Cytotoxic lymphocytes target characteristic biophysical vulnerabilities in cancer.

Immune cells identify and destroy tumors by recognizing cellular traits indicative of oncogenic transformation. In this study, we found that myocardin-related transcription factors (MRTFs), which promote migration and metastatic invasion, also sensitize cancer cells to the immune system. Melanoma and breast cancer cells with high MRTF expression were selectively eliminated by cytotoxic lymphocytes in mouse models of metastasis. This immunosurveillance phenotype was further enhanced by treatment with immune checkpoint blockade (ICB) antibodies. We also observed that high MRTF signaling in human melanoma is associated with ICB efficacy in patients. Using biophysical and functional assays, we showed that MRTF overexpression rigidified the filamentous actin cytoskeleton and that this mechanical change rendered mouse and human cancer cells more vulnerable to cytotoxic T lymphocytes and natural killer cells. Collectively, these results suggest that immunosurveillance has a mechanical dimension, which we call mechanosurveillance, that is particularly relevant for the targeting of metastatic disease.

STING inhibits the reactivation of dormant metastasis in lung adenocarcinoma.

Metastasis frequently develops from disseminated cancer cells that remain dormant after the apparently successful treatment of a primary tumour. These cells fluctuate between an immune-evasive quiescent state and a proliferative state liable to immune-mediated elimination1-6. Little is known about the clearing of reawakened metastatic cells and how this process could be therapeutically activated to eliminate residual disease in patients. Here we use models of indolent lung adenocarcinoma metastasis to identify cancer cell-intrinsic determinants of immune reactivity during exit from dormancy. Genetic screens of tumour-intrinsic immune regulators identified the stimulator of interferon genes (STING) pathway as a suppressor of metastatic outbreak. STING activity increases in metastatic progenitors that re-enter the cell cycle and is dampened by hypermethylation of the STING promoter and enhancer in breakthrough metastases or by chromatin repression in cells re-entering dormancy in response to TGFß. STING expression in cancer cells derived from spontaneous metastases suppresses their outgrowth. Systemic treatment of mice with STING agonists eliminates dormant metastasis and prevents spontaneous outbreaks in a T cell- and natural killer cell-dependent manner-these effects require cancer cell STING function. Thus, STING provides a checkpoint against the progression of dormant metastasis and a therapeutically actionable strategy for the prevention of disease relapse.

Attenuated replication and pathogenicity of SARS-CoV-2 B.1.1.529 Omicron.

The Omicron (B.1.1.529) variant of SARS-CoV-2 emerged in November 2021 and is rapidly spreading among the human population1. Although recent reports reveal that the Omicron variant robustly escapes vaccine-associated and therapeutic neutralization antibodies2-10, the pathogenicity of the virus remains unknown. Here we show that the replication of Omicron is substantially attenuated in human Calu3 and Caco2 cells. Further mechanistic investigations reveal that Omicron is inefficient in its use of transmembrane serine protease 2 (TMPRSS2) compared with wild-type SARS-CoV-2 (HKU-001a) and previous variants, which may explain its reduced replication in Calu3 and Caco2 cells. The replication of Omicron is markedly attenuated in both the upper and lower respiratory tracts of infected K18-hACE2 mice compared with that of the wild-type strain and Delta (B.1.617.2) variant, resulting in its substantially ameliorated lung pathology. Compared with wild-type SARS-CoV-2 and the Alpha (B.1.1.7), Beta (1.351) and Delta variants, infection by Omicron causes the lowest reduction in body weight and the lowest mortality rate. Overall, our study demonstrates that the replication and pathogenicity of the Omicron variant of SARS-CoV-2 in mice is attenuated compared with the wild-type strain and other variants.

UTX condensation underlies its tumour-suppressive activity.

