Deregulation Of Pathways Research Articles

High Frequency of PIK3R1 Alterations in Ovarian Cancers: Clinicopathological and Molecular Associations

Background: The phosphoinositide 3-kinase (PI3K) pathway is activated in multiple cancers. However, the significance of PIK3R1 encoding the PI3K regulatory subunit, an inhibitor of the PI3K catalytic subunit encoded by PIK3CA, in ovarian cancer development is largely unknown. Methods: Here, we investigated PIK3R1 genomic alterations and gene expression by direct sequencing and qPCR methods in 197 ovarian cancers. The results were correlated with clinicopathological and molecular variables and patient outcomes. Results: In addition to mutations (3.5%) and allelic losses (28.4%), we observed a very high frequency of decreased PIK3R1 mRNA levels in ovarian carcinomas (95.8%). Tumors with PIK3R1 mutations mostly represented low-stage cancers of endometrioid and clear-cell type. Tumors with PIK3R1 deletion and underexpression shared similar phenotypes of high-grade carcinomas (p = 0.003 and p = 0.025, respectively). Allelic loss was also associated with advanced stages (p = 0.003) and high-grade serous histotypes (p = 0.004). The PIK3R1 copy number correlated with mRNA levels (p = 0.009). PIK3R1 mutations coexisted with PTEN mutations (p = 0.041), whereas PIK3R1 deletion and underexpression were linked to PIK3CA amplification (p = 0.038 and p = 0.033, respectively). Low PIK3R1 expression diminished the probability of a complete response (OR 0.07, p = 0.03) in patients treated with platinum-based regimens. Conclusions: PIK3R1 alterations may contribute to the development of ovarian cancers with different malignant potential and molecular changes. The high frequency of PIK3R1 aberrations suggests their importance in PI3K pathway deregulation, and they may potentially serve as an alternative to PIK3CA markers for therapy with these pathway inhibitors.

Differential tumor protein expression at follicular lymphoma diagnosis reveals dysregulation of key molecular pathways associated with histological transformation

Follicular lymphoma (FL) is the most common low-grade lymphoma. Despite its indolent nature, FL carries an inherent risk of histological transformation (HT) to a more aggressive lymphoma. Existing biomarkers are insufficient to predict HT, indicating the need for more robust biological predictors. Previously, we used mass spectrometry-based proteomics to identify differentially expressed proteins in diagnostic FLs with and without subsequent HT. This study sought to further investigate identified proteins in transformation of FL, generally acting in important cellular pathways such as (i) apoptosis (BID), (ii) cell cycle (CDC26, CDK6, SRSF1, SRSF2), (iii) GTPase signaling (IQGAP2, MEK1), (iv) cytoskeletal rearrangement and cellular migration (ACTB, CD11a, MMP9, SEPT6), and (v) immune processes (CD81, IgG, MPO, PIK3AP1). We analyzed pre-therapeutic samples from 48 FL patients, either non-transforming FL (nt-FL, n = 30) or subsequently-transforming FL (st-FL, n = 18), the latter with histologically-confirmed transformation after their initial FL diagnosis. Paired high-grade lymphomas (tFL, n = 18) from the time of transformation were also analyzed. We used immunohistochemistry and digital image analysis to quantify protein levels. In all five pathway classes, several proteins were differentially expressed between either the diagnostic nt-FL and st-FL samples, or between the paired st-FL and tFL samples (p < 0.05). Interestingly, we found correlation between expression levels of several proteins, indicating a complex involvement between several pathways. Differential expression of most proteins was also associated with shorter transformation-free survival (p < 0.05). These findings emphasize underlying differences in FL biology predictive of subsequent transformation, highlighting deregulation of important interconnected cellular pathways.

YAP1 induces bladder cancer progression and promotes immune evasion through IL-6/ STAT3 pathway and CXCL deregulation.

