# A metabolic decision point in the progression of lymphoid malignancies

> **NIH VA I01** · WM S. MIDDLETON MEMORIAL VETERANS HOSP · 2021 · —

## Abstract

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 patie...

## Key facts

- **NIH application ID:** 10258308
- **Project number:** 1I01CX002240-01A1
- **Recipient organization:** WM S. MIDDLETON MEMORIAL VETERANS HOSP
- **Principal Investigator:** Stefan M Schieke
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2021
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2022-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10258308

## Citation

> US National Institutes of Health, RePORTER application 10258308, A metabolic decision point in the progression of lymphoid malignancies (1I01CX002240-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10258308. Licensed CC0.

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