Publications by authors named "Thomas M Marti"

Ferroptosis is an oxidative, non-apoptotic cell death frequently inactivated in cancer, but the underlying mechanisms in oncogene-specific tumors remain poorly understood. Here, we discover that lactate dehydrogenase (LDH) B, but not the closely related LDHA, subunits of active LDH with a known function in glycolysis, noncanonically promotes ferroptosis defense in KRAS-driven lung cancer. Using murine models and human-derived tumor cell lines, we show that LDHB silencing impairs glutathione (GSH) levels and sensitizes cancer cells to blockade of either GSH biosynthesis or utilization by unleashing KRAS-specific, ferroptosis-catalyzed metabolic synthetic lethality, culminating in increased glutamine metabolism, oxidative phosphorylation (OXPHOS) and mitochondrial reactive oxygen species (mitoROS).

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Metastasis, the leading cause of cancer death, is closely linked to lactate metabolism. Our study aimed to investigate the role of lactate dehydrogenase B (LDHB), which mainly catalyzes the conversion of lactate to pyruvate, in the metastatic potential of lung cancer. We found that LDHB silencing reduced the invasion and migration ability of lung cancer cells in vitro.

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Metastatic lung cancer remains a leading cause of death worldwide, with its intricate metastatic cascade posing significant challenges to researchers and clinicians. Despite substantial progress in understanding this cascade, many aspects remain elusive. Microfluidic-based vasculature-on-chip models have emerged as powerful tools in cancer research, enabling the simulation of specific stages of tumor progression.

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Pleural mesothelioma (PM) is an aggressive cancer with limited treatment options. In particular, the frequent loss of tumor suppressors, a key oncogenic driver of the disease that is therapeutically intractable, has hampered the development of targeted cancer therapies. Here, we interrogate the PM genome using CRISPR-mediated gene editing to systematically uncover PM cell susceptibilities and provide an evidence-based rationale for targeted cancer drug discovery.

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The combination of cisplatin and pemetrexed remains the gold standard chemotherapy for malignant pleural mesothelioma (MPM), although resistance and poor response pose a significant challenge. Cytidine deaminase (CDA) is a key enzyme in the nucleotide salvage pathway and is involved in the adaptive stress response to chemotherapy. The cytidine analog capecitabine and its metabolite 5'-deoxy-5-fluorocytidine (5'-DFCR) are converted via CDA to 5-fluorouracil, which affects DNA and RNA metabolism.

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Article Synopsis
  • Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer with limited treatment options; recent advancements in immunotherapy using immune checkpoint inhibitors (ICIs) show varied patient responses and the need for better biomarkers.
  • Researchers analyzed data from The Cancer Genome Atlas and other cohorts to explore how BAP1 gene deficiency influences the immune environment in MPM, finding that BAP1 deficiency enhances immune pathways linked to inflammation and increased T-cell activity.
  • The study concludes that MPM tumors lacking BAP1 may respond better to immunotherapy and suggests further research into targeting these tumors with ICIs or MEK inhibitors due to their unique immune characteristics.
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Background: The inducible Kras/p53 lung adenocarcinoma mouse model, which faithfully recapitulates human disease, is routinely initiated by the intratracheal instillation of a virus-based Cre recombinase delivery system. Handling virus-based delivery systems requires elevated biosafety levels, e.g.

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Prolonged exposure to environmental respirable toxicants can lead to the development and worsening of severe respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD) and fibrosis. The limited number of FDA-approved inhaled drugs for these serious lung conditions has led to a shift from towards the use of alternative human-relevant models to better predict the toxicity of inhaled particles in preclinical research. While there are several inhalation exposure models for the upper airways, the fragile and dynamic nature of the alveolar microenvironment has limited the development of reproducible exposure models for the distal lung.