The Hippo signaling pathway plays a key role in tumorigenesis in different cancer types. We investigated the role of the Hippo "effector" YAP1 on the tumor immune microenvironment (TIME) of urothelial carcinoma of bladder (UCB) and evaluated the efficacy of immunotherapy in the context of YAP1 signaling. We performed numerous in vitro and in vivo experiments to determine the role of YAP1 using genetic and pharmacological attenuation of YAP1 activity. Briefly, RNA sequencing was carried out with mice and human cell lines to identify novel YAP1-regulated downstream targets unbiasedly. We then experimentally confirmed that YAP1 regulates the TIME through the IL-6/STAT3 signaling pathway and varied C-X-C motif chemokine regulation. We analyzed several human sample sets to explore the TIME status in the context of YAP1 expression. Our data indicate that YAP1 attenuation decreases M2 macrophages and MDSCs in the TIME compared to YAP1 expressing cells. In summary, this study provides insights on YAP1 signaling as a driver for cancer stemness and an inducer of immunosuppressive TIME. Moreover, the therapeutic efficacy of YAP1 attenuation indicates that combined blockade of YAP1 and immune checkpoints may yield clinical value for treating UCB patients.

Metabolic Transcriptional Activation in Ulcerative Colitis Identified Through scRNA-seq Analysis.

Ulcerative colitis is a chronic inflammatory disease affecting the colon. During chronic inflammation of epithelial cells, lipid metabolism via pro-inflammatory eicosanoids is known to modify the immune response. Starting from the Mammalian Metabolic Database, the expression of metabolic enzymes was investigated in two independent cohorts from transcriptome datasets GSE38713 and GSE11223, which analyzed ulcerative colitis tissue samples from the digestive tract. In the first cohort, 145 differentially expressed enzymes were identified as significantly regulated between ulcerative colitis tissues and normal controls. Overexpressed enzymes were selected to tune an Elastic Net model in the second cohort. Using the best parameters, the model achieved a prediction accuracy for ulcerative colitis with an area under the curve (AUC) of 0.79. Twenty-two metabolic enzymes were found to be commonly overexpressed in both independent cohorts, with decreasing Elastic Net predictive coefficients as follows: LIPG (3.98), PSAT1 (3.69), PGM3 (2.74), CD38 (2.28), BLVRA (1.99), CBR3 (1.94), NT5DC2 (1.76), PHGDH (1.71), GPX7 (1.58), CASP1 (1.56), ASRGL1 (1.4), SOD3 (1.25), CHST2 (0.965), CHST11 (0.95), KYNU (0.94), PLAG2G7 (0.92), SRM (0.87), PTGS2 (0.80), LPIN1 (0.47), ME1 (0.31), PTGDS (0.14), and ADA (0.13). Functional enrichment analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database highlighted the main implications of these enzymes in cysteine and methionine metabolism (adjusted p-value = 0.01), arachidonic acid and prostaglandin metabolism (adjusted p-value = 0.01), and carbon metabolism (adjusted p-value = 0.04). A metabolic score based on the transcriptional activation of the validated twenty-two enzymes was found to be significantly greater in Ulcerative colitis samples compared to healthy donor samples (p-value = 1.52 × 10-8). A metabolic expression score was established and reflects the implications of heterogeneous metabolic pathway deregulations in the digestive tract of patients with ulcerative colitis.

C3 glomerulopathy: a kidney disease mediated by alternative pathway deregulation.

C3 glomerulopathy (C3G) is an ultra-rare complement-mediated kidney disease caused by to the deregulation of the alternative pathway (AP) of proximal complement. Consequently, all effector loops of the complement are active and can lead to pathologies, such as C3a- and C5a-mediated inflammation, C3b opsonization, surface C3b-mediated AP C3 convertase assembly, C3 cleavage product deposition in the glomerulus, and lytic C5b-9/MAC cell damage. The most common pathologic mechanisms are defective chronic alternative pathway deregulation, mostly occurring in the plasma, often causing C3 consumption, and chronic complement-mediated glomerular damage. C3G develops over several years, and loss of renal function occurs in more than 50% of patients. C3G is triggered by both genetic and autoimmune alterations. Genetic causes include mutations in individual complement genes and chromosomal variations in the form of deletions and duplications affecting genes encoding complement modulators. Many genetic aberrations result in increased AP C3 convertase activity, either due to decreased activity of regulators, increased activity of modulators, or gain-of-function mutations in genes encoding components of the convertase. Autoimmune forms of C3G do also exist. Autoantibodies target individual complement components and regulators or bind to neoepitopes exposed in the central alternative pathway C3 convertase, thereby increasing enzyme activity. Overactive AP C3 convertase is common in C3G patients. Given that C3G is a complement disease mediated by defective alternative pathway action, complement blockade is an emerging concept for therapy. Here, we summarize both the causes of C3G and the rationale for complement inhibition and list the inhibitors that are being used in the most advanced clinical trials for C3G. With several inhibitors in phase II and III trials, it is expected that effectice treatment for C3G will become availabe in the near future.

