Obesity increases both the incidence and mortality of numerous types of cancer. Children and adults who are obese at the time of diagnosis of high-risk acute lymphoblastic leukemia (ALL) have a 50% increased risk of relapse compared to their lean counterparts. Using mouse and tissue culture models, we showed that obesity directly impacts the progression and treatment outcome of ALL. We discovered that adipocytes and ALL cells participate in a two-way communication; ALL cells induce changes in adipocyte morphology and function, and adipocytes in turn release FFA which are used as a fuel for ALL cells. In the present grant, we will further elucidate the mechanisms behind these effects. We will first investigate how ALL cells, in the context of chemotherapy, affect adipocytes, both in culture and in mice and humans. We will then focus on how adipocyte-derived FFA affect ALL cell growth and survival. We have developed novel techniques to perform these studies, including intravital imaging techniques to visualize bone marrow adipocyte and ALL interactions, and single cell lipidomics techniques to elucidate the effects of adipocytes on ALL cell metabolism. These studies will increase our understanding of how leukemia interacts with its microenvironment. They will also improve our understanding of the relationships between ALL and obesity, and they have the potential to change the way we treat cancer in our increasingly overweight population.
Obese children who get leukemia have a 50% higher chance of having the cancer come back after treatment. We have found that fat cells provide fuels to leukemia cells, which helps them survive and resist chemotherapy, and are now investigating how this works and how we might reverse these effects.
| Tucci, Jonathan; Alhushki, Waseem; Chen, Ting et al. (2018) Switch to low-fat diet improves outcome of acute lymphoblastic leukemia in obese mice. Cancer Metab 6:15 |
| Cannon, Andrew; Thompson, Christopher; Hall, Bradley R et al. (2018) Desmoplasia in pancreatic ductal adenocarcinoma: insight into pathological function and therapeutic potential. Genes Cancer 9:78-86 |
| Sheng, Xia; Parmentier, Jean-Hugues; Tucci, Jonathan et al. (2017) Adipocytes Sequester and Metabolize the Chemotherapeutic Daunorubicin. Mol Cancer Res 15:1704-1713 |
| Sheng, Xia; Tucci, Jonathan; Parmentier, Jean-Hugues et al. (2016) Adipocytes cause leukemia cell resistance to daunorubicin via oxidative stress response. Oncotarget 7:73147-73159 |
