Changes in intestinal microbiota and biochemical parameters in patients with inflammatory bowel disease and irritable bowel syndrome induced by the prolonged addition of soluble fibers to usual drug therapy.

OBJECTIVES: Partially hydrolyzed guar gum (PHGG) is a soluble dietary fiber;in addition to improving bowel movements, it maintains intestinal health by producing short-chain fatty acids. However, majority of clinical studies on PHGG have been concluded within a month and excluded usual drug therapy. Hence, this study aimed to determine the effects of long-term consumption of PHGG, in combination with drug therapy, on gut bacteria ratios, laboratory values for inflammatory response, and fecal characteristics. METHODS AND RESULTS: The study was performed in patients with irritable bowel syndrome (IBS), Crohn's disease (CD), and ulcerative colitis (UC), by the administration of PHGG for six months while they continued their usual treatment. PHGG treatment caused significant changes in patients with IBS, including an increase in the abundance of short-chain fatty acid-producing bacteria, a significant decrease in Bacteroides abundance, and normalization of the Bristol scale of stool. In patients with UC, non-significant normalization of soft stools and decrease in fecal calprotectin were observed. Adverse events were not observed in any of the groups. CONCLUSION: Thus, it would be beneficial to include PHGG in the usual drug therapies of patients with IBS. J. Med. Invest. 71 : 121-128, February, 2024.

Effectiveness and safety of lubiprostone after switching from stimulant laxatives in elderly patients with chronic constipation.

Background and Aim: Stimulant laxatives may cause electrolyte abnormalities, dehydration, and abdominal pain; their long-term use can lead to tolerance and subsequent refractory constipation. We investigated the effectiveness, safety, and quality of life after switching from stimulant laxatives to lubiprostone in elderly patients with chronic constipation (CC). Methods: This multicenter, interventional, open-label, single-arm, before-and-after comparison study enrolled 99 Japanese patients aged 65-90 years with CC who took stimulant laxatives for ≥2 weeks prior to switching to lubiprostone monotherapy. Results: The mean ± SD spontaneous defecations at Week 1 of 7.8 ± 6.2 times/week was not significantly different from that at baseline (8.3 ± 4.7). Spontaneous defecations were significantly reduced at Weeks 2 (-1.5 ± 4.0, P < 0.001) and 4 (-1.5 ± 3.7, P < 0.001). The Bristol Stool Form Scale score did not change from baseline (4.7 ± 0.9) at Weeks 1 (4.5 ± 1.3) or 4 (4.3 ± 1.3), but it did at Week 2 (4.3 ± 1.5, P < 0.05). The Patient Assessment of Constipation Quality of Life questionnaire score increased (0.36 ± 0.07, P < 0.001) after 28 days. Nausea was the only symptom that worsened from baseline and was the most frequently reported adverse drug reaction (15.2%). Conclusion: Switching to lubiprostone monotherapy for CC was not associated with significant concerns in short-term spontaneous defecation frequency and safety, but it might affect the efficacy and patient quality of life over 2 weeks. Careful treatment strategies facilitating gradual switching to lubiprostone monotherapy may be needed in patients using stimulant laxatives.

TIP60 is required for tumorigenesis in non-small cell lung cancer.

Histone modifications play crucial roles in transcriptional activation, and aberrant epigenetic changes are associated with oncogenesis. Lysine (K) acetyltransferases 5 (TIP60, also known as KAT5) is reportedly implicated in cancer development and maintenance, although its function in lung cancer remains controversial. Here we demonstrate that TIP60 knockdown in non-small cell lung cancer cell lines decreased tumor cell growth, migration, and invasion. Furthermore, analysis of a mouse lung cancer model with lung-specific conditional Tip60 knockout revealed suppressed tumor formation relative to controls, but no apparent effects on normal lung homeostasis. RNA-seq and ChIP-seq analyses of inducible TIP60 knockdown H1975 cells relative to controls revealed transglutaminase enzyme (TGM5) as downstream of TIP60. Investigation of a connectivity map database identified several candidate compounds that decrease TIP60 mRNA, one that suppressed tumor growth in cell culture and in vivo. In addition, TH1834, a TIP60 acetyltransferase inhibitor, showed comparable antitumor effects in cell culture and in vivo. Taken together, suppression of TIP60 activity shows tumor-specific efficacy against lung cancer, with no overt effect on normal tissues. Our work suggests that targeting TIP60 could be a promising approach to treating lung cancer.

Imaging Classification of Constipation.

