Biology subjects

Schlicker, L.

Publications and source records attributed to Schlicker, L..

10 recordsLinked to original sources

bioRxiv2026

Catabolism of extracellular glutathione is a driver of metastasis formation

Metastasizing cancer cells require metabolic plasticity to adapt to the microenvironment of the target organ. Analyzing metabolites in interstitial fluids, we found that the liver microenvironment is devoid of cystine but contains high concentrations of glutathione (GSH). Detailed mechanistic analysis revealed that cancer cells degrade extracellular GSH utilizing gamma-glutamyl-transferase (GGT) activity for provision of cysteine to support proliferation and prevent ferroptosis under cystine-free conditions. This was independent of system Xc- but required activity of glutamate-cysteine ligase (GCLC). GGT1 expression was associated with poor survival and upregulated in liver metastases of human breast cancer patients. Overexpression of Ggt1 in murine breast cancer cells enhanced their capacity for liver colonization and promoted lung metastases after orthotopic implantation. This identifies extracellular GSH catabolism as driver of metastasis that supports proliferation and oxidative stress resistance in metabolically challenging microenvironments.

cancer biology↗

bioRxiv2026

A novel role for Oxaloacetate Decarboxylase FAHD1 in cardiomyocyte maturation

Mitochondrial metabolism undergoes dramatic reprogramming during postnatal cardiac maturation, yet the enzymatic regulators that ensure continuity of TCA cycle flux in this period remain incompletely defined. FAHD1 is a mitochondrial oxaloacetate decarboxylase (ODx) with proposed roles in modulating the activity of Complex II of the electron transport chain (ETC), but its physiological relevance in vivo has remained unclear. Here, we identify FAHD1 as a critical regulator of mitochondrial function with strong impact on cardiomyocyte (CM) maturation. Using a germline Fahd1-knockout (KO) mouse model, we show that Fahd1 deficiency impairs Complex II respiration, reduces pyruvate levels, and induces a compensatory metabolic shift toward glycolysis and anabolic biosynthesis. Loss of FAHD1 disrupts sarcomere organization, delays the fetal-to-adult myosin isoform switch, and leads to left ventricle systolic dysfunction and cardiomyocyte hypertrophy. These findings highlight FAHD1 as a mitochondrial gatekeeper and potential target for modulating cardiac development and disease.

cell biology↗

bioRxiv2026

Pharmacological arginine deprivation renders pancreatic cancer cells susceptible to senolysis and inhibition of the integrated stress response

Pancreatic ductal adenocarcinoma (PDAC) is almost inevitably fatal and largely resistant to current chemotherapy regimens. Senolysis, i. e. the selective elimination of senescent cells, and the targeting of cancer specific cellular metabolism are two novel treatment approaches that have proven to be effective for a variety of cancer types in pre-clinical studies. We now demonstrate that pharmacological depletion of arginine with pegylated recombinant human arginase 1 (PEG-rhARG1) induced senescence and activated the integrated stress response (IRS) in PDAC cells. Cells treated in such a manner were strikingly susceptible towards senolysis with ABT-263 (navitoclax) and also sensitive towards inhibition of the IRS. These results demonstrate a novel mechanism for an induced sensitivity of PDAC cells that could be exploited for cancer therapy.

cancer biology↗

bioRxiv2025

GLYATL1 is associated with metabolic and epigenetic changes and with endocrine resistance in luminal breast cancer

Estrogen receptor alpha (ER)-positive luminal breast cancer is commonly treated with aromatase inhibitors (AI) to block estrogen signaling; however, resistance frequently develops, limiting therapy success. We observed that GLYATL1 (Glycine-N-Acyltransferase Like 1) expression is upregulated in AI-resistant breast cancer cell models and in patients undergoing AI therapy, correlating with poorer survival. Here we demonstrate that GLYATL1 promotes resistance to estrogen deprivation by elevating succinate levels and altering epigenetic histone marks associated with active transcription. Knockdown or knockout of GLYATL1 reverses these effects and reduces proliferation under estrogen-deprived conditions. Notably, GLYATL1 expression is positively regulated by estrogen receptor alpha signaling independently of estrogen. These findings reveal GLYATL1 as a metabolic and epigenetic mediator of endocrine therapy resistance, suggesting it as a potential target to overcome AI resistance in luminal breast cancer.

cancer biology↗

bioRxiv2025

CAMK2-NR4A1 signaling initiates metabolic substrate switching to induce heart failure with reduced ejection fraction