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Malignant pleural mesothelioma (MPM) is a lethal malignancy etiologically caused by asbestos exposure, for which there are few effective treatment options. Although asbestos carcinogenesis is associated with reactive oxygen species (ROS), the bona fide oncogenic signaling pathways that regulate ROS homeostasis and bypass ROS-evoked apoptosis in MPM are poorly understood. In this study, we demonstrate that the mitogen-activated protein kinase (MAPK) pathway RAS-RAF-MEK-ERK is hyperactive and a molecular driver of MPM, independent of histological subtypes and genetic heterogeneity.

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Purpose: Oncogene addiction provides important therapeutic opportunities for precision oncology treatment strategies. To date the cellular circuitries associated with driving oncoproteins, which eventually establish the phenotypic manifestation of oncogene addiction, remain largely unexplored. Data suggest the DNA damage response (DDR) as a central signaling network that intersects with pathways associated with deregulated addicting oncoproteins with kinase activity in cancer cells.

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Adaptions to therapeutic pressures exerted on cancer cells enable malignant progression of the tumor, culminating in escape from programmed cell death and development of resistant diseases. A common form of cancer adaptation is non-genetic alterations that exploit mechanisms already present in cancer cells and do not require genetic modifications that can also lead to resistance mechanisms. Epithelial-to-mesenchymal transition (EMT) is one of the most prevalent mechanisms of adaptive drug resistance and resulting cancer treatment failure, driven by epigenetic reprogramming and EMT-specific transcription factors.

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The histone H3 lysine 36 (H3K36) methyltransferase , a neighboring gene of , has been identified as a critical genetic driver of lung squamous cell carcinoma (LUSC). However, the molecular characteristics, especially the immunological roles of in driving carcinogenesis, are poorly understood. In this study, we systematically integrated multi-omics data (e.

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Malignant pleural mesothelioma (MPM) is a rare but aggressive thoracic malignancy with limited treatment options. One of the standard treatments for MPM is chemotherapy, which consists of concurrent treatment with pemetrexed and cisplatin. Pemetrexed limits tumor growth by inhibiting critical metabolic enzymes involved in nucleotide synthesis.

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Article Synopsis
  • The Omicron-BA.1 variant of concern became the dominant strain globally in early 2022, prompting the need for extensive research using primary cell cultures and animal models to understand its characteristics compared to the Delta variant.* -
  • In laboratory studies, Omicron-BA.1 showed increased early replication in human nasal cells but less replication in bronchial cells; however, in animal models like hamsters and ferrets, Delta variant remained more dominant.* -
  • The research revealed that the spike gene from Omicron-BA.1 leads to lower replication and pathogenicity in certain mice, while also indicating that this variant may escape immune responses generated by mRNA vaccines, contributing to its dominance over other variants.*
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Once considered a waste product of anaerobic cellular metabolism, lactate has been identified as a critical regulator of tumorigenesis, maintenance, and progression. The putative primary function of lactate dehydrogenase B (LDHB) is to catalyze the conversion of lactate to pyruvate; however, its role in regulating metabolism during tumorigenesis is largely unknown. To determine whether LDHB plays a pivotal role in tumorigenesis, we performed 2D and 3D in vitro experiments, utilized a conventional xenograft tumor model, and developed a novel genetically engineered mouse model (GEMM) of non-small cell lung cancer (NSCLC), in which we combined an LDHB deletion allele with an inducible model of lung adenocarcinoma driven by the concomitant loss of p53 (also known as Trp53) and expression of oncogenic KRAS (G12D) (KP).

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The evaluation of inhalation toxicity, drug safety and efficacy assessment, as well as the investigation of complex disease pathomechanisms, are increasingly relying on lung models. This is due to the progressive shift towards human-based systems for more predictive and translational research. While several cellular models are currently available for the upper airways, modelling the distal alveolar region poses several constraints that make the standardization of reliable alveolar models relatively difficult.