The link between amyloid β and ferroptosis pathway in Alzheimer’s disease progression

Alzheimer’s disease (AD) affects millions of people worldwide and represents the most prevalent form of dementia. Treatment strategies aiming to interfere with the formation of amyloid β (Aβ) plaques and neurofibrillary tangles (NFTs), the two major AD hallmarks, have shown modest or no effect. Recent evidence suggests that ferroptosis, a type of programmed cell death caused by iron accumulation and lipid peroxidation, contributes to AD pathogenesis. The existing link between ferroptosis and AD has been largely based on cell culture and animal studies, while evidence from human brain tissue is limited. Here we evaluate if Aβ is associated with ferroptosis pathways in post-mortem human brain tissue and whether ferroptosis inhibition could attenuate Aβ-related effects in human brain organoids. Performing positive pixel density scoring on immunohistochemically stained post-mortem Brodmann Area 17 sections revealed that the progression of AD pathology was accompanied by decreased expression of nuclear receptor co-activator 4 and glutathione peroxidase 4 in the grey matter. Differentiating between white and grey matter, allowed for a more precise understanding of the disease’s impact on different brain regions. In addition, ferroptosis inhibition prevented Aβ pathology, decreased lipid peroxidation and restored iron storage in human AD iPSCs-derived brain cortical organoids at day 50 of differentiation. Differential gene expression analysis of RNAseq of AD organoids compared to isogenic controls indicated activation of the ferroptotic pathway. This was also supported by results from untargeted proteomic analysis revealing significant changes between AD and isogenic brain organoids. Determining the causality between the development of Aβ plaques and the deregulation of molecular pathways involved in ferroptosis is crucial for developing potential therapeutic interventions.

Impaired striatal glutathione-ascorbate metabolism induces transient dopamine increase and motor dysfunction.

Identifying initial triggering events in neurodegenerative disorders is critical to developing preventive therapies. In Huntington's disease (HD), hyperdopaminergia-probably triggered by the dysfunction of the most affected neurons, indirect pathway spiny projection neurons (iSPNs)-is believed to induce hyperkinesia, an early stage HD symptom. However, how this change arises and contributes to HD pathogenesis is unclear. Here, we demonstrate that genetic disruption of iSPNs function by Ntrk2/Trkb deletion in mice results in increased striatal dopamine and midbrain dopaminergic neurons, preceding hyperkinetic dysfunction. Transcriptomic analysis of iSPNs at the pre-symptomatic stage showed de-regulation of metabolic pathways, including upregulation of Gsto2, encoding glutathione S-transferase omega-2 (GSTO2). Selectively reducing Gsto2 in iSPNs in vivo effectively prevented dopaminergic dysfunction and halted the onset and progression of hyperkinetic symptoms. This study uncovers a functional link between altered iSPN BDNF-TrkB signalling, glutathione-ascorbate metabolism and hyperdopaminergic state, underscoring the vital role of GSTO2 in maintaining dopamine balance.

