Biology subjects

Choueiry, F.

Publications and source records attributed to Choueiry, F..

7 recordsLinked to original sources

bioRxiv2026

Metabolic glues as a means of purine sensing and chemotherapeutic response

Molecular glues stabilize weak interactions to impart novel functionalities onto complexes. While plant hormones or drugs are known molecular glues, it is still unknown whether this modality provides endogenous regulation in human cells. Here, we show that purine nucleotides are molecular glues that tether the rate-limiting enzyme of purine biosynthesis, phosphoribosyl-pyrophosphate-amidotransferase (PPAT), to its inhibitor NUDT5. This mechanism allows cells to sense purine levels and establish essential feedback control of their synthesis. Thiopurine chemotherapeutics, in clinical use since the 1950s, act as molecular glues of the same complex, but adopt unique orientations for enhanced function. Distinct from the recognition of many therapeutic glues, metabolic glue pockets can adjust their conformation to significant compound alterations and thereby enable increasing glue potency without sacrificing specificity. Our findings therefore identify endogenous metabolic glues as a mode of nutrient sensing that can be exploited to obtain compounds that rewire metabolic pathways for therapeutic benefit.

biochemistry↗

bioRxiv2025

Candida albicans infiltrates colon and rectal cancers causing therapeutic resistance and decreased survival

The microbiome is increasingly recognized as a modifier of cancer progression and therapy response, yet the role of intratumoral fungi remains poorly defined. Here, we identify Candida albicans colonization within human colorectal tumors as a predictor of reduced survival and impaired radiation response. Leveraging the Oncology Research Information Exchange Network (ORIEN) cohort, we show that high intratumoral Candida burden is associated with decreased survival across multiple gastrointestinal cancers, with the strongest treatment-specific effect in rectal cancer patients receiving radiotherapy. This observation was validated in independent rectal cancer cohorts using RNA sequencing and quantitative PCR. In immune-competent murine colorectal cancer models, oral gavage of C. albicans resulted in intratumoral colonization, accelerated tumor growth, and radiation resistance, effects not observed with Saccharomyces cerevisiae or PBS controls. Colonized tumors exhibited increased hypoxia, altered metabolic and transcriptional programs, and distinct expression of genes linked to cytokine signaling and cell survival. Hypoxia conditioned C. albicans secreted metabolites that directly conferred radiation resistance to colorectal cancer cells in vitro, implicating a cancer cell intrinsic mechanism independent of immune signaling. Untargeted metabolomics revealed enrichment of nucleosides and lipid oxidation intermediates under hypoxia, suggesting that C. albicans metabolites may provide substrates facilitating tumor recovery after irradiation. These findings establish C. albicans as a causal modifier of tumor biology and radiation response, highlighting intratumoral fungi as future potential therapeutic targets. Modulating fungal colonization or metabolism may improve radiotherapy outcomes and broaden our understanding of interactions between microbes and tumors.

cancer biology↗

bioRxiv2025

Ketogenic diet prevents obesity-associated pancreatic cancer independent of weight loss and induces pancreatic metabolic reprogramming

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor outcomes. Obesity is a risk factor for several cancers including PDAC due to metabolic dysregulation and inflammation. The ketogenic diet (KD) can alter metabolism and has been evaluated for its effects on tumor progression in non-obese but not obese PDAC using genetically engineered mouse models (GEMMs). We hypothesized that ketone bodies and a KD alter cell and tumor metabolism. We show that ketone treatments altered pyrimidine metabolism in PDAC cells. Moreover, in an obese PDAC GEMM, KD prevented tumor progression independent of weight loss but promoted PDAC in a non-obese PDAC GEMM. The KD-specific delay of obesity-associated PDAC was associated with pancreatic metabolic shifts in pyrimidine, cysteine and methionine, and arginine and proline pathways. These findings suggest potential benefits of a KD in preventing obesity-associated PDAC, but highlights some risks in non-obese settings.

cancer biology↗

bioRxiv2025

Invasive lobular carcinoma integrated multi-omics analysis reveals silencing of Arginosuccinate synthase and upregulation of nucleotide biosynthesis in tamoxifen resistance