UTX (also known as KDM6A) encodes a histone H3K27 demethylase and is an important tumour suppressor that is frequently mutated in human cancers1. However, as the demethylase activity of UTX is often dispensable for mediating tumour suppression and developmental regulation2-8, the underlying molecular activity of UTX remains unknown. Here we show that phase separation of UTX underlies its chromatin-regulatory activity in tumour suppression. A core intrinsically disordered region (cIDR) of UTX forms phase-separated liquid condensates, and cIDR loss caused by the most frequent cancer mutation of UTX is mainly responsible for abolishing tumour suppression. Deletion, mutagenesis and replacement assays of the intrinsically disordered region demonstrate a critical role of UTX condensation in tumour suppression and embryonic stem cell differentiation. As shown by reconstitution in vitro and engineered systems in cells, UTX recruits the histone methyltransferase MLL4 (also known as KMT2D) to the same condensates and enriches the H3K4 methylation activity of MLL4. Moreover, UTX regulates genome-wide histone modifications and high-order chromatin interactions in a condensation-dependent manner. We also found that UTY, the Y chromosome homologue of UTX with weaker tumour-suppressive activity, forms condensates with reduced molecular dynamics. These studies demonstrate a crucial biological function of liquid condensates with proper material states in enabling the tumour-suppressive activity of a chromatin regulator.

The role of shear forces in primary and secondary nucleation of amyloid fibrils.

Shear forces affect self-assembly processes ranging from crystallization to fiber formation. Here, the effect of mild agitation on amyloid fibril formation was explored for four peptides and investigated in detail for A[Formula: see text]42, which is associated with Alzheimer's disease. To gain mechanistic insights into the effect of mild agitation, nonseeded and seeded aggregation reactions were set up at various peptide concentrations with and without an inhibitor. First, an effect on fibril fragmentation was excluded by comparing the monomer-concentration dependence of aggregation kinetics under idle and agitated conditions. Second, using a secondary nucleation inhibitor, Brichos, the agitation effect on primary nucleation was decoupled from secondary nucleation. Third, an effect on secondary nucleation was established in the absence of inhibitor. Fourth, an effect on elongation was excluded by comparing the seeding potency of fibrils formed under idle or agitated conditions. We find that both primary and secondary nucleation steps are accelerated by gentle agitation. The increased shear forces facilitate both the detachment of newly formed aggregates from catalytic surfaces and the rate at which molecules are transported in the bulk solution to encounter nucleation sites on the fibril and other surfaces. Ultrastructural evidence obtained with cryogenic transmission electron microscopy and free-flow electrophoresis in microfluidics devices imply that agitation speeds up the detachment of nucleated species from the fibril surface. Our findings shed light on the aggregation mechanism and the role of detachment for efficient secondary nucleation. The results inform on how to modulate the relative importance of different microscopic steps in drug discovery and investigations.

Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-ß signaling.

TGF-ß receptors phosphorylate SMAD2 and SMAD3 transcription factors, which then form heterotrimeric complexes with SMAD4 and cooperate with context-specific transcription factors to activate target genes. Here we provide biochemical and structural evidence showing that binding of SMAD2 to DNA depends on the conformation of the E3 insert, a structural element unique to SMAD2 and previously thought to render SMAD2 unable to bind DNA. Based on this finding, we further delineate TGF-ß signal transduction by defining distinct roles for SMAD2 and SMAD3 with the forkhead pioneer factor FOXH1 as a partner in the regulation of differentiation genes in mouse mesendoderm precursors. FOXH1 is prebound to target sites in these loci and recruits SMAD3 independently of TGF-ß signals, whereas SMAD2 remains predominantly cytoplasmic in the basal state and set to bind SMAD4 and join SMAD3:FOXH1 at target promoters in response to Nodal TGF-ß signals. The results support a model in which signal-independent binding of SMAD3 and FOXH1 prime mesendoderm differentiation gene promoters for activation, and signal-driven SMAD2:SMAD4 binds to promoters that are preloaded with SMAD3:FOXH1 to activate transcription.

Author Correction: Reversing a model of Parkinson's disease with in situ converted nigral neurons.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Reversing a model of Parkinson's disease with in situ converted nigral neurons.

Parkinson's disease is characterized by loss of dopamine neurons in the substantia nigra1. Similar to other major neurodegenerative disorders, there are no disease-modifying treatments for Parkinson's disease. While most treatment strategies aim to prevent neuronal loss or protect vulnerable neuronal circuits, a potential alternative is to replace lost neurons to reconstruct disrupted circuits2. Here we report an efficient one-step conversion of isolated mouse and human astrocytes to functional neurons by depleting the RNA-binding protein PTB (also known as PTBP1). Applying this approach to the mouse brain, we demonstrate progressive conversion of astrocytes to new neurons that innervate into and repopulate endogenous neural circuits. Astrocytes from different brain regions are converted to different neuronal subtypes. Using a chemically induced model of Parkinson's disease in mouse, we show conversion of midbrain astrocytes to dopaminergic neurons, which provide axons to reconstruct the nigrostriatal circuit. Notably, re-innervation of striatum is accompanied by restoration of dopamine levels and rescue of motor deficits. A similar reversal of disease phenotype is also accomplished by converting astrocytes to neurons using antisense oligonucleotides to transiently suppress PTB. These findings identify a potentially powerful and clinically feasible approach to treating neurodegeneration by replacing lost neurons.