Heart failure with reduced ejection fraction (HFrEF) is marked by a shift in cardiac energy metabolism from fatty acid oxidation to glucose utilization. This "fuel switch" promotes accumulation of glucose byproducts that modify calcium-handling proteins and impair cardiac function, yet the initiating signals remain unclear. We identify Ca2+/calmodulin-dependent protein kinase II (CAMK2) as an upstream regulator that triggers pathological substrate switching leading to cardiac systolic dysfunction. Dynamic [18F]FDG-PET imaging showed a six-fold increase in myocardial glucose uptake after pressure overload in control mice, but not in cardiomyocyte-specific Camk2d/Camk2g double knockouts (cDKO), even before functional decline. cDKO hearts retained lipid reserves, indicating preserved fatty acid metabolism. Transcriptomics revealed strong CAMK2-dependent induction of Nr4a1 and early repression of genes for fatty acid uptake and {beta}-oxidation preceding upregulation of genes for glucose utilization. Cardiomyocyte-specific Nr4a1 knockout mice closely mimicked the metabolic protection seen in cDKO, while NR4A1 overexpression in human iPSC-derived cardiomyocytes suppressed fatty acid metabolism. NR4A1 directly bound and repressed the FATP1 (Slc27a1) promoter, thereby secondarily enhancing glucose utilization. Together, these findings define a CAMK2-NR4A1 signaling axis that drives lipid depletion and metabolic remodeling, establishing it as a causal mechanism linking energy substrate switching to HFrEF.

physiology↗

bioRxiv2023

Spatial single-cell isotope tracing reveals heterogeneity of de novo fatty acid synthesis in cancer cells

Metabolism has emerged as a key factor in homeostasis and disease including cancer. Yet, little is known about the heterogeneity of metabolic activity of cancer cells due to the lack of tools to directly probe it. Here, we present a novel method, 13C-SpaceM for spatial single-cell isotope tracing of glucose-dependent de novo lipogenesis. The method combines imaging mass spectrometry for spatially-resolved detection of 13C6-glucose-derived 13C label incorporated into esterified fatty acids with microscopy and computational methods for data integration and analysis. We validated 13C-SpaceM on a spatially-heterogeneous normoxia-hypoxia model of liver cancer cells. Investigating cultured cells, we revealed single-cell heterogeneity of lipogenic acetyl-CoA pool labelling degree upon ACLY knockdown that is hidden in the bulk analysis and its effect on synthesis of individual fatty acids. Next, we adapted 13C-SpaceM to analyze tissue sections of mice harboring isocitrate dehydrogenase (IDH)-mutant gliomas. We found a strong induction of de novo fatty acid synthesis in the tumor tissue compared to the surrounding brain. Comparison of fatty acid isotopologue patterns revealed elevated uptake of mono-unsaturated and essential fatty acids in the tumor. Furthermore, our analysis uncovered substantial spatial heterogeneity in the labelling of the lipogenic acetyl-CoA pool indicative of metabolic reprogramming during microenvironmental adaptation. Overall, 13C-SpaceM enables novel ways for spatial probing of metabolic activity at the single cell level. Additionally, this methodology provides unprecedented insight into fatty acid uptake, synthesis and modification in normal and cancerous tissues.

biochemistry↗

bioRxiv2023

Cancer-associated fibroblasts promote drug resistance in ALK-driven lung adenocarcinoma cells by upregulating lipid biosynthesis

Targeted therapy interventions using tyrosine kinase inhibitors (TKIs) provide encouraging treatment responses in ALK-rearranged lung adenocarcinomas, yet resistances occur almost inevitably. Apart from tumor cell-intrinsic resistance mechanisms, accumulating evidence supports a role of cancer-associated fibroblasts (CAFs) in affecting the therapeutic vulnerability of lung cancer cells. Here, we aimed to investigate underlying molecular networks shaping the therapeutic susceptibility of ALK-driven lung adenocarcinoma cells via tumor microenvironmental cues using three-dimensional (3D) spheroid co-culture settings. We show that CAFs promote therapy resistance of lung tumor cells against ALK inhibition by reducing apoptotic cell death and increasing cell proliferation. Using single-cell RNA-sequencing analysis, we show that genes involved in lipogenesis constitute the major transcriptional difference between TKI-treated homo- and heterotypic lung tumor spheroids. CAF-conditioned medium and CAF-secreted factors HGF and NRG1 were both able to promote resistance of 3D-cultured ALK-rearranged lung tumor cells via AKT signaling, which was accompanied by enhanced de novo lipogenesis and supression of lipid peroxidation. Notably, simultaneous targeting of ALK and SREBP-1 was able to overcome the established CAF-driven lipid metabolic-supportive niche of TKI-resistant lung tumor spheroids. Our findings highlight a crucial role of CAFs in mediating ALK-TKI resistance via lipid metabolic reprogramming and suggest new ways to overcome resistance towards molecular directed drugs by targeting vulnerabilities downstream of oncogenic signaling.