Objectives: The diagnosis of patients with chronic constipation is very complicated. This study aimed to develop a simple imaging classification for the diagnosis of chronic constipation by abdominal computed tomography (CT). Methods: Sixty-two patients who underwent abdominal CT in our hospital between January and June 2022 were enrolled. The CT values of the stool in the rectum and cecum were measured in patients with chronic constipation (C group) and in those without (non-C group). Results: A strong correlation was observed between the Bristol Stool Form Scale (BSFS) and the CT value of rectal stool. Furthermore, the rectal stool CT value was significantly higher in patients with chronic constipation than in those without. The CT value of cecal stool did not differ between the two groups. The cecal stool CT value was significantly higher in patients with severe constipation (BSFS 1) than in those with BSFS 2-6. A cutoff CT value of 100 was selected as the optimal value for indicating chronic constipation. Conclusions: Abdominal CT was useful in the diagnosis of chronic constipation. If the patient had constipation, the optimal cutoff CT value was 100.

Transcriptional Circuitry of NKX2-1 and SOX1 Defines an Unrecognized Lineage Subtype of Small-Cell Lung Cancer.

Rationale: The current molecular classification of small-cell lung cancer (SCLC) on the basis of the expression of four lineage transcription factors still leaves its major subtype SCLC-A as a heterogeneous group, necessitating more precise characterization of lineage subclasses. Objectives: To refine the current SCLC classification with epigenomic profiles and to identify features of the redefined SCLC subtypes. Methods: We performed unsupervised clustering of epigenomic profiles on 25 SCLC cell lines. Functional significance of NKX2-1 (NK2 homeobox 1) was evaluated by cell growth, apoptosis, and xenograft using clustered regularly interspaced short palindromic repeats-Cas9 (CRISPR-associated protein 9)-mediated deletion. NKX2-1-specific cistromic profiles were determined using chromatin immunoprecipitation followed by sequencing, and its functional transcriptional partners were determined using coimmunoprecipitation followed by mass spectrometry. Rb1flox/flox; Trp53flox/flox and Rb1flox/flox; Trp53flox/flox; Nkx2-1flox/flox mouse models were engineered to explore the function of Nkx2-1 in SCLC tumorigenesis. Epigenomic landscapes of six human SCLC specimens and 20 tumors from two mouse models were characterized. Measurements and Main Results: We identified two epigenomic subclusters of the major SCLC-A subtype: SCLC-Aα and SCLC-Aσ. SCLC-Aα was characterized by the presence of a super-enhancer at the NKX2-1 locus, which was observed in human SCLC specimens and a murine SCLC model. We found that NKX2-1, a dual lung and neural lineage factor, is uniquely relevant in SCLC-Aα. In addition, we found that maintenance of this neural identity in SCLC-Aα is mediated by collaborative transcriptional activity with another neuronal transcriptional factor, SOX1 (SRY-box transcription factor 1). Conclusions: We comprehensively describe additional epigenomic heterogeneity of the major SCLC-A subtype and define the SCLC-Aα subtype by the core regulatory circuitry of NKX2-1 and SOX1 super-enhancers and their functional collaborations to maintain neuronal linage state.

Integrative network analysis of early-stage lung adenocarcinoma identifies aurora kinase inhibition as interceptor of invasion and progression.

Here we focus on the molecular characterization of clinically significant histological subtypes of early-stage lung adenocarcinoma (esLUAD), which is the most common histological subtype of lung cancer. Within lung adenocarcinoma, histology is heterogeneous and associated with tumor invasion and diverse clinical outcomes. We present a gene signature distinguishing invasive and non-invasive tumors among esLUAD. Using the gene signatures, we estimate an Invasiveness Score that is strongly associated with survival of esLUAD patients in multiple independent cohorts and with the invasiveness phenotype in lung cancer cell lines. Regulatory network analysis identifies aurora kinase as one of master regulators of the gene signature and the perturbation of aurora kinases in vitro and in a murine model of invasive lung adenocarcinoma reduces tumor invasion. Our study reveals aurora kinases as a therapeutic target for treatment of early-stage invasive lung adenocarcinoma.

Early-Stage Lung Adenocarcinoma MDM2 Genomic Amplification Predicts Clinical Outcome and Response to Targeted Therapy.