Invasive Lobular Carcinoma (ILC), a distinct subtype of breast cancer is hallmarked by E-Cadherin loss, slow proliferation, and strong hormone receptor positivity. ILC faces significant challenges in clinical management due to advanced stage at diagnosis, late recurrence, and development of resistance to endocrine therapy - a cornerstone of ILC treatment. To elucidate the mechanisms underlying endocrine resistance in ILC, ILC cell lines (MDA-MB-134-VI, SUM44PE) were generated to be resistant to tamoxifen, a selective estrogen receptor modulator. The tamoxifen-resistant (TAMR) cells exhibit a 2-fold increase tamoxifen IC50 relative to parental cells. Metabolomics and RNA-sequencing revealed deregulation of alanine, aspartate, and glutamate metabolism, purine metabolism, and arginine and proline metabolism in TAMR cells. Among the fifteen commonly dysregulated genes in these pathways, low ASS1 expression was identified in the TAMR cells and was significantly correlated with poor outcome in ILC patients, specifically in the context of endocrine therapy. Our study reveals methylation mediated silencing of ASS1 in TAMR cells as a likely mechanism of downregulation. Demethylation restored ASS1 expression and correspondingly reduced tamoxifen IC50 toward parental levels. Nucleic acid biosynthesis is augmented in TAMR cells, evidenced by increase in nucleotide intermediates. Both TAMR cell lines demonstrated increased expression of several nucleic acid biosynthesis enzymes, including PAICS, PRPS1, ADSS2, CAD, and DHODH. Furthermore, CAD, the key multifunctional protein of de novo pyrimidine biosynthesis pathway is differentially activated in TAMR cells. Treating TAMR cell with Decitabine, a demethylating agent, or Farudodstat, a pyrimidine biosynthesis inhibitor, markedly augmented efficacy of tamoxifen. Collectively, our study unveils ASS1 downregulation as a novel mechanism underlying acquired tamoxifen resistance in ILC and establishes a metabolic link between ASS1 and nucleic acid biosynthesis. Restoring ASS1 expression or inhibiting pyrimidine biosynthesis restored tamoxifen sensitivity. ASS1 could be a potential biomarker and therapeutic target in tamoxifen resistant ILC patients, warranting further investigation.

cancer biology↗

bioRxiv2023

The tumor microbiome reacts to hypoxia and can influence response to radiation treatment in colorectal cancer

Tumor hypoxia has been shown to predict poor patient outcomes in several cancer types, partially because it reduces radiations ability to kill cells. We investigated whether some of the clinical effects of hypoxia could also be due to its impact on the tumor microbiome. We examined the RNA-seq data from the Oncology Research Information Exchange Network (ORIEN) database of colorectal cancer (CRC) patients treated with radiotherapy. For each tumor, we identified microbial RNAs and related them to the hypoxic gene expression scores calculated from host mRNA. Our analysis showed that the hypoxia expression score predicted poor patient outcomes and identified tumors enriched with certain microbes such as Fusobacterium nucleatum. The presence of other microbes, such as Fusobacterium canifelinum, predicted poor patient outcomes, suggesting a potential interaction between hypoxia, the microbiome, and radiation response. To investigate this concept experimentally, we implanted CT26 CRC cells into both immune-competent BALB/c and immune-deficient athymic nude mice. After growth, where tumors passively acquired microbes from the gastrointestinal tract, we harvested tumors, extracted nucleic acids, and sequenced host and microbial RNAs. We stratified tumors based on their hypoxia score and performed metatranscriptomic analysis of microbial gene expression. In addition to hypoxia-trophic and -phobic microbial populations, analysis of microbial gene expression at the strain level showed expression differences based on the hypoxia score. Hypoxia appears to not only associate with different microbial populations but also elicit an adaptive transcriptional response in intratumoral microbes. SIGNIFICANCETumor hypoxia reduces radiations ability to kill cells. We explored whether some of the clinical effects of hypoxia could also be due to interaction with the tumor microbiome. Hypoxic expression scores associated with certain microbes and elicited an adaptive transcriptional response in others.