The Augmented R-Loop Is a Unifying Mechanism for Myelodysplastic Syndromes Induced by High-Risk Splicing Factor Mutations.

Mutations in several general pre-mRNA splicing factors have been linked to myelodysplastic syndromes (MDSs) and solid tumors. These mutations have generally been assumed to cause disease by the resultant splicing defects, but different mutations appear to induce distinct splicing defects, raising the possibility that an alternative common mechanism is involved. Here we report a chain of events triggered by multiple splicing factor mutations, especially high-risk alleles in SRSF2 and U2AF1, including elevated R-loops, replication stress, and activation of the ataxia telangiectasia and Rad3-related protein (ATR)-Chk1 pathway. We further demonstrate that enhanced R-loops, opposite to the expectation from gained RNA binding with mutant SRSF2, result from impaired transcription pause release because the mutant protein loses its ability to extract the RNA polymerase II (Pol II) C-terminal domain (CTD) kinase-the positive transcription elongation factor complex (P-TEFb)-from the 7SK complex. Enhanced R-loops are linked to compromised proliferation of bone-marrow-derived blood progenitors, which can be partially rescued by RNase H overexpression, suggesting a direct contribution of augmented R-loops to the MDS phenotype.

NMDAR antagonists suppress tumor progression by regulating tumor-associated macrophages.

Neurotransmitter receptors are increasingly recognized to play important roles in anti-tumor immunity. The expression of the ion channel N-methyl-D-aspartate receptor (NMDAR) on macrophages was reported, but the role of NMDAR on macrophages in the tumor microenvironment (TME) remains unknown. Here, we show that the activation of NMDAR triggered calcium influx and reactive oxygen species production, which fueled immunosuppressive activities in tumor-associated macrophages (TAMs) in the hepatocellular sarcoma and fibrosarcoma tumor settings. NMDAR antagonists, MK-801, memantine, and magnesium, effectively suppressed these processes in TAMs. Single-cell RNA sequencing analysis revealed that blocking NMDAR functionally and metabolically altered TAM phenotypes, such that they could better promote T cell- and Natural killer (NK) cell-mediated anti-tumor immunity. Treatment with NMDAR antagonists in combination with anti-PD-1 antibody led to the elimination of the majority of established preclinical liver tumors. Thus, our study uncovered an unknown role for NMDAR in regulating macrophages in the TME of hepatocellular sarcoma and provided a rationale for targeting NMDAR for tumor immunotherapy.

Genomic analysis reveals a cryptic pangolin species.

Eight extant species of pangolins are currently recognized. Recent studies found that two mitochondrial haplotypes identified in confiscations in Hong Kong could not be assigned to any known pangolin species, implying the existence of a species. Here, we report that two additional mitochondrial haplotypes identified in independent confiscations from Yunnan align with the putative species haplotypes supporting the existence of this mysterious species/population. To verify the new species scenario we performed a comprehensive analysis of scale characteristics and 138 whole genomes representing all recognized pangolin species and the cryptic new species, 98 of which were generated here. Our morphometric results clearly attributed this cryptic species to Asian pangolins (Manis sp.) and the genomic data provide robust and compelling evidence that it is a pangolin species distinct from those recognized previously, which separated from the Philippine pangolin and Malayan pangolin over 5 Mya. Our study provides a solid genomic basis for its formal recognition as the ninth pangolin species or the fifth Asian one, supporting a new taxonomic classification of pangolins. The effects of glacial climate changes and recent anthropogenic activities driven by illegal trade are inferred to have caused its population decline with the genomic signatures showing low genetic diversity, a high level of inbreeding, and high genetic load. Our finding greatly expands current knowledge of pangolin diversity and evolution and has vital implications for conservation efforts to prevent the extinction of this enigmatic and endangered species from the wild.

