Biology subjects

Kenner, L.

Publications and source records attributed to Kenner, L..

At least 19 recordsLinked to original sources

bioRxiv2026

Amygdala metabolic activity on FDG PET is associated with survival, response to immune checkpoint inhibition, and tumor immune signaling in non-small cell lung cancer

Amygdala metabolic activity (AmygAc) measured by [18F]FDG PET has been associated with chronic psychological stress and adverse clinical outcomes, but its relationship with antitumor immunity and treatment response remains incompletely understood. We investigated AmygAc as a host-derived imaging biomarker in non-small cell lung cancer (NSCLC) and examined its association with survival, response to immune checkpoint inhibition (ICI), and the tumor immune microenvironment. Methods: In this multicenter retrospective study, baseline [18F]FDG PET scans from 256 treatment-naive patients with NSCLC were analyzed to quantify AmygAc. Overall survival was assessed in the full cohort, and treatment response was evaluated in 79 patients who subsequently received neoadjuvant ICI therapy. AmygAc was integrated with clinical and tumor-derived imaging parameters. To investigate its biological correlates, tumor tissue from a selected subcohort was analyzed using multiplex immunofluorescence and spatial transcriptomics.

cancer biology↗

bioRxiv2026

Nanoplastic-mediated non-B DNA mutagenicity

Plastic-derived materials have become persistent ecological contaminants since their industrial introduction in the mid-20th century. In that context, nanoplastics (NPs) have been discussed as an emerging, ubiquitous plastic-derived pollutant with unique physicochemical properties. Their increased surface-to-volume ratio enhances their adsorption, reactivity, and cellular penetration, driving distinct ecotoxicological behaviours when compared to larger plastic particles. In this study, we identify direct NP-induced DNA mutagenesis in Salmonella enterica. Using a combination of biochemical and biophysical studies, as well as mutagenicity assays, we show that functionalized and non-functionalized NPs induce mutations, depending on the energy state of the bacteria and the NP surface chemistry, by disrupting base-stacking and base-pairing - an intrinsic property of all DNA. Whole-genome analysis revealed that exposure to NPs alters the mutational spectrum and mutation frequency, while circular dichroism spectroscopy demonstrated NP-induced helical flipping from B- to non-B DNA conformations. These motifs preferentially adopt Z-like or A/B-hybrid structures associated with localized mutagenesis through DNA destabilization. Our combined data reveal that NP-mediated mutagenesis is based on surface chemistry and DNA topology, linking surface chemistry on nanoplastics to genomic instability in vivo. The proposed mechanism redefines the current perspective on nanoplastic toxicity shifting it from an indirect stress to direct macromolecular interactions. This mechanism provides a molecular framework for understanding how NPs could impose mutation bias, environmental selection pressure, and potential genomic risk across biological systems.

microbiology↗

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

Small Particles, Big Problems: Polystyrene nanoparticles induce DNA damage, oxidative stress, migration, and mitogenic pathways predominantly in non-malignant lung cells

Polystyrene micro-and nanoplastics (PS-MNPs) are emerging environmental pollutants with potential implications for human health. In this study, we used two different sizes of PS-MNPs (0.25 {micro}m and 1 {micro}m) on non-small cell lung cancer (A549, H460), small cell lung cancer (DMS53, H372), and normal lung epithelial (BEAS-2B) cells, as well as on human-derived lung organoids, to investigate the cytotoxic effects of PS particles. At lower concentrations (< 30 {micro}g/cm2, equivalent to 50 {micro}g/ml), neither PS-MPs nor PS-NPs did not interfere with cell viability or proliferation. Intracellular kinetic assays revealed that non-malignant (BEAS-2B) lung cells showed the strongest turnover of PS-NPs compared to malignant cells. Since PS-NPs exhibited more pronounced cellular effects, we focused further analyses on their impact. Furthermore, we observed significantly increased migration, prolonged S-phase arrest along with induced DNA damage, and oxidative stress in non-malignant (BEAS-2B) lung cells. Thus, our data suggest that BEAS-2B cells exhibit the highest sensitivity to PS-NPs. We also demonstrate that after PS-NP treatment, these cells displayed decreased base excision repair capacity and increased activation of survival pathways, including AKT and ERK phosphorylation. PS-NP internalization and increase of signal pathways were validated in a more physiological lung organoid setting. Altogether, our findings suggest that PS-NPs do not significantly affect the malignant behavior of cancer cells. However, they could promote tumor-like features in normal lung cells by inducing survival pathways, migration, and alterations in stress response mechanisms. Environmental ImplicationsThis study investigates the effects of polystyrene micro-and nanoplastics (PS-MNPs) at environmentally relevant concentrations. The tested concentrations of PS-MNPs (0, 15, 30, and 60 {micro}g/cm2, equivalent to 0, 25, 50, and 100 {micro}g/ml) are commonly studied in the literature in lung cells. While these findings provide insights into cellular responses, the overall environmental impact of PS-MNPs remains limited at realistic exposure levels. HighlightsO_LIPS-MNPs are internalized into lung cells, with higher uptake in non-malignant cells. C_LIO_LIPS-NPs lead to increased migration, DNA damage, oxidative stress, and disturbed cell cycle progression. C_LIO_LIPS-NPs promote activation of survival pathways in non-malignant cells and lung organoids. C_LIO_LIExposure of PS-NPs may cause potential implications for lung cancer development and progression. C_LI