Integrative study of skeletal muscle mitochondrial dysfunction in a murine pancreatic cancer-induced cachexia model

Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic cancer, is a deadly cancer, often diagnosed late and resistant to current therapies. PDAC patients are frequently affected by cachexia characterized by muscle mass and strength loss (sarcopenia) contributing to patient frailty and poor therapeutic response. This study assesses the mechanisms underlying mitochondrial remodeling in the cachectic skeletal muscle, through an integrative exploration combining functional, morphological, and omics-based evaluation of gastrocnemius muscle from KIC genetically engineered mice developing autochthonous pancreatic tumor and cachexia. Cachectic PDAC KIC mice exhibit severe sarcopenia with loss of muscle mass and strength associated with reduced muscle fiber’s size and induction of protein degradation processes. Mitochondria in PDAC atrophied muscles show reduced respiratory capacities and structural alterations, associated with deregulation of oxidative phosphorylation and mitochondrial dynamics pathways. Beyond the metabolic pathways known to be altered in sarcopenic muscle (carbohydrates, proteins, and redox), lipid and nucleic acid metabolisms are also affected. Although the number of mitochondria per cell is not altered, mitochondrial mass shows a twofold decrease and the mitochondrial DNA threefold, suggesting a defect in mitochondrial genome homeostasis. In conclusion, this work provides a framework to guide toward the most relevant targets in the clinic to limit PDAC-induced cachexia.

Integrative study of skeletal muscle mitochondrial dysfunction in a murine pancreatic cancer-induced cachexia model.

Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic cancer, is a deadly cancer, often diagnosed late and resistant to current therapies. PDAC patients are frequently affected by cachexia characterized by muscle mass and strength loss (sarcopenia) contributing to patient frailty and poor therapeutic response. This study assesses the mechanisms underlying mitochondrial remodeling in the cachectic skeletal muscle, through an integrative exploration combining functional, morphological, and omics-based evaluation of gastrocnemius muscle from KIC genetically engineered mice developing autochthonous pancreatic tumor and cachexia. Cachectic PDAC KIC mice exhibit severe sarcopenia with loss of muscle mass and strength associated with reduced muscle fiber's size and induction of protein degradation processes. Mitochondria in PDAC atrophied muscles show reduced respiratory capacities and structural alterations, associated with deregulation of oxidative phosphorylation and mitochondrial dynamics pathways. Beyond the metabolic pathways known to be altered in sarcopenic muscle (carbohydrates, proteins, and redox), lipid and nucleic acid metabolisms are also affected. Although the number of mitochondria per cell is not altered, mitochondrial mass shows a twofold decrease and the mitochondrial DNA threefold, suggesting a defect in mitochondrial genome homeostasis. In conclusion, this work provides a framework to guide toward the most relevant targets in the clinic to limit PDAC-induced cachexia.

Cyclin C promotes development and progression of B-cell acute lymphoblastic leukemia by counteracting p53-mediated stress responses.

Despite major therapeutic advances in the treatment of acute lymphoblastic leukemia (ALL), resistances and long-term toxicities still pose significant challenges. Cyclins and their associated cyclin-dependent kinases are one focus of cancer research when looking for targeted therapies. We discovered cyclin C as a key factor for B-ALL development and maintenance. While cyclin C is non-essential for normal hematopoiesis, CcncΔ/Δ BCR::ABL1+ B-ALL cells fail to elicit leukemia in mice. RNA sequencing experiments revealed a p53 pathway deregulation in CcncΔ/Δ BCR::ABL1+ cells resulting in the incapability of the leukemic cells to adequately respond to stress. A genome-wide CRISPR/Cas9 loss-of-function screen supplemented with additional knock-outs unveiled a dependency of human B-lymphoid cell lines on CCNC. High cyclin C levels in B-cell precursor (BCP) ALL patients were associated with poor event-free survival and increased risk of early disease recurrence after remission. Our findings highlight cyclin C as potential therapeutic target for B-ALL, particularly to enhance cancer cell sensitivity to stress and chemotherapy.

Targeting heparanase/heparan sulfate proteoglycans by non‐anticoagulant heparins: Opportunities for innovative therapeutic approaches in sarcomas