Focal adhesion kinase-mediated signaling controls the onset of pancreatic cell differentiation.

Signals from the endothelium play a pivotal role in pancreatic lineage commitment. As such, the fate of the epithelial cells relies heavily on the spatiotemporal recruitment of the endothelial cells to the embryonic pancreas. Although it is known that VEGFA secreted by the epithelium recruits the endothelial cells to the specific domains within the developing pancreas, the mechanism that controls the timing of such recruitment is poorly understood. Here, we have assessed the role of focal adhesion kinase (FAK) in mouse pancreatic development based on our observation that the presence of the enzymatically active form of FAK (pFAK) in the epithelial cells is inversely correlated with vessel recruitment. To study the role of FAK in the pancreas, we conditionally deleted the gene encoding focal adhesion kinase in the developing mouse pancreas. We found that homozygous deletion of Fak (Ptk2) during embryogenesis resulted in ectopic epithelial expression of VEGFA, abnormal endothelial recruitment and a delay in endocrine and acinar cell differentiation. The heterozygous mutants were born with no pancreatic phenotype but displayed gradual acinar atrophy due to cell polarity defects in exocrine cells. Together, our findings imply a role for FAK in controlling the timing of pancreatic lineage commitment and/or differentiation in the embryonic pancreas by preventing endothelial recruitment to the embryonic pancreatic epithelium.

Impacted spike frequency adaptation associated with reduction of KCNQ2/3 exacerbates seizure activity in temporal lobe epilepsy.

Numerous epilepsy-related genes have been identified in recent decades by unbiased genome-wide screens. However, the available druggable targets for temporal lobe epilepsy (TLE) remain limited. Furthermore, a substantial pool of candidate genes potentially applicable to TLE therapy awaits further validation. In this study, we reveal the significant role of KCNQ2 and KCNQ3, two M-type potassium channel genes, in the onset of seizures in TLE. Our investigation began with a quantitative analysis of two publicly available TLE patient databases to establish a correlation between seizure onset and the downregulated expression of KCNQ2/3. We then replicated these pathological changes in a pilocarpine seizure mouse model and observed a decrease in spike frequency adaptation due to the affected M-currents in dentate gyrus granule neurons. In addition, we performed a small-scale simulation of the dentate gyrus network and confirmed that the impaired spike frequency adaptation of granule cells facilitated epileptiform activity throughout the network. This, in turn, resulted in prolonged seizure duration and reduced interictal intervals. Our findings shed light on an underlying mechanism contributing to ictogenesis in the TLE hippocampus and suggest a promising target for the development of antiepileptic drugs.

Magnetic Covalent Organic Framework for Efficient Solid-Phase Extraction of Uranium for on-Site Determination by Portable X-ray Fluorescence Spectrometry.

Uranium plays a pivotal role in the nuclear industry; however, its inadvertent release has raised concerns regarding health and environmental implications. It is crucial for a prompt warning and accurate tracing of uranium contamination in emergency scenarios. In this study, a novel and simple method was proposed that combines magnetic dispersive solid-phase extraction (MDSPE) with portable X-ray fluorescence spectrometry (XRF) for the on-site sampling and determination of trace uranium in real samples. A magnetic covalent organic framework (Fe3O4@COF) composite with excellent chemical stability and a large adsorption capacity of 311 mg/g was synthesized and employed as an efficient adsorbent for the solid-phase extraction of trace uranium. Without the need for a centrifuge or filter requirement, the established method by benchtop wavelength-dispersive X-ray fluorescence spectrometry (WDXRF) exhibits an exceptionally low limit of detection (LOD) of 0.008 µg/L with a sample volume of 50 mL and a fast adsorption time of 15 min, rendering it suitable for environmental monitoring of UO22+. Consequently, this approach, in combination with a hand-held portable XRF instrument with an LOD of 0.1 µg/L, was successfully implemented for the on-site extraction and quality assessment of real water samples, yielding accurate results and satisfactory spike recoveries.

Molecular classification reveals the sensitivity of lung adenocarcinoma to radiotherapy and immunotherapy: multi-omics clustering based on similarity network fusion.

