A metabolic decision point in the progression of lymphoid malignancies

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Despite recent therapeutic advances, curing lymphoid malignancies such as non-Hodgkin lymphoma and lymphoid leukemia remains a clinical challenge. While critical for prognosis, the mechanisms regulating malignant lymphocyte trafficking, migration, and solid organ infiltration are incompletely understood. Metabolic flexibility plays a critical role during cancer progression aligning metabolic requirements of cancer cells with specific tissue environments. In lymphoid cancers, however, little is known about the impact of metabolic programming on cell migration and disease progression. Our preliminary studies demonstrate that malignant lymphocyte migration and solid organ infiltration are tightly connected to cellular metabolic preferences. We discovered that T- and B-lymphoid cancer cell migration and organ infiltration in xenograft models is determined by mitochondrial reactive oxygen species (mROS) through analysis of mROSlow and mROShigh states. This innovative strategy permits us to isolate cells with different migratory potentials to dissect fuel preferences of the “enhanced migratory potential”-mROShigh (EMP-mROShigh) state. We identified glucose as an essential fuel driving migration through activation of mROS/HIF-1a signaling. Initial 13C-glucose tracing studies showed reprogrammed glucose metabolism in migrating cells. Reduced pyruvate oxidation in the TCA cycle and enhanced lactate generation promoted migration through HIF-1a signaling. These results support our hypothesis that the branch point in pyruvate flux is a critical “metabolic decision point” controlling malignant lymphocyte migration and organ infiltration. We predict that dynamic shifts in pyruvate flux between mitochondrial oxidation and conversion into lactate control migratory and infiltrative potential through transcriptional regulation of mROS/HIF-1a-dependent cellular migration programs. The following specific aims will test this hypothesis: Aim 1. Establish the role of pyruvate flux as a decision point to control malignant lymphocyte migration and infiltration. We will test the hypothesis that a shift in pyruvate metabolism between TCA cycle oxidation and reduction to lactate represents a critical checkpoint of malignant lymphocyte migration and solid organ infiltration through modulation of mROS/HIF-1a signaling. Aim 2. Identify the molecular mechanisms for control of migratory behavior by the metabolic decision point. This aim will test the hypothesis that pyruvate flux as a metabolic decision point controls migration through transcriptional regulation of mROS/HIF1a-dependent cellular migration programs. We will perform RNAseq analyses of CLL cells followed by functional analyses to identify genes translating metabolic reprogramming into migration potential. Aim 3: Dissect fuel preferences and metabolic reprogramming of enhanced migratory cancer cells through in vivo metabolic tracing in CLL patients. We will test the hypothesis that the EMP-mROShigh cells in CLL patients in vivo show reprogrammed glucose and TCA cycle metabolism analogous to the in vitro phenotype. Patients will be infused with 13C-labeled nutrients to determine pyruvate flux and TCA cycle fueling in “enhanced migratory potential” CLL cells in their in vivo habitat critical to help define therapeutic strategies targeting the EMP-mROShigh phenotype in patients. Elucidating the metabolic underpinnings of malignant lymphocyte migration and solid organ infiltration will provide important insight into disease biology and uncover novel treatment strategies for lymphoid malignancies such as CLL which are highly relevant to the Veteran population due to their link to Agent Orange and other herbicide exposures during military service.