AbstractSarcomas are a heterogeneous group of aggressive mesenchymal malignancies. They account for 1% of all tumors in the general population and 15–20% in pediatric age and young adults. Despite differences in histology and pathobiology, the diverse types of sarcomas are traditionally managed with a common multi‐modal approach including surgery, radiotherapy, and aggressive polychemotherapy. Unfortunately, the prognosis for advanced or recurrent disease remains poor. Moreover, the disease rarity and a high cellular, molecular, and genetic/epigenetic heterogeneity make identification of therapeutic targets challenging. Therefore it remains an urgent need to identify effective therapies to improve patients' outcome. Common or peculiar biological motifs including deregulation of growth factor signaling, proangiogenic and promigratory pathways, tumor‐microenviroment interactions, transcriptional and epigenetic machinery, and differentiation program, provide actionable dependencies exploitable for therapeutic intervention. Among these, a deregulated heparan sulfate proteoglycan system due to aberrant expression of key components as well as structural/functional modifications mediated by endosulfatases and the endoβ‐d‐glycosidase heparanase, is emerging as a crucial player in tumor growth and progression and as a valuable therapeutic target across different sarcoma subtypes. In preclinical studies, non‐anticoagulant heparins have been shown to counteract the growth and metastatic dissemination of various sarcoma models according to their heparan sulfate mimetic and anti‐heparanase activities. Heparin derivatives also improved the anti‐sarcoma efficacy of molecularly targeted agents and cytotoxic drugs. In this minireview, we summarize the current knowledge about the interplay between the heparanase/heparan sulfate proteoglycan system and pathways involved in sarcomagenesis and disease progression. We illustrate the current understanding of the mechanisms of action of non‐anticoagulant heparins and the contribution of their anti‐heparanase, anti‐receptor tyrosine kinase, and likely immunomodulatory activities to their anti‐sarcoma effects. Finally, we discuss a few aspects worthy of exploration highlighting how elucidation of mechanisms underpinning antitumor activities of non‐anticoagulant heparin derivatives in the different sarcoma biological contexts may suggest new vulnerabilities and therapeutic approaches.

Molecular correlates of social adversity in breast cancer.

48 Background: Neighborhood disadvantage (ND) is associated with shorter breast cancer (BCa) survival independent of individual, tumor, and treatment factors, suggesting more aggressive tumor biology in women from disadvantaged neighborhoods. This study evaluates how differential DNA methylation (DNAm), gene expression, and biologic pathways are wired with each other to delineate the regulatory landscape of ND on BCa. Methods: We leveraged 55 geocoded ER+/HER2- BCa samples from Hispanic White women enrolled in a prospective genomic-epidemiologic cohort study. Objective ND was evaluated using the Area Deprivation Index (ADI) and subjective ND was evaluated using the patient-reported Neighborhood Social Environment Adversity Survey and the Everyday Expanded Discrimination Survey. We analyzed the association between ND and (1) DNAm, (2) RNA transcription and miRNAs, and (3) blood concentration levels of DNAm co-factors (B12 and folate) from the same patient. To evaluate how the DNAm/expressed pathways are wired with each other to delineate the regulatory landscape of ND in these tumors, we performed correlation analyses among CpGs, genes, and miRNAs in the same topologically associated domain (TAD). We used Spearman correlation as our metric and adjusted the resulting p-values to FDR values. Results: The cohort was divided into low ND (ADI&lt;5; 31%) and a high ND (ADI&gt;=5; 69%). There were no significant differences between groups by age, race/ethnicity, genetic ancestry, BMI, smoking/alcohol, subtype, stage, or OncotypeDX scores. We discovered that high ND exhibits epigenetic deregulation of immune pathways, consistent with our findings of lower circulating B12 in high ND, suggesting activation of immune pathways through reduced systemic availability of methyl donors. RNA-seq identified higher tumor infiltration of immune cells in patients from high ND (e.g., Interferon alpha and gamma responses and inflammatory responses) consistent with aggressive biology. Estrogen response genes were downregulated suggesting that patients from high ND may develop estrogen-resistant tumors. Higher subjective ND scores discovered epigenetic changes on cell adhesion and calcium signaling genes, along with gene expression of E2F targets and cell cycle’s G2M checkpoint, indicative of a more proliferative/stemness signature. TAD analysis discovered significant developmental, immune, and signaling pathways when correlating DNAm with gene expression (e.g., estrogen response and EMT). Conclusions: In this multi-omic matched cohort, we discovered differentially methylated/expressed pathways, consistent with aggressive biology, wired with each other to identify a novel regulatory landscape of ND on BCa. These findings can inform interventions such as improved access to healthy nutrition (B12) in ND/food deserts or targeted stress-reduction interventions based on our survey findings to ultimately reverse aggressive tumor biology and reduce BCa disparities by ND.

