Biology subjects

Uribe, A. H.

Publications and source records attributed to Uribe, A. H..

6 recordsLinked to original sources

bioRxiv2026

System xc- imaging maps ferroptosis-linked redox remodeling in cancer

Ferroptosis is a regulated non-apoptotic form of programmed cell death that is implicated in tumor suppression and the normal tissue damage response. While the link between redox stress and ferroptosis is well established, no non-invasive methods exist to assess ferroptosis in vivo. Here, we demonstrate that the redox-sensitive positron emission tomography radiotracer and system xc-substrate, 18F-(S)-4-(3-fluoropropyl)-L-glutamic acid ([18F]FSPG), serves as a non-invasive marker of tumor ferroptosis. Global changes in amino acids, glutathione, and system xc- activity occurred before loss of membrane integrity in cells sensitive to ferroptosis, but not in resistant cells. Resistant cells sensitized to ferroptosis through nuclear factor erythroid 2-related factor 2 (NRF2) knockout had reduced glutathione and [18F]FSPG retention, which were rescued by ferroptosis inhibitors. In vivo, immune checkpoint blockade decreased ferroptosis-specific [18F]FSPG tumor retention prior to immune cell infiltration. Together, our data demonstrate that [18F]FSPG can identify early redox changes that precede ferroptosis and enabled real-time monitoring of immunotherapeutic efficacy.

cancer biology↗

bioRxiv2025

Thiol Scarcity in Cerebrospinal Fluid Renders Leptomeningeal Acute Lymphoblastic Leukaemia Therapeutically Vulnerable to Ferroptosis

The leptomeninges present a challenging tumour microenvironment with cells receiving low levels of nutrients and oxygen from cerebrospinal fluid (CSF), however these metabolic constraints are yet to be exploited therapeutically. Central nervous system (CNS) relapse in acute lymphoblastic leukaemia (ALL) remains a formidable clinical challenge because the leptomeningeal niche restricts drug penetration and immune surveillance. Current CNS-directed treatments rely on neurotoxic intrathecal chemotherapy, underscoring the urgent need for novel targeted strategies. Here, we uncover a profound niche-specific metabolic vulnerability in CNS-resident ALL cells, characterised by an obligate reliance on LRP8-mediated selenium uptake to sustain selenocysteine biosynthesis and GPX4 activity under profound glutathione limitation. We show that scarcity of thiols and cystine in CSF creates an inherently pro-ferroptotic microenvironment. Interference with selenocysteine biosynthesis under these conditions induces synthetic lethality in both in vitro and in vivo CNS-ALL models. This vulnerability is exploitable both by genetic targeting of the selenocysteine biosynthesis pathway and, notably, through repurposing the FDA-approved agent Auranofin, which disrupts selenium utilisation, induces lipid peroxidation, and demonstrates CNS-specific anti-leukaemic eaicacy with excellent tolerability in vivo. These findings identify a novel mechanistically grounded approach, leveraging features of the unique leptomeningeal microenvironment to selectively kill invading cells, with potential implications for all leptomeningeal-tropic malignancies. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=116 SRC="FIGDIR/small/693383v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@2303dforg.highwire.dtl.DTLVardef@d357ceorg.highwire.dtl.DTLVardef@129cb26org.highwire.dtl.DTLVardef@d83183_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical Abstract:C_FLOATNO The leptomeningeal tumour microenvironment is intrinsically pro-ferroptotic due to low concentrations of free thiols and cystine in cerebrospinal fluid. ALL cells in this niche exhibit disrupted glutathione metabolism and a novel dependency on LRP8-mediated SELENOP uptake to sustain GPX4 levels and thus protect themselves from spontaneous ferroptotic cell death. Perturbation of selenocysteine biosynthesis via genetic inhibition SEPHS2 or LRP8 leads to synthetic lethality in leukaemic cells exposed to CSF in vitro and in vivo - an effect phenocopied by use of Auranofin. C_FIG

cancer biology↗

bioRxiv2025

ABHD11 inhibition drives sterol metabolism to modulate T cell effector function and alleviate autoimmunity

Chronic inflammation in autoimmunity is driven by T cell hyperactivation. This unregulated response to self is fuelled by heightened metabolic programmes, which offers a promising new direction to uncover novel treatment strategies. /{beta}-hydrolase domain-containing protein 11 (ABHD11) is a mitochondrial hydrolase that maintains the catalytic function of -ketoglutarate dehydrogenase (-KGDH), and its expression in CD4+ T cells has been linked to remission status in rheumatoid arthritis (RA). However, the importance of ABHD11 in regulating T cell metabolism and function - and thus, the downstream implication for autoimmunity - is yet to be explored. Here, we show that pharmacological inhibition of ABHD11 dampens cytokine production by human and mouse T cells. Mechanistically, the anti-inflammatory effects of ABHD11 inhibition are attributed to increased 24,25-epoxycholesterol (24,25-EC) biosynthesis and subsequent liver X receptor (LXR) activation, which arise from a compromised TCA cycle. The impaired cytokine profile established by ABHD11 inhibition is extended to two patient cohorts of autoimmunity. Importantly, using a murine model of accelerated type 1 diabetes (T1D), we show that targeting ABHD11 suppresses cytokine production in antigen-specific T cells and delays the onset of diabetes in vivo. Collectively, our work provides pre-clinical evidence that ABHD11 is an encouraging drug target in T cell-mediated autoimmunity. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/643996v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@bb3fcborg.highwire.dtl.DTLVardef@1594fc8org.highwire.dtl.DTLVardef@84e078org.highwire.dtl.DTLVardef@1ad023e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2023