molecular biology↗

bioRxiv2025

Biobank of genetically defined murine prostate cancer tumoroids uncovers oncogenic pathways and drug vulnerabilities driven by PTEN-loss

Prostate cancer (PCa) is the second most common cancer in men and shows high inter- and intra-patient heterogeneity. Consequently, treatment options are limited and there is a lack of representative preclinical models. Here we establish a comprehensive biobank of murine organoids and tumoroids that reflect common patient mutations. We demonstrate that the deletion of Pten alone, or in combination with Stat3, or Tp53, drives the activation of cancer-related pathways in both prostate organoids and tumour-derived tumoroids. A medium-throughput drug screen identified two potent compounds, the PDPK1/AKT/FLT dual pathway inhibitor and the sirtuin inhibitor tenovin-6, which effectively suppressed tumoroid proliferation. Notably, these compounds also inhibited the growth of several human PCa cell lines and displayed synergistic effects when combined with the standard-of-care antiandrogen enzalutamide. Together, our findings provide evidence that murine tumoroids are versatile preclinical models for studying PCa tumorigenesis and drug sensitivities to develop novel therapeutic options for PCa patients.

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↗

bioRxiv2025

Targeting Pre-existing Club-Like Cells in Prostate Cancer Potentiates Androgen Deprivation Therapy

A critical knowledge gap in prostate cancer research is understanding whether castration-tolerant progenitor-like cells that reside in treatment-naive tumors play a direct role in therapy resistance and tumor progression. Herein, we reveal that the castration tolerance of LSCmed (Lin-, Sca-1+, CD49fmed) progenitor cells, the mouse equivalent of human prostatic Club cells, arises not from intrinsic properties, but from significant transcriptional reprogramming. Utilizing single-cell RNA sequencing of LSCmed cells isolated from prostate-specific Pten-deficient (Ptenpc-/-) mice, we identify the emergence of castration-resistant LSCmed cells enriched in stem-like features, driven by the transcription factor FOSL1/AP-1. We demonstrate that cells exhibiting Ptenpc-/- LSCmed characteristics are prevalent in aggressive double-negative prostate cancer (DNPC) subtypes recently identified in human castration-resistant prostate cancer (CRPC). Furthermore, our findings show that the dual-targeting agents JQ-1 and CX-6258--focused on FOSL1/AP-1 and PIM kinases, respectively--effectively suppress both the progenitor properties and the growth of mouse and human DNPC surrogates in vitro and in vivo. Thus, early eradication of castration-tolerant Club-like cells presents a promising therapeutic strategy to mitigate prostate cancer progression toward CRPC.

cancer biology↗

bioRxiv2025

Context-dependent translation inhibition as a novel oncology therapeutic modality

