Biology subjects

Elia, I.

Publications and source records attributed to Elia, I..

5 recordsLinked to original sources

bioRxiv2026

Sertraline and Carfilzomib Synergize to Target T-cell Malignancies with Serine/Glycine synthesis activity via Cholesterol Dysregulation, Cellular Stress and Immune Modulation

BackgroundT-cell acute lymphoblastic leukemia (T-ALL) and peripheral T-cell lymphoma (PTCL) are aggressive hematological malignancies requiring novel therapeutic strategies. The majority of T-ALL and PTCL tumors display metabolic activation and addiction to endogenous serine/glycine synthesis (SSP), providing opportunities for targeted therapy with the clinically used antidepressant sertraline, inhibiting SSP enzymes SHMT1/2. However, sertraline monotherapy only induces cell cycle arrest and has limited efficacy in suppressing disease progression in vivo. MethodsDrug synergy of sertraline combined with clinically used proteasome inhibitors carfilzomib and bortezomib was evaluated. Drug effects on cell cycle, proliferation and apoptosis were assessed in T-ALL, PTCL and healthy blood cells using flow cytometry assays. Proteomic, lipidomic and metabolic analyses on drug treated T-ALL cells were performed to elucidate the molecular mechanisms underlying drug synergy, followed by validation of changes of interest, metabolic rescues and shRNA-knockdown of SSP enzymes in T-ALL cells. In vivo therapeutic efficacy and immune remodelling were evaluated in an immunocompetent MYCN-overexpressing PTCL mouse model. ResultsSertraline acted synergistically with clinically used proteasome inhibitor carfilzomib to induce cell cycle arrest and apoptosis in T-ALL and PTCL cells with SSP activity, with minimal effects on SSP-inactive T-ALL cells or healthy blood cells. Adding carfilzomib also enhanced the therapeutic efficacy of sertraline in an aggressive MYCN PTCL model. Sertraline rewired cell metabolism towards increased cholesterol uptake and biosynthesis in SSP-active T-ALL cells, and this effect was not obtained by other means of SSP inhibition. In contrast to sertraline, carfilzomib promoted cholesterol efflux. Moreover, carfilzomib reduced total lipid levels, further restricting nutrients in sertraline - carfilzomib treated cells. Additionally, the drug combination impaired mitochondrial respiration and elevated reactive oxygen species (ROS) levels and DNA damage in SSP-active tumor cells, which was rescued by citrate supplementation. Interestingly, these metabolic changes were associated with microenvironmental changes in our mouse model, where the drug combination elevated natural killer T-cells, neutrophils and eosinophils. ConclusionsOur study identifies synergy of sertraline - carfilzomib combination treatment mediated through metabolic impairment and is associated with remodelling of the immune microenvironment. This invites for further clinical investigation of this drug combination as a therapeutic strategy for SSP-active T-cell malignancies.

cancer biology↗

bioRxiv2026

Label-Free Monitoring of Cancer-associated Fibroblast Activation using NADH Fluorescence Lifetime Imaging

Cancer-associated fibroblasts (CAFs) are key regulators of tumor progression, yet their activation state is commonly assessed using static, endpoint assays that do not allow dynamic analysis in living cells. Although CAF activation is accompanied by pronounced metabolic remodeling, label-free approaches that exploit these changes for real-time monitoring remain limited. Here, we demonstrate that NADH fluorescence lifetime imaging microscopy (FLIM) provides a non-invasive readout of this process. CAFs activated with transforming growth factor beta (TGF-{beta}) exhibit a reproducible shift toward longer NADH fluorescence lifetimes compared to non-activated cells, consistent with changes in the relative contributions of free and protein-bound NADH. By combining live-cell FLIM with -smooth muscle actin staining in the same cells, we directly link metabolic signatures to cellular activation state. We further demonstrate the potential of this approach to dynamically monitor CAF activation in live, migrating cells. Together, these results establish NADH fluorescence lifetime imaging as a label-free metabolic approach for monitoring CAF activation dynamics, complementing conventional marker-based methods and enabling continuous monitoring of tumor-stroma interactions.

biochemistry↗

bioRxiv2025

Non-canonical TERT function mitigates adipose tissue inflammation in obesity by modulating stem cell-macrophage communication and macrophage states

