Lactate dehydrogenase B noncanonically promotes ferroptosis defense in KRAS-driven lung cancer.

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).

Inhibition of LDHB suppresses the metastatic potential of lung cancer by reducing mitochondrial GSH catabolism.

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.

Anisotropic Etching of Monolayer MoS Flakes for Zigzag Edges in Chemical Vapor Deposition.

The edge of two-dimensional (2D) flakes of transition metal dichalcogenide (TMD) profoundly influences their optical, electronic, catalytic, and magnetic properties due to the asymmetric atomic configurations on the edge. As a reverse process of growth, the etching of monolayer MoS flakes can be modulated by tuning the sulfur stoichiometric ratio in chemical vapor deposition. Here, we report studies of the high-density formation of etched pores with defined orientations on MoS flakes.

Crispr-mediated genome editing reveals a preponderance of non-oncogene addictions as targetable vulnerabilities in pleural mesothelioma.

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.

Chemotherapy increases CDA expression and sensitizes malignant pleural mesothelioma cells to capecitabine treatment.

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.

CRISPRing : A Winding Road with a Bright Future in Basic and Translational Cancer Research.

Once considered "undruggable" due to the strong affinity of RAS proteins for GTP and the structural lack of a hydrophobic "pocket" for drug binding, the development of proprietary therapies for KRAS-mutant tumors has long been a challenging area of research. CRISPR technology, the most successful gene-editing tool to date, is increasingly being utilized in cancer research. Here, we provide a comprehensive review of the application of the CRISPR system in basic and translational research in KRAS-mutant cancer, summarizing recent advances in the mechanistic understanding of KRAS biology and the underlying principles of drug resistance, anti-tumor immunity, epigenetic regulatory networks, and synthetic lethality co-opted by mutant KRAS.

An optimized protocol for the generation and monitoring of conditional orthotopic lung cancer in the KP mouse model using an adeno-associated virus vector compatible with biosafety level 1.

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.

Tuning Smith-Purcell radiation by rotating a metallic nanodisk array.

Smith-Purcell radiation (SPR) refers to the far-field, strong, spike radiation generated by the interaction of the evanescent Coulomb field of the moving charged particles and the surrounding medium. In applying SPR for particle detection and nanoscale on-chip light sources, wavelength tunability is desired. Here we report on tunable SPR achieved by moving an electron beam parallel to a two-dimensional (2D) metallic nanodisk array.

MEK1 drives oncogenic signaling and interacts with PARP1 for genomic and metabolic homeostasis in malignant pleural mesothelioma.

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.

Battles against aberrant KEAP1-NRF2 signaling in lung cancer: intertwined metabolic and immune networks.

The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway is well recognized as a key regulator of redox homeostasis, protecting cells from oxidative stress and xenobiotics under physiological circumstances. Cancer cells often hijack this pathway during initiation and progression, with aberrant KEAP1-NRF2 activity predominantly observed in non-small cell lung cancer (NSCLC), suggesting that cell/tissue-of-origin is likely to influence the genetic selection during malignant transformation. Hyperactivation of NRF2 confers a multi-faceted role, and recently, increasing evidence shows that a close interplay between metabolic reprogramming and tumor immunity remodelling contributes to its aggressiveness, treatment resistance (radio-/chemo-/immune-therapy) and susceptibility to metastases.

Non-genetic adaptive resistance to KRAS inhibition: EMT is not the only culprit.

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.

Dissecting the Immunological Profiles in -Amplified LUSC through Integrative Multi-Scale Analyses.

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.

Schedule-Dependent Treatment Increases Chemotherapy Efficacy in Malignant Pleural Mesothelioma.

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.

Organoids as a Model for Precision Medicine in Malignant Pleural Mesothelioma: Where Are We Today?

MPM is an aggressive tumor originating from pleural mesothelial cells. A characteristic feature of the disease is the dominant prevalence of therapeutically intractable inactivating alterations in TSGs, making MPM one of the most difficult cancers to treat and the epitome of a cancer characterized by a significant lack of therapy options and an extremely poor prognosis (5-year survival rate of only 5% to 10%). Extensive interpatient heterogeneity poses another major challenge for targeted therapy of MPM, warranting stratified therapy for specific subgroups of MPM patients.

Targeting lactate dehydrogenase B-dependent mitochondrial metabolism affects tumor initiating cells and inhibits tumorigenesis of non-small cell lung cancer by inducing mtDNA damage.

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).

Multichannel Distribution and Transformation of Entangled Photons with Dielectric Metasurfaces.

Photonic quantum information processing relies on operating the quantum state of photons, which usually involves bulky optical components unfavorable for system miniaturization and integration. Here, we report on the transformation and distribution of polarization-entangled photon pairs with multichannel dielectric metasurfaces. The entangled photon pairs interact with metasurface building blocks, where the geometrical-scaling-induced phase gradients are imposed, and are transformed into two-photon entangled states with the desired polarization.

Multi-scale integrative analyses identify THBS2 cancer-associated fibroblasts as a key orchestrator promoting aggressiveness in early-stage lung adenocarcinoma.

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.

Direct observation of terahertz topological valley transport.

Topological photonics offers the possibility of robust transport and efficiency enhancement of information processing. Terahertz (THz) devices, such as waveguides and beam splitters, are prone to reflection loss owing to their sensitivity to defects and lack of robustness against sharp corners. Thus, it is a challenge to reduce backscattering loss at THz frequencies.

Pushing the Limits of Functionality-Multiplexing Capability in Metasurface Design Based on Statistical Machine Learning.

As 2D metamaterials, metasurfaces provide an unprecedented means to manipulate light with the ability to multiplex different functionalities in a single planar device. Currently, most pursuits of multifunctional metasurfaces resort to empirically accommodating more functionalities at the cost of increasing structural complexity, with little effort to investigate the intrinsic restrictions of given meta-atoms and thus the ultimate limits in the design. In this work, it is proposed to embed machine-learning models in both gradient-based and nongradient optimization loops for the automatic implementation of multifunctional metasurfaces.

Formation of magnetic nanowire arrays by cooperative lateral growth.

Nanowires typically grow along their longitudinal axis, and the long-range order among wires sustains only when a template exists. Here, we report an unprecedented electrochemical growth of ordered metallic nanowire arrays from an ultrathin electrolyte layer, which is achieved by solidifying the electrolyte solution below the freezing temperature. The thickness of the electrodeposit is instantaneously tunable by the applied electric pulses, leading to parallel ridges on webbed film without using any template.

A Breakthrough Brought about by Targeting KRAS: Nonconformity Is Punished.

KRAS is the most frequently mutated oncogene in lung carcinomas, accounting for 25% of total incidence, with half of them being KRAS mutations. In past decades, KRAS enjoyed the notorious reputation of being untargetable-that is, until the advent of G12C inhibitors, which put an end to this legend by covalently targeting the G12C (glycine to cysteine) substitution in the switch-II pocket of the protein, inhibiting the affinity of the mutant KRAS with GTP and subsequently the downstream signaling pathways, such as Raf/MEK/ERK. KRAS-selective inhibitors, e.