Biology subjects

Schlederer, M.

Publications and source records attributed to Schlederer, M..

10 recordsLinked to original sources

bioRxiv2026

Single-Cell Profiling Reveals Developmental Trajectories and identifies SYK and TIM3 as Targets in some T Cell Lymphomas

T cell lymphomas (TCL) are a heterogeneous collection of malignancies whose origins and pathogenesis are poorly understood and for which few efficacious therapeutic options exist. Here, we conduct single-cell transcriptomic profiling spanning eight TCL entities and describe entity-associated programmes. We predict the cell of origin for these tumours through an integrative analysis of transcriptome and T cell receptor (TCR) maturation states. By identifying tumours with TCR states ranging from the pre-TCR through non-productive and productive TCR alpha and beta chain rearrangements we shed new light on their developmental origins. Furthermore, we apply our drug2cell computational drug target predictions with drug screens using patient-derived cell models, systematically benchmarking the performance of drug2cell and validating compounds and targets. This process identifies SYK inhibitors as a therapeutic opportunity and prioritises TIM3 for immunotherapy based on combined spatial transcriptomics analysis. Overall, our data provide a resource for diagnostics and therapies for tumours of critical unmet need.

cancer biology↗

bioRxiv2025

Targeting the hyperactive STAT3/5 pathway in cutaneous T-cell lymphoma with the multi-kinase nuclear transporter inhibitor IQDMA

Cutaneous T-cell lymphoma (CTCL), particularly its tumor stage mycosis fungoides (MF) subtype, presents considerable therapeutic challenges since current treatment modalities show limited efficacy. This study addresses the unmet need for novel targeted therapies that inhibit the STAT3/5 pathway, which is hyperactive in CTCL. Utilizing a murine model with intradermally grafted malignant T-cell lymphoma cells, we compared the efficacy of the multi-kinase inhibitor IQDMA with the conventional, topical psoralen + UV-A (PUVA) phototherapeutic regimen. Our data show that IQDMA reduced tumor volume by 90.7% (p = 0.0001) and was significantly more effective than PUVA, which reduced the tumor volume by only 46.2% (p = 0.0074). Results of an immunobiological analysis reveal that IQDMA treatment decreased tumor cell infiltration by 29.8% (p = 0.03) and the percentage of Ki67+ cells by 25.3% (p = 0.03), indicating a reduced tumor cell proliferation rate. Moreover, remarkable 40.0% and 45.6% reductions were observed in the total STAT5 (p = 0.047) and STAT3 (p = 0.01) levels of the infiltrating tumor cells upon IQDMA treatment. STAT5 levels are directly correlated with CD3+ tumor cell infiltration, confirming the role of the STAT3/5 pathway in the disease pathogenesis. Intriguingly, while phospho-STAT5 and total STAT5 levels directly correlated in the vehicle-treated group, a negative correlation was observed in the IQDMA-treated group, indicating IQDMA action in blocking STAT5 hyperactivation. IQDMA targets PAK kinase, a nuclear transporter for phospho-STAT5; in turn, we observed a compartmental shift of phospho-STAT5 from the nucleus to the cytoplasm. These key findings establish the properties of IQDMA as a potent targeted therapy for CTCL and offer compelling evidence for its clinical evaluation.

cancer biology↗

bioRxiv2025

Thyroid Hormone Receptor Beta Signaling is a Targetable Driver of Prostate Cancer Growth

Thyroid hormone (TH) signaling plays a major role in the development, energy homeostasis, and metabolism of most tissues. Recent observations have identified THs as drivers of prostate cancer (PCa) tumor development and progression. We reported that the T3-scavenger protein {micro}-crystallin (CRYM) regulates the development and progression of PCa and that this involved crosstalk with the androgen receptor (AR) signaling. However, the mechanisms remain incompletely understood. Here, we explored the role of thyroid hormone receptor {beta} (TR{beta}), which is the main effector of TH signaling, in the context of PCa. The use of the TR{beta}-selective antagonist NH-3 inhibited PCa cell proliferation in vitro and reduced tumor size in PCa xenograft models. Notably, NH-3 was highly effective in the engrafted 22Rv1 cell line, a model for castration-resistant PCa (CRPC). Mechanistic studies revealed that NH-3 downregulates AR and the AR target genes Nkx3.1 and KLK3 (PSA). NH-3 was a more effective anticancer agent than enzalutamide and showed synergistic properties in combined use. Evidence from human datasets corroborates our findings whereby elevated TR{beta} expression and mutations in TH signaling pathways are associated with the onset of PCa. Collectively, these results establish TR{beta} as a mediator of tumorigenesis in PCa and identify NH-3 as a promising therapeutic agent for targeting AR signaling, particularly in CRPC.

cancer biology↗

bioRxiv2024

FGFR2 promotes resistance to ALK tyrosine kinase inhibitors and its inhibition acts synergistically with lorlatinib in the treatment of ALK-expressing neuroblastoma