Background and aimsObesity drives adipose tissue (AT) expansion and chronic inflammation, leading to metabolic dysfunction through adipocyte hypertrophy, impaired ASPC differentiation, immune infiltration, and fibrosis. Stromal vascular remodeling prominently features expansion of Gdf15- and Trem2-expressing lipid-associated macrophages (LAMs), which respond to adipocyte stress and act as lipid scavengers to buffer excess lipids released by adipocytes. Here, we examined macrophage reprogramming in p21+/Tert and p21+/TertCi mice, which express active TERT or its catalytically inactive TERTCi mutant from the endogenous Cdkn1a promoter. ResultsFollowing HFD exposure, conditional expression of TERT or TERTCi resulted in a pronounced downregulation of p21 in macrophage subsets, accompanied by a reduction in AT inflammation. Notably, TERT and TERTCi expression reshaped the adipose-tissue macrophage (ATM) landscape depleting Trem2+ and Gdf15+ LAMs while preserving resident macrophages. This shift was accompanied by marked suppression of the Trem2 transcriptional program and down-regulation of PPAR-{gamma} and NR1H3 in LAMs and by impaired ASPC-LAM signaling pathways that normally drive LAM recruitment and activation. Proteomic profiling further showed that p21+/Tert ASPCs secreted markedly higher levels of proteins associated with non-conventional secretion, while extracellular matrix-associated factors and cytokines/chemokines including key mediators of ASPC-LAM communication such as Ccl2, C3, and Csf1 were substantially reduced. However, only p21+/Tert mice, and not p21+/TertCi mice, exhibited significant metabolic improvements, indicating that macrophage remodeling alone is insufficient to restore systemic metabolic function. Consistent with this, enhanced ASPC expansion and differentiation, supporting improved adipose-tissue remodeling, was observed exclusively in p21+/Tert obese mice. ConclusionsTERT remodels adipose tissue immunity independently of its enzymatic activity, and TERT-driven reprogramming of the ASPC secretome may emerge as a promising strategy to combat obesity-related metabolic dysfunction. HighlightsO_LIConditional expression of TERT or catalytically inactive TERTCi results in the depletion Trem2+ and Gdf15+ LAMs while preserving resident macrophages C_LIO_LITERT and TERTCi expression impairs ASPC-adipocyte/LAM communication pathways that normally drive LAM recruitment and activation. C_LIO_LIIn vitro, TERT conditional expression in ASPCs promotes non-conventional protein secretion and reduces the secretion of key mediators of ASPC-LAM communication C_LIO_LIOnly p21+/Tert mice, and not p21+/TertCi mice, exhibited enhanced ASPC expansion, improved adipose-tissue remodeling, and systemic metabolic benefits, demonstrating that macrophage remodeling alone is insufficient to restore metabolic function. C_LI

physiology↗

bioRxiv2025

Dual Ribosome Profiling reveals metabolic limitations of cancer and stromal cells in thetumor microenvironment

Cancer cells, immune cells, and stromal cells within the tumor microenvironment (TME) collaboratively influence disease progression and therapeutic responses. The nutrient-limited conditions of the TME, particularly the scarcity of glucose, amino acids, and lipids, challenge cancer cell survival1-4. However, the metabolic constraints faced by immune and stromal cells in comparison to cancer cells, and how these limitations affect therapeutic outcomes, remain poorly understood. Here, we introduce Dual Ribosome Profiling (DualRP), a method that allows for simultaneous analysis of translation and identification of ribosome stalling, revealing amino acid shortages in different cell types within tumors. Using DualRP, we uncover that interactions between cancer cells and fibroblasts trigger an inflammatory response, mitigating amino acid limitations during glucose starvation. In immunocompetent mouse models, we observe that immune checkpoint blockade therapy induces serine and glycine restrictions specifically in T cells, but not in cancer cells. We further demonstrate that these amino acids are essential for optimal T cell function both in vitro and in vivo, highlighting their critical role in effective immunotherapy. Our findings show that therapeutic interventions create distinct metabolic demands across different tumor cell types, with nutrient availability significantly influencing the success of immunotherapy. DualRPs ability to explore cell type-specific metabolic vulnerabilities offers a promising tool for advancing our understanding of tumor biology and improving therapeutic strategies.

cancer biology↗

bioRxiv2020

Age-induced methylmalonic acid accumulation promotes tumor progression and aggressiveness

From age 65 onwards, the risk of cancer incidence and associated mortality is substantially higher1-3. Nonetheless, our understanding of the complex relationship between age and cancer is still in its infancy4. For decades, the link has largely been attributed to increased exposure time to mutagens in older individuals. However, this view does not account for the well-established role of diet, exercise and small molecules that target the pace of metabolic aging5-8. Here, we show that metabolic alterations that occur with age can render a systemic environment favorable to progression and aggressiveness of tumors. Specifically, we show that methylmalonic acid (MMA), a by-product of propionate metabolism, is significantly up-regulated in the serum of older people, and functions as a mediator of tumor progression. We traced this to the induction of SOX4 and a consequent transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, accumulation of MMA represents a novel link between aging and cancer progression, implicating MMA as a novel therapeutic target for advanced carcinomas.

cancer biology↗