BACKGROUND: Due to individual differences in tumors and immune systems, the response rate to immunotherapy is low in lung adenocarcinoma (LUAD) patients. Combinations with other therapeutic strategies improve the efficacy of immunotherapy in LUAD patients. Although radioimmunotherapy has been demonstrated to effectively suppress tumors, the underlying mechanisms still need to be investigated. METHODS: Total RNA from LUAD cells was sequenced before and after radiotherapy to identify differentially expressed radiation-associated genes. The similarity network fusion (SNF) algorithm was applied for molecular classification based on radiation-related genes, immune-related genes, methylation data, and somatic mutation data. The changes in gene expression, prognosis, immune cell infiltration, radiosensitivity, chemosensitivity, and sensitivity to immunotherapy were assessed for each subtype. RESULTS: We used the SNF algorithm and multi-omics data to divide TCGA-LUAD patients into three subtypes. Patients with the CS3 subtype had the best prognosis, while those with the CS1 and CS2 subtypes had poorer prognoses. Among the strains tested, CS2 exhibited the most elevated immune cell infiltration and expression of immune checkpoint genes, while CS1 exhibited the least. Patients in the CS2 subgroup were more likely to respond to PD-1 immunotherapy. The CS2 patients were most sensitive to docetaxel and cisplatin, while the CS1 patients were most sensitive to paclitaxel. Experimental validation of signature genes in the CS2 subtype showed that inhibiting the expression of RHCG and TRPA1 could enhance the sensitivity of lung cancer cells to radiation. CONCLUSIONS: In summary, this study identified a risk classifier based on multi-omics data that can guide treatment selection for LUAD patients.

3D Magnetic Metal-Organic Frameworks Current Collectors Accelerate the Lithium-Ion Diffusion Rate for Superlong Cyclic Lithium Metal Anode.

Lithium, is the most ideal anode material for lithium-based batteries. However, the overgrowth of lithium dendrites and the low lithium-ion diffusion rate at low temperatures limit the further application of lithium metal anodes. Here, the applied magnetic field is introduced inside the lithium metal anode by using a novel magnetic metal-organic framework as a current collector. The magnetic field can improve the conductivity of this novel current collector, thus accelerating the diffusion of lithium ions in the battery, an advantage that is particularly prominent at low temperatures. In addition, the current collector can stabilize the solid electrolyte interface and inhibit the growth of lithium dendrites, resulting in excellent electrochemical performance. The symmetrical cell at room temperature can exceed 4600 h with a hysteresis voltage of only 9 mV. After 300 cycles at room temperature, the capacity of full cell is still 142 mA h g-1 , and it remains stable for 380 cycles at 5 °C (capacity above 120 mA h g-1 ). The strategy of constructing novel current collector with magnetic field can promote the further application of lithium batteries in extreme conditions such as low temperatures.

Enhanced Ion Transport Through Mesopores Engineered with Additional Adsorption of Layered Double Hydroxides Array in Alkaline Flow Batteries.

Efficient mass transfer in electrodes is essential for the electrochemical processes of battery charge and discharge, especially at high rates and capacities. This study introduces a 3D electrode design featuring layered double hydroxides (LDHs) nanosheets array grown in situ on a carbon felt surface for flow batteries. The mesoporous structure and surface characteristic of LDH nanosheets, especially, the hydroxyl groups forming a unique "H-bonding-like" geometry with ferrous cyanide ions, facilitate efficient adsorption and ion transport. Thus, the designed LDHs electrode enables the alkaline zinc-iron flow battery to maintain a voltage efficiency of 81.6% at an ultra-high current density of 320 mA cm-2, surpassing the values reported in previous studies. The energy efficiency remains above 84% after 375 cycles at a current density of 240 mA cm-2. Molecular dynamics simulations verify the enhanced adsorption effect of LDH materials on active ions, thus facilitating ion transport in the battery. This study provides a novel approach to improve mass transport in electrodes for alkaline flow batteries and other energy storage devices.

Toward High-Performance Mg/S Batteries with M4-Assisted Mg(AlCl4 )2 /PYR14TFSI/DME Electrolyte and MoS2 @CMK/S Cathode.

