Biology subjects

Shokry, E.

Publications and source records attributed to Shokry, E..

7 recordsLinked to original sources

bioRxiv2026

mTORC2 stabilizes HIF-1β to coordinate metabolic adaptation in lung cancer

Despite extensive genetic heterogeneity, lung tumors frequently converge on shared signaling dependencies that remain therapeutically underexploited. Here, we identify mTORC2 signaling as a convergent dependency across genetically distinct lung cancer subtypes and uncover HIF-1{beta} as a selective metabolic effector downstream of mTORC2 that promotes lung tumor progression. Elevated mTORC2 signaling in lung adenocarcinoma was associated with poor overall survival, metastatic dissemination and metabolic rewiring. Using complementary genetically engineered mouse models of Rictor deletion or overexpression in Kras-driven lung tumors, we show that mTORC2 activity is dispensable for normal lung homeostasis but required for tumor progression and metabolic adaptation in vivo. Mechanistically, mTORC2 stabilized HIF-1{beta} by preventing its ubiquitin-independent proteasomal degradation through a non-canonical PKC-CK2 signaling axis, independently of AKT. Integrated multi-omics analyses identified extensive metabolic rewiring downstream of the mTORC2-HIF-1{beta} axis, with sphingolipid metabolism emerging as a prominent and therapeutically exploitable vulnerability. Accordingly, pharmacological targeting of sphingolipid metabolism markedly impaired the growth of mTORC2-driven lung tumors in vivo. Together, our findings establish a non-canonical mTORC2-HIF-1{beta} signaling axis that couples oncogenic signaling to metabolic adaptation and defines therapeutically actionable metabolic vulnerabilities in lung cancer.

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↗

bioRxiv2024

Metabolic adaptations of micrometastases alter EV production to generate invasive microenvironments

Altered cellular metabolism has been associated with acquisition of invasive phenotypes during metastasis. To study this, we combined a genetically engineered mouse model of mammary carcinoma with syngeneic transplantation and primary tumour resection to generate isogenic cells from primary tumours and their corresponding lung micrometastases. Metabolic analyses indicated that micrometastatic cells increase proline production at the expense of glutathione synthesis leading to a reduction in total glutathione levels. Micrometastatic cells also have altered sphingomyelin metabolism leading to increased intracellular levels of specific ceramides. The combination of these two metabolic adaptations alters small extracellular vesicle (sEV) production to drive generation of an invasive microenvironment. Indeed, micrometastatic cells shut-down Rab27-dependent production of sEVs and, instead, switch-on neutral sphingomyelinase-2 (nSM2)-dependent sEV release. sEVs released in a nSM2-dependent manner from micrometastatic cells, in turn, influence the ability of fibroblasts to deposit extracellular matrix which promotes cancer cell invasiveness. These data provide evidence that metabolic rewiring drives invasive processes in metastasis by influencing sEV release. SummaryBreast cancer cells isolated from lung micrometastases have altered metabolism which influences extracellular vesicle production to generate invasive microenvironments.

cancer biology↗

bioRxiv2024

Noise Stress induces Cardiovascular Metabolic Shifts

Environmental stressors present in the modern world can fundamentally affect humans physiology and health. Exposure to stressors like air pollution, heat, and traffic noise has been linked to a pronounced increase in non-communicable diseases. Specifically, aircraft noise has been identified as a risk factor for cardiovascular and metabolic diseases, such as arteriosclerosis, heart failure, stroke, and diabetes. Noise stress leads to neuronal activation with subsequent stress hormone release that ultimately leads to activation of the renin-angiotensin-aldosterone system, increasing inflammation and oxidative stress, dramatically affecting the cardiovascular system. However, despite the epidemiological evidence of a link between noise stress and metabolic dysfunction, the consequences of exposure at the molecular, metabolic level of the cardiovascular system are largely unknown. Here we use a murine model system of aircraft noise exposure to show that noise stress profoundly alters heart metabolism. Within days of exposing animals to aircraft noise, the heart has a reduced potential for utilising fatty-acid beta-oxidation, the tricarboxylic acid cycle, and the electron transport chain for generating ATP. This is compensated by shifting energy production towards glycolysis. Intriguingly, the metabolic shift is reminiscent of what is observed in failing and ischaemic hearts. Our results demonstrate that within a relatively short exposure time, the cardiovascular system undergoes a fundamental metabolic shift that bears the hallmarks of cardiovascular disease. Overall, aircraft noise induces rapid, detrimental metabolic shifts in the heart, resembling patterns seen in cardiovascular diseases. These findings underscore the urgent need to comprehend the molecular consequences of environmental stressors, paving the way for targeted interventions aiming at mitigating health risks associated with chronic noise exposure in our modern, noisy environments.

systems biology↗

bioRxiv2023

Paracrine secretion of MUFAs prevents ferroptosis in triple-negative breast cancer and reveals selenocysteine synthesis dependency for lung metastasis

The limited availability of therapeutic options for patients with triple-negative breast cancer (TNBC) contributes to the high rate of metastatic recurrence and poor prognosis. Ferroptosis is a type of cell death caused by iron-dependent lipid peroxidation and counteracted by the antioxidant activity of the selenoprotein GPX4. Here, we show that TNBC cells secrete an anti-ferroptotic factor in the extracellular environment when cultured at high cell densities but are primed to ferroptosis when forming colonies at low density. We found that secretion of the anti-ferroptotic factors, identified as monounsaturated fatty acid (MUFA) containing lipids, and the vulnerability to ferroptosis of single cells depends on the low expression of stearyl-CoA desaturase (SCD) that is proportional to cell density. Finally, we show that the inhibition of Sec-tRNAsec biosynthesis, an essential step for selenoprotein production, causes ferroptosis and impairs the lung seeding of circulating TNBC cells that are no longer protected by the MUFA-rich environment of the primary tumour.

cancer 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↗

bioRxiv2023

Metabolic profiling stratifies colorectal cancer and reveals adenosylhomocysteinase as a therapeutic target

With colorectal cancer (CRC) being the second most common cause of cancer-related deaths worldwide1, there is an urgent need for better diagnostic tools and new, more targeted therapies. Here we used genetically engineered mouse models (GEMMs), and multimodal mass spectrometry-based metabolomics to study the impact of common genetic drivers of CRC on the metabolic landscape of the intestine. We show that unsupervised metabolic profiling can stratify intestinal tissues according to underlying genetic alterations, and use mass spectrometry imaging (MSI) to identify tumour, stromal and normal adjacent tissues. By identifying ions that drive variation between normal and transformed tissues, we found dysregulation of the methionine cycle to be a hallmark of APC-mutant CRC, and propose one of its enzymes, i.e. adenosylhomocysteinase (AHCY), as a new therapeutic target. Collectively, we show that the profound genotype-dependent alterations in both lipid and small molecule metabolism in CRC may be exploited for tissue classification with no need for ion identification, and we applied further data analysis to expose a novel metabolic vulnerability of CRC.

cancer biology↗