Lung cancer is the most common cause of cancer-related deaths in both men and women, accounting for one-quarter of total cancer-related mortality globally. Lung adenocarcinoma is the major subtype of non-small cell lung cancer (NSCLC) and accounts for around 40% of lung cancer cases. Lung adenocarcinoma is a highly heterogeneous disease and patients often display variable histopathological morphology, genetic alterations, and genomic aberrations. Recent advances in transcriptomic and genetic profiling of lung adenocarcinoma by investigators, including our group, has provided better stratification of this heterogeneous disease, which can facilitate devising better treatment strategies suitable for targeted patient cohorts. In a recent study we have shown gene expression profiling identified novel clustering of early stage LUAD patients and correlated with tumor invasiveness and patient survival. In this study, we focused on copy number alterations in LUAD patients. SNP array data identified amplification at chromosome 12q15 on MDM2 locus and protein overexpression in a subclass of LUAD patients with an invasive subtype of the disease. High copy number amplification and protein expression in this subclass correlated with poor overall survival. We hypothesized that MDM2 copy number and overexpression predict response to MDM2-targeted therapy. In vitro functional data on a panel of LUAD cells showed that MDM2-targeted therapy effectively suppresses cell proliferation, migration, and invasion in cells with MDM2 amplification/overexpression but not in cells without MDM2 amplification, independent of p53 status. To determine the key signaling mechanisms, we used RNA sequencing (RNA seq) to examine the response to therapy in MDM2-amplified/overexpressing p53 mutant and wild-type LUAD cells. RNA seq data shows that in MDM2-amplified/overexpression with p53 wild-type condition, the E2F → PEG10 → MMPs pathway is operative, while in p53 mutant genetic background, MDM2-targeted therapy abrogates tumor progression in LUAD cells by suppressing epithelial to mesenchymal transition (EMT) signaling. Our study provides a potentially clinically relevant strategy of selecting LUAD patients for MDM2-targeted therapy that may provide for increased response rates and, thus, better survival.

Upregulation of FGF9 in Lung Adenocarcinoma Transdifferentiation to Small Cell Lung Cancer.

Transdifferentiation of lung adenocarcinoma to small cell lung cancer (SCLC) has been reported in a subset of lung cancer cases that bear EGFR mutations. Several studies have reported the prerequisite role of TP53 and RB1 alterations in transdifferentiation. However, the mechanism underlying transdifferentiation remains understudied, and definitive additional events, the third hit, for transdifferentiation have not yet been identified. In addition, no prospective experiments provide direct evidence for transdifferentiation. In this study, we show that FGF9 upregulation plays an essential role in transdifferentiation. An integrative omics analysis of paired tumor samples from a patient with transdifferentiated SCLC exhibited robust upregulation of FGF9. Furthermore, FGF9 upregulation was confirmed at the protein level in four of six (66.7%) paired samples. FGF9 induction transformed mouse lung adenocarcinoma-derived cells to SCLC-like tumors in vivo through cell autonomous activation of the FGFR pathway. In vivo treatment of transdifferentiated SCLC-like tumors with the pan-FGFR inhibitor AZD4547 inhibited growth. In addition, FGF9 induced neuroendocrine differentiation, a pathologic characteristic of SCLC, in established human lung adenocarcinoma cells. Thus, the findings provide direct evidence for FGF9-mediated SCLC transdifferentiation and propose the FGF9-FGFR axis as a therapeutic target for transdifferentiated SCLC. SIGNIFICANCE: This study demonstrates that FGF9 plays a role in the transdifferentiation of lung adenocarcinoma to small cell lung cancer.

Intrinsic Immunogenicity of Small Cell Lung Carcinoma Revealed by Its Cellular Plasticity.

Small cell lung carcinoma (SCLC) is highly mutated, yet durable response to immune checkpoint blockade (ICB) is rare. SCLC also exhibits cellular plasticity, which could influence its immunobiology. Here we discover that a distinct subset of SCLC uniquely upregulates MHC I, enriching for durable ICB benefit. In vitro modeling confirms epigenetic recovery of MHC I in SCLC following loss of neuroendocrine differentiation, which tracks with derepression of STING. Transient EZH2 inhibition expands these nonneuroendocrine cells, which display intrinsic innate immune signaling and basally restored antigen presentation. Consistent with these findings, murine nonneuroendocrine SCLC tumors are rejected in a syngeneic model, with clonal expansion of immunodominant effector CD8 T cells. Therapeutically, EZH2 inhibition followed by STING agonism enhances T-cell recognition and rejection of SCLC in mice. Together, these data identify MHC I as a novel biomarker of SCLC immune responsiveness and suggest novel immunotherapeutic approaches to co-opt SCLC's intrinsic immunogenicity. SIGNIFICANCE: SCLC is poorly immunogenic, displaying modest ICB responsiveness with rare durable activity. In profiling its plasticity, we uncover intrinsically immunogenic MHC Ihi subpopulations of nonneuroendocrine SCLC associated with durable ICB benefit. We also find that combined EZH2 inhibition and STING agonism uncovers this cell state, priming cells for immune rejection.This article is highlighted in the In This Issue feature, p. 1861.