Colon Cancer Cells Evade Drug Action by Enhancing Drug Metabolism

Colorectal cancer (CRC) is the second most deadly cancer worldwide. One key reason is the failure of therapies that target RAS proteins, which represent approximately 40% of CRC cases. Despite the recent discovery of multiple alternative signalling pathways that contribute to resistance, durable therapies remain an unmet need. Here, we use liquid chromatography/ mass spectrometry (LC/MS) analyses on Drosophila CRC tumour models to identify multiple metabolites in the glucuronidation pathway--a toxin clearance pathway--as upregulated in trametinib-resistant RAS/APC/P53 ("RAP") tumours compared to trametinib-sensitive RASG12V tumours. Elevating glucuronidation was sufficient to direct trametinib resistance in RASG12Vanimals while, conversely, inhibiting different steps along the glucuronidation pathway strongly reversed RAP resistance to trametinib. For example, blocking an initial HDAC1-mediated deacetylation step with the FDA-approved drug vorinostat strongly suppressed trametinib resistance in Drosophila RAP tumours. We provide functional evidence that pairing oncogenic RAS with hyperactive WNT activity strongly elevates PI3K/AKT/GLUT signalling, which in turn directs elevated glucose and subsequent glucuronidation. Finally, we show that this mechanism of trametinib resistance is conserved in an KRAS/APC/TP53 mouse CRC tumour organoid model. Our observations demonstrate a key mechanism by which oncogenic RAS/WNT activity promotes increased drug clearance in CRC. The majority of targeted therapies are glucuronidated, and our results provide a specific path towards abrogating this resistance in clinical trials.s

cancer biology↗

bioRxiv2023

Developmental mitochondrial Complex I activity determines lifespan

Aberrant mitochondrial function has been associated with an increasingly large number of human disease states. Observations from in vivo models where mitochondrial function is altered suggest that adaptations to mitochondrial dysfunction may underpin disease pathology. We hypothesized that the severity of these maladaptations could be shaped by the plasticity of the system when mitochondrial dysfunction manifests. To investigate this, we have used inducible fly models of mitochondrial complex I (CI) dysfunction to reduce mitochondrial function at two stages of the fly lifecycle, from early development and adult eclosion. Here, we show that in early life (developmental) mitochondrial dysfunction results in severe reductions in survival and stress resistance in adulthood, while flies where mitochondrial function is perturbed from adulthood, are long-lived and stress resistant despite having up to an 75% reduction in CI activity. After excluding developmental defects as a cause, we went on to molecularly characterize these two populations of mitochondrially compromised flies, short- and long-lived. We find that our short-lived flies have unique transcriptomic and metabolomic responses which overlap significantly in discreet models of CI dysfunction. Our data demonstrate that early mitochondrial dysfunction via CI depletion elicits an adaptive response which severely reduces survival, while CI depletion from adulthood is not sufficient to reduce survival and stress resistance.

molecular biology↗

bioRxiv2023

Tumour mitochondrial DNA mutations drive aerobic glycolysis to enhance checkpoint blockade

The mitochondrial genome encodes essential machinery for respiration and metabolic homeostasis but is paradoxically among the most common targets of somatic mutation in the cancer genome, with truncating mutations in respiratory complex I genes being most over-represented1. While mitochondrial DNA (mtDNA) mutations have been associated with both improved and worsened prognoses in several tumour lineages1-,3, whether these mutations are drivers or exert any functional effect on tumour biology remains controversial. Here we discovered that complex I-encoding mtDNA mutations are sufficient to remodel the tumour immune landscape and therapeutic resistance to immune checkpoint blockade. Using mtDNA base editing technology4 we engineered recurrent truncating mutations in the mtDNA-encoded complex I gene, Mt-Nd5, into murine models of melanoma. Mechanistically, these mutations promoted utilisation of pyruvate as a terminal electron acceptor and increased glycolytic flux without major effects on oxygen consumption, driven by an over-reduced NAD pool and NADH shuttling between GAPDH and MDH1, mediating a Warburg-like metabolic shift. In turn, without modifying tumour growth, this altered cancer cell-intrinsic metabolism reshaped the tumour microenvironment in both mice and humans, promoting an anti- tumour immune response characterised by loss of resident neutrophils. This subsequently sensitised tumours bearing high mtDNA mutant heteroplasmy to immune checkpoint blockade, with phenocopy of key metabolic changes being sufficient to mediate this effect. Strikingly, patient lesions bearing >50% mtDNA mutation heteroplasmy also demonstrated a >2.5-fold improved response rate to checkpoint inhibitor blockade. Taken together these data nominate mtDNA mutations as functional regulators of cancer metabolism and tumour biology, with potential for therapeutic exploitation and treatment stratification.

cancer biology↗