immunology↗

bioRxiv2023

Physical Activity Delays Obesity-Associated Pancreatic Ductal Adenocarcinoma in Mice and Decreases Inflammation

BACKGROUND & AIMSObesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), a deadly disease with limited preventive strategies. Lifestyle interventions to decrease obesity might prevent obesity-associated PDAC. Here, we examined whether decreasing obesity by increased physical activity (PA) and/or dietary changes would decrease inflammation in humans and prevent PDAC in mice. METHODSCirculating inflammatory-associated cytokines of overweight and obese subjects before and after a PA intervention were compared. PDAC pre-clinical models were exposed to PA and/or dietary interventions after obesity-associated cancer initiation. Body composition, tumor progression, growth, fibrosis, inflammation, and transcriptomic changes in the adipose tissue were evaluated. RESULTSPA decreased the levels of systemic inflammatory cytokines in overweight and obese subjects. PDAC mice on a diet-induced obesity (DIO) and PA intervention, had delayed weight gain, decreased systemic inflammation, lower grade pancreatic intraepithelial neoplasia lesions, reduced PDAC incidence, and increased anti-inflammatory signals in the adipose tissue compared to controls. PA had additional cancer prevention benefits when combined with a non-obesogenic diet after DIO. However, weight loss through PA alone or combined with a dietary intervention did not prevent tumor growth in an orthotopic PDAC model. Adipose-specific targeting of interleukin (IL)-15, an anti-inflammatory cytokine induced by PA in the adipose tissue, slowed PDAC growth. CONCLUSIONSPA alone or combined with diet-induced weight loss delayed the progression of PDAC and reduced systemic and adipose inflammatory signals. Therefore, obesity management via dietary interventions and/or PA, or modulating weight loss related pathways could prevent obesity-associated PDAC in high-risk obese individuals. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=69 SRC="FIGDIR/small/521203v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@961f1org.highwire.dtl.DTLVardef@1fd4da7org.highwire.dtl.DTLVardef@f5247aorg.highwire.dtl.DTLVardef@2de0bf_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2021

Multiomics Integration Elucidates Metabolic Modulators of Drug Resistance in Lymphoma

BackgroundDiffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL). B-cell NHLs rely on Brutons tyrosine kinase (BTK) mediated B-cell receptor signaling for survival and disease progression. However, they are often resistant to BTK inhibitors or soon acquire resistance after drug exposure resulting in the drug tolerant form. The drug tolerant clones proliferate faster, have increased metabolic activity, and shift to oxidative phosphorylation; however, how this metabolic programming occurs in the drug resistant tumor is poorly understood. MethodsIn this study, we explored for the first time the metabolic regulators of ibrutinib-resistant activated B-cell (ABC) DLBCL using a multi-omics analysis that integrated metabolomics (using high-resolution mass spectrometry) and transcriptomic (gene expression analysis). Overlay of the unbiased statistical analyses, genetic perturbation and pharmaceutical inhibition, were further used to identify the key players that contribute to the metabolic reprograming of the drug resistant clone. ResultsGene-metabolite integration revealed interleukin 4 induced 1 (IL4I1) at the crosstalk of two significantly altered metabolic pathways involved in the production of various amino acids. We showed for the first time that drug resistant clones undergo metabolic reprogramming from glycolysis towards oxidative phosphorylation & is activated via the BTK-PI3K-AKT-IL4I1 axis and can be targeted therapeutically. ConclusionsOur report shows how these cells become dependent on PI3K/AKT signaling for survival after acquiring ibrutinib resistance and shift to sustained Oxidative phosphorylation, additionally we outline the compensatory, pathway that regulates this metabolic reprogramming in the drug resistant cells. These findings from our unbiased analyses highlight the role of metabolic reprogramming during drug resistance development. Furthermore, our work demonstrates that a multi-omics approach can be a powerful and unbiased strategy to uncover genes and pathways that drive metabolic dysregulation in cancer cells.

cancer biology↗