Prototypical oncogene family Myc defines unappreciated distinct lineage states of small cell lung cancer.

Comprehensive genomic analyses of small cell lung cancer (SCLC) have revealed frequent mutually exclusive genomic amplification of MYC family members. Hence, it has been long suggested that they are functionally equivalent; however, more recently, their expression has been associated with specific neuroendocrine markers and distinct histopathology. Here, we explored a previously undescribed role of L-Myc and c-Myc as lineage-determining factors contributing to SCLC molecular subtypes and histology. Integrated transcriptomic and epigenomic analyses showed that L-Myc and c-Myc impart neuronal and non-neuroendocrine-associated transcriptional programs, respectively, both associated with distinct SCLC lineage. Genetic replacement of c-Myc with L-Myc in c-Myc-SCLC induced a neuronal state but was insufficient to induce ASCL1-SCLC. In contrast, c-Myc induced transition from ASCL1-SCLC to NEUROD1-SCLC characterized by distinct large-cell neuroendocrine carcinoma-like histopathology. Collectively, we characterize a role of historically defined general oncogenes, c-Myc and L-Myc, for regulating lineage plasticity across molecular and histological subtypes.

Non-chemical fluorination of hexagonal boron nitride by high-energy ion irradiation.

Two-dimensional materials such as hexagonal boron nitride (h-BN) and graphene have attracted wide attention in nanoelectronics and spintronics. Since their electronic characteristics are strongly affected by the local atomic structure, the heteroatom doping could allow us to tailor the electronic and physical properties of two-dimensional materials. In this study, a non-chemical method of heteroatom doping into h-BN under high-energy ion irradiation was demonstrated for the LiF/h-BN/Cu heterostructure. Spectroscopic analysis of chemical states on the relevant atoms revealed that 6% ± 2% fluorinated h-BN is obtained by the irradiation of 2.4 MeV Cu2+ ions with the fluence up to 1014 ions cm-2. It was shown that the high-energy ion irradiation leads to a single-sided fluorination of h-BN by the formation of the fluorinated sp 3-hybridized BN.

Epigenomic Profiling Discovers Trans-lineage SOX2 Partnerships Driving Tumor Heterogeneity in Lung Squamous Cell Carcinoma.

Molecular characterization of lung squamous cell carcinoma (LUSC), one of the major subtypes of lung cancer, has not sufficiently improved its nonstratified treatment strategies over decades. Accumulating evidence suggests that lineage-specific transcriptional regulators control differentiation states during cancer evolution and underlie their distinct biological behaviors. In this study, by investigating the super-enhancer landscape of LUSC, we identified a previously undescribed "neural" subtype defined by Sox2 and a neural lineage factor Brn2, as well as the classical LUSC subtype defined by Sox2 and its classical squamous partner p63. Robust protein-protein interaction and genomic cooccupancy of Sox2 and Brn2, in place for p63 in the classical LUSC, indicated their transcriptional cooperation imparting this unique lineage state in the "neural" LUSC. Forced expression of p63 downregulated Brn2 in the "neural" LUSC cells and invoked the classical LUSC lineage with more squamous/epithelial features, which were accompanied by increased activities of ErbB/Akt and MAPK-ERK pathways, suggesting differential dependency. Collectively, our data demonstrate heterogeneous cell lineage states of LUSC featured by Sox2 cooperation with Brn2 or p63, for which distinct therapeutic approaches may be warranted. SIGNIFICANCE: Epigenomic profiling reveals a novel subtype of lung squamous cell carcinoma with neural differentiation.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/79/24/6084/F1.large.jpg.

Suppression of STING Associated with LKB1 Loss in KRAS-Driven Lung Cancer.

