful for tracking these cells in the body. Their hope is that these approaches will lead to development of new molecularly targeted therapeutics and diagnostic tools to provide alternatives, or additions, to chemotherapy, currently the only type of drug therapy for patients with triple negative breast cancer.