Anaplastic Lymphoma Kinase inhibitors (ALK TKIs) are approved for the treatment of ALK-positive non-small cell lung cancer (NSCLC) and are in clinical trial for ALK-aberrant high-risk neuroblastoma (NB) patients, particularly loratinib. However, resistance to ALK inhibitors can occur in patients, via the activation of bypass-signalling pathways, and there is a need to identify these mechanisms as well as drugs that inhibit them to design therapeutic approaches that prevent resistance, and to treat ALK TKI relapsed/refractory disease. Using genome-wide CRISPR-Cas9 overexpression screens, we identified and validated FGFR2 as a desensitizer to lorlatinib in aberrant ALK-expressing high-risk NB. FGFR2 and FGFR2-associated pathways are up-regulated in lorlatinib-resistant NB cells. Moreover, high-throughput screens using a library of 1,430 FDA approved drugs identified kinase inhibitors including those targeting FGFR2 as efficacious in reducing the survival of lorlatinib resistant NB cells. Hence, the FGFR pathway was investigated as a therapeutic target applying the pan-FGFR inhibitor erdafitinib or the multi-kinase inhibitor ponatinib, resulting in reduced survival of lorlatinib-resitant cells in comparison to their lorlatinib-sensitive counterparts. Moreover, both FGFR inhibitors act synergistically with lorlatinib in vitro and in vivo, using patient-derived xenografts (PDXs) and genetically engineered models (GEMM) of ALK-expressing NB. FGFR2 mRNA expression also correlate with a poorer prognosis for NB patients, regardless of sub-type, suggesting that a broader range of patients may benefit from FGFR inhibitors. Overall, our data suggests that FGFR2 potentially plays roles in lorlatinib resistance in NB and that combined pharmacological inhibition of ALK and FGFR constitutes a therapeutic approach to treat high-risk NB.

cancer biology↗

bioRxiv2024

YAP1 is a key regulator of EWS::FLI1-dependent malignant transformation upon IGF-1 mediated reprogramming of bone mesenchymal stem cells

AbstractEwing sarcoma (EwS) is an aggressive cancer of adolescents in need of effective treatments. Insulin like growth factor (IGF) 1 was previously reported an autocrine growth factor for EwS, but only 10% of patients responded to IGF-1 receptor blockade. Although presumed to originate from mesenchymal progenitors during bone development, targeting of the EwS driver oncogene EWS::FLI1 to the mesenchymal lineage in a conditional mouse model did not result in tumor formation but led to skeletal malformations and perinatal death. We report that transient exposure to IGF-1 concentrations mimicking serum levels during puberty reprogrammed limb-derived mesenchymal cells of EWS::FLI1-mutant mice to stable transformation and tumorigenicity. We identified a modular mechanism of IGF-1-driven tumor promotion in the early steps of EwS pathogenesis, in which Yap1 plays a central role. Pharmacologic Yap1/Tead inhibition reversed the transformed phenotype of EWS::FLI1 expressing cells. Our data provide a rationale for combined IGF-1R and YAP/TEAD inhibition in the treatment of EwS patients. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=185 SRC="FIGDIR/small/603565v1_ufig1.gif" ALT="Figure 1"> View larger version (87K): org.highwire.dtl.DTLVardef@a6a298org.highwire.dtl.DTLVardef@1fcab8aorg.highwire.dtl.DTLVardef@1621e27org.highwire.dtl.DTLVardef@a9994e_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2024

Cell-autonomous GP130 activation suppresses prostate cancer development via STAT3/ARF/p53-driven senescence and confers an immune-active tumor microenvironment

Prostate cancer ranks as the second most frequently diagnosed cancer in men worldwide. Recent research highlights the crucial roles GP130-mediated signaling pathways play in the development and progression of various cancers, particularly through hyperactivated STAT3 signaling. Here, we find that genetic cell-autonomous activation of the GP130 receptor in prostate epithelial cells triggers active STAT3 signaling and significantly reduces tumor growth in vivo. Mechanistically, genetic activation of GP130 signaling mediates senescence via the STAT3/ARF/p53 axis and anti-tumor immunity via recruitment of cytotoxic T-cells, ultimately impeding tumor progression. In prostate cancer patients, high GP130 mRNA expression levels correlate with better recurrence-free survival, increased senescence signals and a transition from an immune-cold to an immune-hot tumor. Our findings reveal a context-dependent role of GP130/STAT3 in carcinogenesis and a tumor-suppressive function in prostate cancer development. We challenge the prevailing concept of blocking GP130/STAT3 signaling as functional prostate cancer treatment and instead propose cell-autonomous GP130 activation as a novel therapeutic strategy.

cancer biology↗

bioRxiv2023

JUN mediates senescence and immune cell recruitment to prevent prostate cancer progression