KRAS-driven lung cancers frequently inactivate TP53 and/or STK11/LKB1, defining tumor subclasses with emerging clinical relevance. Specifically, KRAS-LKB1 (KL)-mutant lung cancers are particularly aggressive, lack PD-L1, and respond poorly to immune checkpoint blockade (ICB). The mechanistic basis for this impaired immunogenicity, despite the overall high mutational load of KRAS-mutant lung cancers, remains obscure. Here, we report that LKB1 loss results in marked silencing of stimulator of interferon genes (STING) expression and insensitivity to cytoplasmic double-strand DNA (dsDNA) sensing. This effect is mediated at least in part by hyperactivation of DNMT1 and EZH2 activity related to elevated S-adenylmethionine levels and reinforced by DNMT1 upregulation. Ectopic expression of STING in KL cells engages IRF3 and STAT1 signaling downstream of TBK1 and impairs cellular fitness, due to the pathologic accumulation of cytoplasmic mitochondrial dsDNA associated with mitochondrial dysfunction. Thus, silencing of STING avoids these negative consequences of LKB1 inactivation, while facilitating immune escape. SIGNIFICANCE: Oncogenic KRAS-mutant lung cancers remain treatment-refractory and are resistant to ICB in the setting of LKB1 loss. These results begin to uncover the key underlying mechanism and identify strategies to restore STING expression, with important therapeutic implications because mitochondrial dysfunction is an obligate component of this tumor subtype.See related commentary by Corte and Byers, p. 16.This article is highlighted in the In This Issue feature, p. 1.

Overcoming Resistance to Dual Innate Immune and MEK Inhibition Downstream of KRAS.

Despite extensive efforts, oncogenic KRAS remains resistant to targeted therapy. Combined downstream RAL-TBK1 and MEK inhibition induces only transient lung tumor shrinkage in KRAS-driven genetically engineered mouse models (GEMMs). Using the sensitive KRAS;LKB1 (KL) mutant background, we identify YAP1 upregulation and a therapy-induced secretome as mediators of acquired resistance. This program is reversible, associated with H3K27 promoter acetylation, and suppressed by BET inhibition, resensitizing resistant KL cells to TBK1/MEK inhibition. Constitutive YAP1 signaling promotes intrinsic resistance in KRAS;TP53 (KP) mutant lung cancer. Intermittent treatment with the BET inhibitor JQ1 thus overcomes resistance to combined pathway inhibition in KL and KP GEMMs. Using potent and selective TBK1 and BET inhibitors we further develop an effective therapeutic strategy with potential translatability to the clinic.

Tumor innate immunity primed by specific interferon-stimulated endogenous retroviruses.

Mesenchymal tumor subpopulations secrete pro-tumorigenic cytokines and promote treatment resistance1-4. This phenomenon has been implicated in chemorefractory small cell lung cancer and resistance to targeted therapies5-8, but remains incompletely defined. Here, we identify a subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in these cells. Stimulated 3 prime antisense retroviral coding sequences (SPARCS) are oriented inversely in 3' untranslated regions of specific genes enriched for regulation by STAT1 and EZH2. Derepression of these loci results in double-stranded RNA generation following IFN-γ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' long terminal repeat of the antisense ERV. Engagement of MAVS and STING activates downstream TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction in human tumors is tightly associated with major histocompatibility complex class 1 expression, mesenchymal markers, and downregulation of chromatin modifying enzymes, including EZH2. Analysis of cell lines with high inducible SPARCS expression reveals strong association with an AXL/MET-positive mesenchymal cell state. While SPARCS-high tumors are immune infiltrated, they also exhibit multiple features of an immune-suppressed microenviroment. Together, these data unveil a subclass of ERVs whose derepression triggers pathologic innate immune signaling in cancer, with important implications for cancer immunotherapy.

Regulatory Architecture of the LßT2 Gonadotrope Cell Underlying the Response to Gonadotropin-Releasing Hormone.