cancer biology↗

bioRxiv2023

A multidimensional atlas of human glioblastoma organoids reveals highly coordinated molecular networks and effective drugs

Recent advances in the genomics of glioblastoma (GBM) led to the introduction of molecular neuropathology but failed to translate into treatment improvement. This is largely attributed to the genetic and phenotypic heterogeneity of GBM, which are considered the major obstacle to GBM therapy. Here, we use advanced human GBM organoid (LEGO: Laboratory Engineered Glioblastoma Organoid) and provide an unprecedented comprehensive characterization of LEGO models using single-cell transcriptome, DNA methylome, metabolome, lipidome, proteome, and phospho-proteome analysis. We discovered that genetic heterogeneity dictates functional heterogeneity across molecular layers and demonstrates that NF1 mutation drives mesenchymal signature. Most importantly, we found that glycerol lipid reprogramming is a hallmark of GBM, and several targets and drugs were discovered along this line. We also provide a genotype-based drug reference map using LEGO-based drug screen. This study provides novel human GBM models and a research path toward effective GBM therapy.

cancer biology↗

bioRxiv2022

Selenocysteine metabolism is a targetable vulnerability in MYCN-amplified cancers

Understanding the operational molecular, and metabolic networks that determine the balance between pro- and anti-ferroptotic regulatory pathways could unravel unique vulnerabilities to be exploited for cancer therapy. Here we identify the selenoprotein P (SELENOP) receptor, LRP8, as a key determinant protecting MYCN-amplified neuroblastoma cells from ferroptosis in vitro and in orthotopic neuroblastoma mouse models. Specifically, the exquisite dependency on LRP8-mediated selenocysteine import is caused by the failure of MYCN-amplified cells to efficiently utilize alternative forms of selenium/selenocysteine based uptake necessary for selenoprotein biosynthesis. Increased activity of one of such transporters, SLC7A11, in MYCN-amplified cells leads to cysteine overload, progressive mitochondrial decline and impaired proliferation. These data reveal in LRP8 a targetable, and specific vulnerability of MYCN-amplified neuroblastoma cells and disclose a yet-unaccounted mechanism for selective ferroptosis induction that has the potential to become an important therapeutic entry point for MYCN-amplified neuroblastoma. Statement of significanceGiven the largely unsuccessful repurposing of adult oncology drugs for the treatment of neuroblastoma, our discoveries pave the way for novel ferroptosis based strategies for this entity. Specifically, targeting of LRP8 may offer novel therapeutic and safer opportunities for a number of pediatric malignancies and MYCN driven cancers.

cancer biology↗

bioRxiv2021

c-Myc plays a key role in IFN-γ induced persistence of Chlamydia trachomatis

Chlamydia trachomatis (Ctr) can persist over long periods of time within their host cell and thereby establish chronic infections. One of the major inducers of chlamydial persistence is interferon-gamma (IFN-{gamma}) released by immune cells as a mechanism of immune defence. IFN-{gamma} activates the catabolic depletion of L-tryptophan (Trp) via indoleamine 2,3-dioxygenase (IDO), resulting in persistent Chlamydia. Here we show that IFN-{gamma} depletes c-Myc, the key regulator of host cell metabolism, in a STAT1-dependent manner. Expression of c-Myc rescued Chlamydia from IFN-{gamma}-induced persistence in cultured cell lines, but also in human fallopian tube organoids. L-tryptophan concentrations control c-Myc levels via the PI3K-GSK3{beta} axis. Unbiased metabolic analysis revealed that Chlamydia infection reprograms the host cell tricarboxylic acid (TCA) cycle to support pyrimidine biosynthesis. Addition of TCA cycle intermediates or pyrimidine/purine nucleosides to infected cells rescued Chlamydia from IFN-{gamma}-induced persistence. Thus, our results challenge the longstanding hypothesis of L-tryptophan depletion through IDO as the major mechanism of IFN-{gamma}-induced metabolic immune defence and significantly extends the understanding of the role IFN-{gamma} as a broad modulator of host cell metabolism.

microbiology↗