|Sughra Raza, MD
Associate Professor of Radiology
Harvard medical School
|Lisa Becker, PhD
VIB-KU Leuven, Belgium
Sughra is currently Associate Professor of Radiology at HMS and has worked as a breast imaging radiologist at Brigham & Women’s Hospital since 2001.
She has had an interest in translational research and will share the story of how this particular project began.
Lisa is currently a postdoctoral fellow at VIB KU Leuven in Leuven, Belgium in the lab of Peter Carmeliet, working on cancer angiogenesis. Lisa has received her BSc and MSc degrees at Mannheim University of Applied Sciences, in Mannheim, Germany. She received her PhD in Cancer Biology from the University of Texas MD Anderson Cancer Center under the supervision of Dr. Raghu Kalluri. Her PhD work focused on deciphering the heterogenous roles of fibroblasts during tumor initiation and progression.
Cancer-associated fibroblasts (CAFs) are important players in breast tumorigenesis. Similar to cancer cells, CAFs have been suggested to undergo a metabolic shift towards aerobic glycolysis and to help fuel the metabolism of cancer cells. The mechanisms underlying this phenomenon and how it is sustained is largely unknown. Using novel genetically engineered mouse models, as well as fibroblasts isolated from patients with benign breast tissue findings (controls) and malignant breast tumors, we show that CAFs exhibit enhanced glycolysis and lactate production compared to controls. We show that CAF-derived metabolites are taken up by cancer cells to fuel the biosynthesis of nucleotides. Depletion of CAFs, or suppression of lactate production specifically in CAFs in vivo, alters the overall metabolic profile of tumors, resulting in impeded tumor growth. Our studies suggest this phenotype in CAFs is sustained through epigenetic modifications of Hif1a and rate-limiting glycolytic enzymes. Normal fibroblasts, when exposed to hypoxia, acquire a pro-glycolytic, CAF-like transcriptome via epigenetic regulation of rate-limiting glycolytic enzymes. In summary, we propose that changes in oxygen tension in a developing tumor induces epigenetic changes in CAFs, leading to a pro-glycolytic phenotype that promotes breast tumor growth.