The LßT2 mouse pituitary cell line has many characteristics of a mature gonadotrope and is a widely used model system for studying the developmental processes and the response to gonadotropin-releasing hormone (GnRH). The global epigenetic landscape, which contributes to cell-specific gene regulatory mechanisms, and the single-cell transcriptome response variation of LßT2 cells have not been previously investigated. Here, we integrate the transcriptome and genome-wide chromatin accessibility state of LßT2 cells during GnRH stimulation. In addition, we examine cell-to-cell variability in the transcriptional response to GnRH using Gel bead-in-Emulsion Drop-seq technology. Analysis of a bulk RNA-seq data set obtained 45 min after exposure to either GnRH or vehicle identified 112 transcripts that were regulated >4-fold by GnRH (FDR < 0.05). The top regulated transcripts constitute, as determined by Bayesian massive public data integration analysis, a human pituitary-relevant coordinated gene program. Chromatin accessibility [assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq)] data sets generated from GnRH-treated LßT2 cells identified more than 58,000 open chromatin regions, some containing notches consistent with bound transcription factor footprints. The study of the most prominent open regions showed that 75% were in transcriptionally active promoters or introns, supporting their involvement in active transcription. Lhb, Cga, and Egr1 showed significantly open chromatin over their promoters. While Fshb was closed over its promoter, several discrete significantly open regions were found at -40 to -90 kb, which may represent novel upstream enhancers. Chromatin accessibility determined by ATAC-seq was associated with high levels of gene expression determined by RNA-seq. We obtained high-quality single-cell Gel bead-in-Emulsion Drop-seq transcriptome data, with an average of >4,000 expressed genes/cell, from 1,992 vehicle- and 1,889 GnRH-treated cells. While the individual cell expression patterns showed high cell-to-cell variation, representing both biological and measurement variation, the average expression patterns correlated well with bulk RNA-seq data. Computational assignment of each cell to its precise cell cycle phase showed that the response to GnRH was unaffected by cell cycle. To our knowledge, this study represents the first genome-wide epigenetic and single-cell transcriptomic characterization of this important gonadotrope model. The data have been deposited publicly and should provide a resource for hypothesis generation and further study.

Suppression of Adaptive Responses to Targeted Cancer Therapy by Transcriptional Repression.

Acquired drug resistance is a major factor limiting the effectiveness of targeted cancer therapies. Targeting tumors with kinase inhibitors induces complex adaptive programs that promote the persistence of a fraction of the original cell population, facilitating the eventual outgrowth of inhibitor-resistant tumor clones. We show that the addition of a newly identified CDK7/12 inhibitor, THZ1, to targeted therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in diverse cellular and in vivo cancer models. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant, which THZ1 can exploit by blocking dynamic transcriptional responses, promoting remodeling of enhancers and key signaling outputs required for tumor cell survival in the setting of targeted therapy. These findings suggest that the addition of THZ1 to targeted therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations.Significance: CDK7/12 inhibition prevents active enhancer formation at genes, promoting resistance emergence in response to targeted therapy, and impedes the engagement of transcriptional programs required for tumor cell survival. CDK7/12 inhibition in combination with targeted cancer therapies may serve as a therapeutic paradigm for enhancing the effectiveness of targeted therapies. Cancer Discov; 8(1); 59-73. ©2017 AACR.See related commentary by Carugo and Draetta, p. 17This article is highlighted in the In This Issue feature, p. 1.

Integrin alpha 11 in the regulation of the myofibroblast phenotype: implications for fibrotic diseases.

Tissue fibrosis, characterized by excessive accumulation of aberrant extracellular matrix (ECM) produced by myofibroblasts, is a growing cause of mortality worldwide. Understanding the factors that induce myofibroblastic differentiation is paramount to prevent or reverse the fibrogenic process. Integrin-mediated interaction between the ECM and cytoskeleton promotes myofibroblast differentiation. In the present study, we explored the significance of integrin alpha 11 (ITGA11), the integrin alpha subunit that selectively binds to type I collagen during tissue fibrosis in the liver, lungs and kidneys. We showed that ITGA11 was co-localized with α-smooth muscle actin-positive myofibroblasts and was correlatively induced with increasing fibrogenesis in mouse models and human fibrotic organs. Furthermore, transcriptome and protein expression analysis revealed that ITGA11 knockdown in hepatic stellate cells (liver-specific myofibroblasts) markedly reduced transforming growth factor ß-induced differentiation and fibrotic parameters. Moreover, ITGA11 knockdown dramatically altered the myofibroblast phenotype, as indicated by the loss of protrusions, attenuated adhesion and migration, and impaired contractility of collagen I matrices. Furthermore, we demonstrated that ITGA11 was regulated by the hedgehog signaling pathway, and inhibition of the hedgehog pathway reduced ITGA11 expression and fibrotic parameters in human hepatic stellate cells in vitro, in liver fibrosis mouse model in vivo and in human liver slices ex vivo. Therefore, we speculated that ITGA11 might be involved in fibrogenic signaling and might act downstream of the hedgehog signaling pathway. These findings highlight the significance of the ITGA11 receptor as a highly promising therapeutic target in organ fibrosis.

Erratum: Lkb1 inactivation drives lung cancer lineage switching governed by Polycomb Repressive Complex 2.

This corrects the article DOI: 10.1038/ncomms14922.