BackgroundProstate cancer develops through malignant transformation of the prostate epithelium in a stepwise, mutation-driven process. Although activator protein-1 transcription factors such as JUN have been implicated as potential oncogenic drivers, the molecular programs contributing to prostate cancer progression are not fully understood. MethodsWe analyzed JUN expression in clinical prostate cancer samples across different stages and investigated its functional role in a Pten-deficient mouse model. We performed histopathological examinations, transcriptomic analyses and explored the senescence-associated secretory phenotype in the tumor microenvironment. ResultsElevated JUN levels characterized early-stage prostate cancer and predicted improved survival in human and murine samples. Immune-phenotyping of Pten-deficient prostates revealed high accumulation of tumor-infiltrating leukocytes, particularly innate immune cells, neutrophils and macrophages as well as high levels of STAT3 activation and IL-1{beta} production. Jun depletion in a Pten-deficient background prevented immune cell attraction which was accompanied by significant reduction of active STAT3 and IL-1{beta} and accelerated prostate tumor growth. Comparative transcriptome profiling of prostate epithelial cells revealed a senescence-associated gene signature, upregulation of pro-inflammatory processes involved in immune cell attraction and of chemokines such as IL-1{beta}, CCL3 and CCL8 in Pten-deficient prostates. Strikingly, JUN depletion reversed both, senescence and senescence-associated immune cell infiltration and consequently accelerated tumor growth. ConclusionsOur results suggest that JUN acts as tumor-suppressor and decelerates the progression of prostate cancer by transcriptional regulation of senescence- and inflammation-associated genes. This study opens avenues for novel treatment strategies that could impede disease progression and improve patient outcomes.

cancer biology↗

bioRxiv2022

STAT3 restricts prostate cancer metastasis and antiandrogen resistance by controlling LKB1/CREB signaling pathway

Prostate cancer (PCa) lethality is driven by its progression to a metastatic castration-resistant state, yet the signaling mechanisms underlying metastatic spread remain unknown. Here we show that STAT3 converges with the LKB1/mTORC1 and CREB to control metastatic disease in PCa mouse models. Unexpectedly, STAT3 was found to be upregulated in diabetic PCa patients undergoing metformin therapy with a concomitant reduction in mTORC1 expression. In preclinical mouse models of PCa, genetic ablation or activation of STAT3 had opposing effects on LKB1/AMPK/mTORC1- dependent tumorigenesis. Using genetic and pharmacological approaches, we identified LKB1 as a direct STAT3 target while repressing CREB. Furthermore, PCa patients with high CREB expression had inferior clinical outcome with significantly increased risk of disease and metastatic recurrence. We observe that castration state lowers STAT3 abundance and increases AR and CREB levels, leading to castration-resistant PCa (CRPC). Our findings revealed that STAT3 controls mTORC1 and CREB in metastatic disease, suggesting CREB as a promising target for lethal CRPC.

cancer biology↗

bioRxiv2019

Thyroid and androgen receptor signaling are antagonized by CRYM in prostate cancer

Androgen deprivation therapy (ADT) remains a key approach in the treatment of prostate cancer (PCa). However, PCa inevitably relapses and becomes ADT resistant. Besides androgens, there is evidence that thyroid hormone thyroxine (T4) and its active form 3,5,3-triiodo-L-thyronine (T3) are involved in the progression of PCa. Epidemiologic evidence indicates a higher incidence of PCa in men with elevated thyroid hormone levels. The thyroid hormone binding protein -Crystallin (CRYM) mediates intracellular thyroid hormone action by sequestering T3 and blocks its binding to cognate receptors (TRa/TRb) in target tissues. We show in this study that low CRYM expression levels in PCa patient samples are associated with early BCR and poor prognosis. Moreover, we found a disease stage-specific expression of CRYM in PCa. CRYM counteracted thyroid and androgen signaling and blocked intracellular choline uptake. CRYM inversely correlated with [18F]fluoromethylcholine (FMC) levels in PET/MRI imaging of PCa patients. Our data suggest CRYM as a novel antagonist of T3 and androgen-mediated signalling. The role of CRYM could therefore be an essential control mechanism for the prevention of aggressive PCa growth. HighlightsO_LIThyroid and androgen hormone driven pathways in prostate cancer (PCa) are antagonized by - Crystallin (CRYM). C_LIO_LI[18F]fluoromethylcholine uptake and prognostic values in PCa correlate with CRYM protein levels. C_LIO_LIReduced CRYM expression predicts early biochemical recurrence (BCR) in PCa patients. C_LI

cancer biology↗

bioRxiv2019

STAT3-dependent systems-level analysis reveals PDK4 as an independent predictor of biochemical recurrence in prostate cancer

Prostate cancer (PCa) has a broad spectrum of clinical behaviour, hence biomarkers are urgently needed for risk stratification. We previously described the protective effect of STAT3 in a prostate cancer mouse model. By utilizing a gene co-expression network in addition to laser microdissected proteomics from human and murine prostate FFPE samples, we describe STAT3-induced downregulation of the TCA cycle/OXPHOS in PCa on transcriptomic and proteomic level. We identify pyruvate dehydrogenase kinase 4 (PDK4), a key regulator of the TCA cycle, as a promising independent prognostic marker in PCa. PDK4 predicts disease recurrence independent of diagnostic risk factors such as grading, staging and PSA level. Furthermore, PDK4 expression is causally linked to type 2 diabetes mellitus, which is known to have a protective effect on PCa. We conclude that this effect is related to PDK4 expression and that PDK4 loss could serve as a biomarker for PCa with dismal prognosis.

cancer biology↗