Inhibitors of protein synthesis, including anisomycin, homoharringtonine, and other natural products bind in the peptidyl-transferase center (PTC) of the eukaryotic ribosome to inhibit translation. Recent work has demonstrated that some PTC-binding antibiotics act in a sequence-selective manner, inhibiting translation elongation at specific amino acids while the polypeptide is engaged in the PTC. However, this phenomenon has yet to be documented for compounds that inhibit translation by the human ribosome. Here we use structure-based design to guide synthesis of molecules called interdictors that bind to the human ribosome PTC and act in a context-selective manner to inhibit translation elongation. Using ribosome profiling, in combination with in vitro biochemistry and cryo-electron microscopy, we characterize the context selectivity of unique analogues and observe their preferred interactions with nascent chain residues with complementary properties. Furthermore, we present a structure for an interdictor bound to a portion of the MYC protein at [~] 1.9 [A] resolution and identify resulting structural rearrangements in both the nascent chain and ribosomal RNA. In cells, we document how these compounds differentially impact the ribotoxic stress response pathway which monitors ribosome collisions and can trigger apoptosis. Finally, we confirm their tumor growth inhibition activity after oral dosing in cell line derived xenografts in mice using the MDA-MB-231 model for triple-negative breast cancer. Together, our data establish sequence-selective inhibition of translation as a novel small-molecule therapeutic modality for historically difficult to address cancers by targeting translation of oncogenic dependency factors in the human ribosome PTC.

cancer biology↗

bioRxiv2024

Detection of Unlabeled Micro- and Nanoplastics in Unstained Tissue with Optical Photothermal Infrared Spectroscopy

In this study, we investigate the efficacy of Optical Photothermal Infrared (O-PTIR) spectroscopy, also known as mid-infrared photothermal (MIP) microscopy, for the detection of micro- and nano plastics (MNPs) down to diameters of 250 nm in mammalian tissues. Experiments with both in vitro 3D cell cultures derived from HTC116 colorectal cancer cell line and in vivo mouse tissue models were conducted to evaluate the spatial resolution limits and quality of spectra that formed the basis for label-free and non- destructive identification of MNPs. Our findings demonstrate the superior resolution of O-PTIR in imaging individual particles of 250 nm in mouse kidney tissues, surpassing the capabilities of traditional FTIR spectroscopy, which was applied as a reference technique. Furthermore, we introduce a semi-automated image analysis that incorporates machine learning algorithms to accelerate the detection process, thus improving throughput and minimizing the potential for human error. The results confirm that O-PTIR produces high-quality, artefact-free spectral images in a contact-less manner and significantly outperforms FTIR in terms of spatial resolution and signal-to-noise ratio in complex biological matrices.

biophysics↗

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

Conventional therapy induces tumor immunoediting and modulates the immune contexture in colorectal cancer

BackgroundCancer immunotherapies for patients with colorectal cancer (CRC) continue to lag behind other solid cancer types with the exception of 4% of patients with microsatellite-instable tumors. Thus, there is an urgent need to broaden the clinical benefit of checkpoint blockers to CRC by combining conventional therapies to sensitise tumors to immunotherapy. However, the impact of conventional drugs on immunoediting, potentially promoting the positive selection of less immunogenic variants, and on the tumor immune contexture in CRC, remain elusive. MethodsWe performed comprehensive multimodal profiling using longitudinal samples from metastatic CRC patients undergoing neoadjuvant therapy with mFOLFOX6 and Bevacizumab. Exome-sequencing, RNA-sequencing and multiplexed immunofluorescence imaging was carried out on tumor samples obtained before and after therapy and the data was analysed using established methods. The results of the analysis were extrapolated to publicly available datasets (TCGA and CPTAC). In order to identify a surrogate marker, an explainable artificial intelligence method was developed using a transformer-based analytical pipeline for the identification of features in Hematoxylin and Eosin (H&E) images associated with specific biological processes, followed by manual evaluation of highly informative tiles by a pathologist. ResultsMutational profiles were highly modified and the level of genetic intertumoral heterogeneity between patients varied following treatment. Evolutionary analysis indicated eradication of some clones and dominant clonal prevalence of others, supporting the notion of pharmacologically-induced cancer immunoeditin. Post treatment samples showed upregulation of HLA class II genes, activation of differentiation and stemness pathways, and changes in the consensus molecular subtypes. The tumor immune contexture was characterised by increased densities of CD8+ and CD4+ T cells, but reduced T cell-tumor cell interactions (and increased T cell exhaustion. The AI-guided analyses of the H&E images pinpointed extracellular mucin deposits associated with stemness genes, suggesting a surrogate marker for routine pathological evaluation. ConclusionsConventional therapy induces immunoediting and modulates the immune contexture in metastatic CRC patients.