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Article Synopsis
  • * In laboratory tests, DHEA showed the ability to lower pro-fibrotic markers without being toxic, and it influenced cell growth by changing the cell cycle and reducing G6PD activity.
  • * Low levels of DHEAS in patients with idiopathic pulmonary fibrosis and other fibrotic ILDs were linked to worse lung function and increased risk of early mortality, suggesting that DHEAS could serve as a potential biomarker for disease severity.
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Subsets of patients with early-stage lung adenocarcinoma (LUAD) have a poor post-surgical course after curative surgery. However, biomarkers stratifying this high-risk subset and molecular underpinnings underlying the aggressive phenotype remain unclear. We integrated bulk and single-cell transcriptomics, proteomics, secretome and spatial profiling of clinical early-stage LUAD samples to identify molecular underpinnings that promote the aggressive phenotype.

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Antibody-mediated cancer immunotherapy targets inhibitory surface molecules, such as PD1, PD-L1, and CTLA-4, aiming to re-invigorate dysfunctional T cells. We purified and characterized tumor-infiltrating lymphocytes (TILs) and their patient-matched non-tumor counterparts from treatment-naïve NSCLC patient biopsies to evaluate the effect of PD1 expression on the functional and molecular profiles of tumor-resident T cells. We show that PD1+ CD8+ TILs have elevated expression of the transcriptional regulator ID3 and that the cytotoxic potential of CD8 T cells can be improved by knocking down ID3, defining it as a potential regulator of T cell effector function.

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  • Oncogenic KRAS mutations are common in cancers, but treating these mutations effectively is difficult; this study aims to explore metabolic dependencies created by mutant KRAS for potential therapeutic strategies.
  • The researchers utilized functional genomic techniques and a targeted library of chemical inhibitors to discover that the nucleolar protein NOP56 is crucial for the survival of KRAS-mutant lung cancer cells, specifically by regulating reactive oxygen species (ROS) levels.
  • Depleting NOP56 increases ROS and makes cancer cells more vulnerable to mTOR inhibition, suggesting that targeting both NOP56 and mTOR could enhance the effectiveness of cancer treatments against KRAS-mutant tumors.
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Despite evidence suggesting that the tumor microenvironment (TME) in malignant pleural mesothelioma (MPM) is linked with poor prognosis, there is a lack of studies that functionally characterize stromal cells and tumor-infiltrating lymphocytes (TILs). Here, we aim to characterize the stromal subsets within MPM, investigate their relationship to TILs, and explore the potential therapeutic targets. We curated a core set of genes defining stromal/immune signatures expressed by mesenchymal cells within the TME using molecular analysis of The Cancer Genome Atlas (TCGA) MPM cohort.

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Background: Although T cell abundance in solid tumours is associated with better outcomes, it also correlates with a stroma-mediated source of immune suppression driven by TGFβ1 and poor overall survival. Whether this also is observed in non-small cell lung cancer (NSCLC) is unknown.

Methods: We utilized molecular analysis of The Cancer Genome Atlas (TCGA) NSLCC cohort to correlate immune activation (IA) gene expression and extracellular matrix/stromal (ECM/stromal) gene expression with patient survival.

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KRAS oncoprotein is commonly mutated in human cancer, but effective therapies specifically targeting KRAS-driven tumors remain elusive. Here, we show that combined treatment with fibroblast growth factor receptor 1 (FGFR1) and polo-like kinase 1 (PLK1) inhibitors evoke synergistic cytotoxicity in KRAS-mutant tumor models in vitro and in vivo. Pharmacological and genetic suppression of FGFR1 and PLK1 synergizes to enhance anti-proliferative effects and cell death in KRAS-mutant lung and pancreatic but not colon nor KRAS wild-type cancer cells.

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Lung-resident (LR) mesenchymal stem and stromal cells (MSCs) are key elements of the alveolar niche and fundamental regulators of homeostasis and regeneration. We interrogated their function during virus-induced lung injury using the highly prevalent respiratory syncytial virus (RSV) which causes severe outcomes in infants. We applied complementary approaches with primary pediatric LR-MSCs and a state-of-the-art model of human RSV infection in lamb.

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