Biology subjects

Blume, S. Y.

Publications and source records attributed to Blume, S. Y..

3 recordsLinked to original sources

bioRxiv2026

Systemic hypoxia suppresses solid tumor growth

Local hypoxia is a hallmark of solid tumors and a negative prognostic factor in the progression and treatment of cancer. Here, we showed that systemic hypoxia, in contrast to localized tumor hypoxia, decreases tumor growth in vivo across multiple cancer types and preclinical models. The reduced tumor growth in systemic hypoxia was not explained by hypoglycemia, hypoinsulinemia, or HIF activation. Instead, metabolite profiling in tumors and tumor interstitial fluid revealed extensive perturbations in purine-related metabolites. Stable isotope tracing demonstrated that systemic hypoxia caused tumors to suppress de novo purine synthesis. Furthermore, tumors did not develop resistance to systemic hypoxia therapy, and when used in combination with chemotherapy or immunotherapy, systemic hypoxia dramatically suppressed tumor growth. Finally, we showed that systemic hypoxia can be achieved pharmacologically with the small molecule HypoxyStat. These findings challenge the long-held paradigm of hypoxia as a negative prognostic factor in cancer progression, and they suggest a potential therapeutic role for systemic hypoxia in suppressing solid tumor growth.

cancer biology↗

bioRxiv2026

Genome-wide CRISPRi screen identifies basigin loss as protective in cardiac hypoxia

Cardiac function depends on continuous oxidative metabolism, rendering cardiomyocytes highly vulnerable to oxygen deprivation. Here, we performed a genome-wide CRISPR interference (CRISPRi) screen in human iPSC-derived cardiomyocytes to identify genes that modulate survival during chronic hypoxia. This screen revealed that knockdown of basigin (BSG), a chaperone for the monocarboxylate transporters MCT1 and MCT4, confers robust protection. Canonically, hypoxic cells suppress pyruvate dehydrogenase (PDH) activity to reduce the oxidation of major fuel sources, thereby limiting TCA cycle flux, lowering oxygen consumption, and minimizing reactive oxygen species generated by an overly reduced electron transport chain (ETC). In contrast, we found that BSG inhibition reverses this response, prioritizing ATP maintenance during hypoxia and enhancing cardiomyocyte survival. Mechanistically, BSG loss restricts lactate efflux, leading to decreased PDH phosphorylation and increased glucose uptake for oxidation. Consistent with this, ETC subunits are more essential under hypoxia, highlighting cardiomyocytes unusual reliance on aerobic ATP production even when oxygen is limited. These findings challenge prevailing models of hypoxic adaptation by revealing cardiomyocyte-specific bioenergetic requirements and motivating future therapeutic efforts.

cell biology↗

bioRxiv2025

Red Blood Cells Serve as a Primary Glucose Sink to Improve Glucose Tolerance at Altitude

High altitude conditions result in improved glucose tolerance and lower diabetes risk across species, yet the underlying physiological mechanism remains unclear. Using mouse models, we found that hypoxia alone robustly improved glucose tolerance, independent of insulin sensitivity. This effect persisted for weeks after mice returned to normoxia. PET-CT imaging revealed that internal organs explained only a small fraction of increased glucose uptake in hypoxia, suggesting the presence of an unknown glucose sink. We hypothesized that increased glucose tolerance might be linked to the hypoxia-induced increase in red blood cells (RBCs), whose metabolism relies entirely on glucose. Experimental manipulation of RBC numbers through phlebotomy or transfusion directly altered blood glucose levels, demonstrating the necessity and sufficiency of RBCs as primary glucose sinks in hypoxia. Moreover, RBCs produced during systemic hypoxia exhibited a sustained [~]3-fold increase in glucose uptake, rapidly synthesizing the hemoglobin allosteric regulator 2,3-DPG that allows for increased oxygen release in hypoxia. Therapeutically, we demonstrated that both chronic hypoxia and our recently developed pharmacological hypoxia mimetic, HypoxyStat, effectively rescued hyperglycemia in mouse models of type 1 and type 2 diabetes. Our findings identify RBCs as critical regulators of systemic glucose metabolism under hypoxic conditions, illuminating a conserved physiological adaptation and suggesting novel therapeutic avenues for hyperglycemic disorders. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=184 SRC="FIGDIR/small/650365v1_ufig1.gif" ALT="Figure 1"> View larger version (51K): org.highwire.dtl.DTLVardef@b6e505org.highwire.dtl.DTLVardef@175e720org.highwire.dtl.DTLVardef@198efdborg.highwire.dtl.DTLVardef@1ab2418_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