Research
Cancer metabolism and immunometabolism
Tumors are metabolically heterogeneous, composed of cancer cells, immune cells, and fibroblasts that compete for the same nutrients. Local nutrient availability shapes how these populations function within the tumor microenvironment. However, little is known about how metabolism differs among the cell populations that comprise a tumor, or how these differences shape immune responses and metastatic progression. Our laboratory has developed approaches that resolve the metabolism of individual cell populations within intact tumors and that allow the metabolic environment of a tissue to be altered in vivo. We are applying these tools to define: (1) how metabolism differs across the cell populations of primary tumors and metastases, (2) the role of local tissue nutrient composition in shaping metastatic growth and anti-tumor immunity, and (3) the metabolite programs that regulate immune cell function within the tumor microenvironment.
Metastasis and organotropism
Metastasis is the leading cause of mortality in most cancers. It is a multistep process in which tumor cells disseminate from the primary site, and only a small fraction survive and grow into overt metastatic lesions. Our prior work has shown that metastases grow and evolve differently depending on the organ in which they reside, suggesting that organ-specific microenvironments impose distinct constraints on metastatic outgrowth and therapeutic response. This is reflected in the clinic, where patients with liver metastases fare worse than those with lung metastases. Building on these findings, our laboratory is defining: (1) how tumor cells adapt to the metabolic and cellular niches they encounter in different organs, (2) the impact these adaptations have on shaping the local immune environment, and (3) whether modifying these environments can improve responses to immunotherapy at metastatic sites.
Tumor heterogeneity and spatial biology
In nearly every cancer, tumors show a predilection for particular regions within a tissue, and this is associated with distinct clinical phenotypes. For instance, lesions arising in the head versus tail of the pancreas, or the right versus left side of the colon, carry distinct prognoses and biology. The anatomic position of a tumor therefore provides the context on which mutations act to define its behavior. We have developed novel genetic toolkits that initiate tumorigenesis at defined positions within living tissue to model spatial patterns of human cancer. We are applying this platform to determine how regional context shapes tumor identity, cellular heterogeneity, and metastatic behavior.
Tumor-immune crosstalk and immunotherapy
Tumor-associated macrophages (TAMs) are the major immune population within the tumor microenvironment. TAMs can function to suppress anti-tumor T-cell responses, promote invasion, and support therapeutic resistance. This is a major contributor to the limited efficacy of immune checkpoint therapy in many solid cancers. Our laboratory studies the signals through which tumor cells and TAMs communicate to establish and maintain this suppressive state. We identified macrophage migration inhibitory factor (MIF) and its receptor CD74 as regulators of this process. We are now defining the mechanisms by which this axis maintains pro-tumorigenic macrophage states, and testing whether disrupting it can reprogram TAMs to activate cytotoxic T-cell responses and improve immunotherapy responses.
UTSW Affiliations
Department of Internal Medicine
Children’s Research Institute
Harold C. Simmons Comprehensive Cancer Center
Contact
Ravi Maddipati | Department of Internal Medicine
6000 Harry Hines Blvd., NB8.221a
Dallas, TX 75390
Ravikanth.Maddipati@UTSouthwestern.edu
UT Southwestern Medical Center