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↗

bioRxiv2023

Small molecule STAT3/5 inhibitors exhibit therapeutic potential in acute myeloid leukemia and extra-nodal natural killer/T cell lymphoma

The oncogenic transcription factors STAT3, STAT5A and STAT5B are essential to steer hematopoiesis and immunity, but their enhanced expression and activation drives the development or progression of blood cancers. Current therapeutic strategies focus on blocking upstream tyrosine kinases, but frequently occurring resistance often leads to disease relapse, emphasizing the need for more targeted therapies. Here we evaluate JPX-0700 and JPX-0750, which are STAT3/5-specific covalent cysteine binders that lead to growth arrest of acute myeloid leukemia (AML) and natural killer/T cell lymphoma (NKCL) cell lines in vitro and in vivo, as well as reduce cell viability of primary AML blasts ex vivo. Our non-PROTAC small molecular weight degraders selectively reduce STAT3/5 activation and total protein levels, as well as downstream target oncogene expression, exhibiting nanomolar to low micromolar efficacy. We found that both AML and NKCL cells hijack STAT3/5 signaling through either upstream activating mutations in tyrosine kinases, activating gain-of-function mutations in STAT3, mutational loss of negative STAT regulators, or genetic gains in anti-apoptotic, pro-proliferative or epigenetic-modifying STAT3/5 targets. Moreover, we have shown synergistic inhibitory action of JPX-0700 and JPX-0750 upon combinatorial use with approved chemotherapeutics (doxorubicin, daunorubicin, cytarabine), epigenetic enzyme blocker vorinostat, tyrosine kinase inhibitor cabozantinib or BCL-2 inhibitor venetoclax. Importantly, JPX-0700 or JPX-0750 treatment reduced leukemic cell growth in human AML/NKCL xenograft mouse models without adverse side effects. These potent small molecule degraders of STAT3/5 could propel further clinical development for use in AML and NKCL patients.

cancer biology↗

bioRxiv2022

STAT3 cooperates with the core transcriptional regulatory circuitry to drive MYC expression and oncogenesis in anaplastic large cell lymphoma

Anaplastic large cell lymphoma (ALCL) is an aggressive, CD30+ T-cell lymphoma of children and adults. ALK fusion transcripts or mutations in the JAK-STAT pathway are observed in most ALCL tumors, but the mechanisms underlying tumorigenesis are not fully understood. Here we show that dysregulated STAT3, together with a core transcriptional regulatory circuit consisting of BATF3-IRF4- IKZF1, co-occupies gene enhancers to establish an oncogenic transcription program and maintain the malignant state of ALCL. Critical downstream targets of this network in ALCL cells include the proto-oncogene MYC, which requires active STAT3 to facilitate high levels of MYC transcription. The activity of this auto-regulatory transcription loop is reinforced by MYC binding to the enhancer regions associated with STAT3 and each of the core regulatory transcription factors. These findings provide new insights for understanding how dysregulated signaling pathways hijack cell-type-specific transcriptional machinery to drive tumorigenesis and create therapeutic vulnerabilities in genetically defined tumors.

cancer biology↗

bioRxiv2020

Requirement of DNMT1 to orchestrate epigenomic reprogramming during NPM-ALK driven T cell lymphomagenesis

Malignant transformation depends on genetic and epigenetic events that result in a burst of deregulated gene expression and chromatin changes. To dissect the sequence of events in this process, we used a T cell-specific lymphoma model based on the human oncogenic NPM-ALK translocation. We find that transformation of T cells shifts thymic cell populations to an undifferentiated immunophenotype, which occurs only after a period of latency, accompanied by induction of the MYC-NOTCH1 axis and deregulation of key epigenetic enzymes. We discover aberrant DNA methylation patterns, overlapping with regulatory regions, plus a high degree of epigenetic heterogeneity between individual tumors. In addition, ALK positive tumors show a loss of collaborative methylation patterns of neighboring CpG sites. Notably, deletion of the maintenance DNA methyltransferase DNMT1 completely abrogates lymphomagenesis in this model, despite oncogenic signaling through NPM-ALK, suggesting that faithful maintenance of tumor-specific methylation through DNMT1 is essential for sustained proliferation and tumorigenesis. STATEMENT OF SIGNIFICANCEEpigenetic alterations are causally involved in tumorigenesis. Here we show that induction of a single human oncogene in murine T cells induces specific deregulation of epigenetic enzymes resulting in epigenomic alterations similar to human tumors. Our findings are of broader implication to understand how epigenomic processes are shaped by oncogene induced transformation.

cancer biology↗