Characterizing the Metabolic Microenvironment to Understand and Revert the Pro-Tumoral effects of Tumor-Associated Macrophages This proposal is aimed at deciphering the understudied role of metabolites in tumor-stroma interactions. Increasing evidence has shown that stromal cells, such as Tumor-Associated Macrophages (TAMs), can promote tumor initiation, growth, and metastasis3-6. Unfortunately, TAMs display highly variable cellular and molecular phenotypes that hinder our ability to target tumor-TAM interactions. Additionally, these interactions take place in microenvironments that are constantly reshaped by the deranged tumor metabolism and by the differential accessibility to the blood supply. Despite its importance, the link between spatial differences of extracellular metabolites and variability in TAM phenotypes remains largely unexplored. Here we show that environmental conditions, such as low oxygen and lactate accumulation, have profound effects on TAMs that can directly impact tumor progression. These metabolically modified macrophages display altered levels of cell surface markers, metabolic enzymes and cytokines; and can boost cancer cell growth in culture. In this proposal we will combine quantitative experiments with mathematical modeling to study (1) how metabolites modulate TAM phenotypes, (2) how different cells change the metabolic composition of the tumor microenvironment and (3) explore strategies to exploit these microenvironmental effects. We believe that this innovative program will provide us with an unprecedented view of the tumor microenvironment, and is poised to play an important role in our understanding and treatment of cancer. I have assembled an outstanding mentoring team with complementary expertise for the K99 period of the award. Dr. Joao Xavier (Computational Biology) will act as primary mentor and I will be co-mentored by Dr. Craig B. Thompson (Cancer Metabolism) and Dr. Johanna Joyce (Tumor Microenvironment). Dr. Xavier is an expert in systems biology of cell-cell interactions with whom I will develop image and data analysis tools, as well as biophysically relevant models to understand how metabolism and cell signaling are integrated by cell populations. Dr. Joyce is a widely recognized expert in the tumor microenvironment field. Dr. Thompson is a world-leading expert and pioneer researcher on apoptosis, growth factors and cell metabolism and how their misregulation contributes to cancer. Together, we have established a multidisciplinary research and training plan to advance towards an independent academic career. Mentoring will include developing key skills in quantitative and computational biology, in vivo mouse work and metabolomics. In addition, the mentoring will emphasize on career development training. The hosting institution, Memorial Sloan Kettering Cancer Center (MSKCC), is at the leading edge of cancer research. It has unparalleled resources for laboratory research, excellent opportunities for training in career development and a collaborative scientific environment that excels the requirements to achieve my training goals. With this mentoring and support, I aim to secure a tenure-track faculty position at an academic institution supportive of interdisciplinary research and with the infrastructure capable of supporting the research goals of the R00 period of the award and future independent research projects.
The microenvironment experienced by cancer cells plays a fundamental role in their tumorigenicity. Understanding how tumor cells integrate many external signals is necessary to predict and eventually control cancer progression. This proposal seeks to unravel how metabolic features of the microenvironment, such as low oxygen and nutrient scarcity, interact with cell communication to determine tumor growth and the behavior of stromal cells.
|Intlekofer, Andrew M; Wang, Bo; Liu, Hui et al. (2017) L-2-Hydroxyglutarate production arises from noncanonical enzyme function at acidic pH. Nat Chem Biol 13:494-500|