Rechargeable magnesium batteries (RMBs) are considered as one of the most promising candidates for next-generation batteries. However, the popularization of RMBs is seriously plagued due to the lack of suitable non-nucleophilic electrolytes and the passivation of Mg anode. Herein, a novel non-nucleophilic electrolyte is developed by introducing (s)-1-methoxy-2-propylamine (M4) into themagnesium aluminum chloride complex (MACC)-like electrolyte. The as-synthesizes Mg(AlCl4 )2 -IL-DME-M4 electrolyte enables robust reversible cycling of Mg plating/stripping with low overpotential, high anodic stability, and ionic conductivity (8.56 mS cm-1 ). These features should be mainly attributed to the in situ formation of an MgF2 containing Mg2+ -conducting interphase, which dramatically suppresses the passivation and parasitic reaction of Mg anode with electrolyte. Remarkably, the Mg/S batteries assemble with as-synthesize electrolyte and a new type MoS2 @CMK/S cathode deliver unprecedented electrochemical performance. Specifically, the Mg/S battery exhibited the highest reversible capacity up to 1210 mAh g-1 at 0.1 C, excellent rate capability and satisfactory long-term cycling stability with a reversible capacity of 370 mAh g-1 (coulombic efficiency of ≈100%) at 1.0 C for 600 cycles. The study findings provide a novel strategy and inspiration for designing efficient non-nucleophilic Mg electrolyte and suitable sulfur-host materials for practical Mg/S battery applications.

DTSyn: a dual-transformer-based neural network to predict synergistic drug combinations.

Drug combination therapies are superior to monotherapy for cancer treatment in many ways. Identifying novel drug combinations by screening is challenging for the wet-lab experiments due to the time-consuming process of the enormous search space of possible drug pairs. Thus, computational methods have been developed to predict drug pairs with potential synergistic functions. Notwithstanding the success of current models, understanding the mechanism of drug synergy from a chemical-gene-tissue interaction perspective lacks study, hindering current algorithms from drug mechanism study. Here, we proposed a deep neural network model termed DTSyn (Dual Transformer encoder model for drug pair Synergy prediction) based on a multi-head attention mechanism to identify novel drug combinations. We designed a fine-granularity transformer encoder to capture chemical substructure-gene and gene-gene associations and a coarse-granularity transformer encoder to extract chemical-chemical and chemical-cell line interactions. DTSyn achieved the highest receiver operating characteristic area under the curve of 0.73, 0.78. 0.82 and 0.81 on four different cross-validation tasks, outperforming all competing methods. Further, DTSyn achieved the best True Positive Rate (TPR) over five independent data sets. The ablation study showed that both transformer encoder blocks contributed to the performance of DTSyn. In addition, DTSyn can extract interactions among chemicals and cell lines, representing the potential mechanisms of drug action. By leveraging the attention mechanism and pretrained gene embeddings, DTSyn shows improved interpretability ability. Thus, we envision our model as a valuable tool to prioritize synergistic drug pairs with chemical and cell line gene expression profile.

COL8A1 Regulates Esophageal Squamous Carcinoma Proliferation and Invasion Through PI3K/AKT Pathway.

PURPOSE: Esophageal squamous carcinoma (ESCC) is a gastrointestinal malignancy with a high mortality, but the tumorigenesis is still unclear, restricting the target therapy development of ESCC. We explored the role of COL8A1 in ESCC development. METHODS: Tissue microarrays were used to investigate the expression level of COL8A1 in ESCC tissues. The association between COL8A1 and the overall survival of ESCC patients was assessed. The effect of differential COL8A1 expression on tumor growth was investigated by the xenograft model. The regulation of COL8A1 on tumor growth, migration, and invasion was studied by using ESCC cell lines. The signal transduction pathways involved in COL8A1 were bioinformatically profiled and validated. RESULTS: The COL8A1 was significantly expressed in cancerous tissues and was associated with poor prognosis in patients with ESCC. In vivo, the tumor growth obviously declined after inhibition of the COL8A1 expression. The abilities of cell proliferation and invasion were both decreased when the expression of COL8A1 was knockdown in ESCC cell line. Furthermore, we found the inactivation of the PI3K/AKT pathway that was mediated by knockdown of COL8A1 in ESCC cells, which was reversed with COL8A1 overexpression, whereas the cell proliferation and invasion ability were restored. CONCLUSIONS: This is the first report that COL8A1 promote ESCC progression, which hopefully will provide a theoretical basis for clinical targeting of ESCC.