Caspase 3 Expression Profiles in Meningioma Subtypes Based on Tissue Microarray Analysis.

Concerning primary central nervous system neoplasms, meningiomas demonstrate the most common type in adults worldwide. Deregulation of apoptotic pathways in malignancies, including meningiomas, is correlated with chemoresistance and poor prognosis. Caspases represent crucial proteins that induce cell apoptosis. This study aimed to correlate caspase 3 protein expression levels to meningioma clinic-pathological features. A set of fifty (n=50) meningioma lesions was included in the current analysis including a broad spectrum of histopathological subtypes (meningotheliomatous, psammomatus, transitional, fibrous, angiomatous, microcystic, atypical and anaplastic). Immunohistochemistry was implemented on tissue microarray cores of selected paraffin blocks by applying an anti-caspase 3 antibody. Additionally, an image analysis protocol was also performed in the corresponding immunostained slides. Caspase 3 protein over-expression was detected in 17/50 (34%) cases, whereas the remaining 33 cases (66%) were characterized by medium to low levels of the molecule. Caspase 3 expression was statistically significantly associated with the grade of the analyzed tumors and the mitotic index (p=0.002, p=0.001, respectively). Caspase 3 expression status was also correlated with the histotype of the selected meningiomas (p=0.016). Caspase 3 demonstrated low expression levels in a significant subset of the examined meningiomas correlated with differentiation grade, mitotic activity, and partially with specific histotypes. Agents that could enhance caspase 3 expression - inducing its apoptotic activity - represent a very promising area in oncology for developing novel treatment regimens.

New insights into PSAT1 as a therapeutic target for myelodysplastic syndrome (MDS).

The metabolomic landscape in myelodysplastic syndrome (MDS) is highly deregulated and presents promising avenues for understanding disease pathogenesis and potential molecular dependencies. Here, we evaluated the transcriptomic landscape in MDS in multiple independent studies focusing more on metabolomics pathways. Identifying molecular dependencies will pave the way for a more precise disease stratification as well as the development of novel personalized treatment strategies. The study adopted a retrospective, cross-sectional approach, utilizing transcriptomic data from multiple MDS studies. The transcriptomic data were then subjected to comprehensive analyses, including differential gene expression, gene enrichment analysis, gene co-expression analysis, protein-protein interaction analyses, and survival analyses. PSAT1 showed a significant upregulation profile in MDS patients. This observed upregulation is correlated with the deregulation of immune-related pathways in MDS samples. This observation suggests a novel role for PSAT1 in immune modulation and potentially in augmenting immune evasion, which may lead to poor prognosis. This was evident in other tumors in the TCGA database, where cancer patients with high PSAT1 expression have a shorter overall survival. This study unveils a novel potential therapeutic avenue in MDS. Identifying the role of the PSAT1 gene sheds light on the disease's intricate biology, highlighting the ongoing cross-talk between metabolism and immune regulation, which may pave the way for innovative treatment modalities.

Distinctive field effects of smoking and lung cancer case-control status on bronchial basal cell growth and signaling

RationalBasal cells (BCs) are bronchial progenitor/stem cells that can regenerate injured airway that, in smokers, may undergo malignant transformation. As a model for early stages of lung carcinogenesis, we set out to characterize cytologically normal BC outgrowths from never-smokers and ever-smokers without cancers (controls), as well as from the normal epithelial “field” of ever-smokers with anatomically remote cancers, including lung adenocarcinoma (LUAD) and squamous cell carcinoma (LUSC) (cases).MethodsPrimary BCs were cultured and expanded from endobronchial brushings taken remote from the site of clinical or visible lesions/tumors. Donor subgroups were tested for growth, morphology, and underlying molecular features by qRT-PCR, RNAseq, flow cytometry, immunofluorescence, and immunoblot.Results(a) the BC population includes epithelial cell adhesion molecule (EpCAM) positive and negative cell subsets; (b) smoking reduced overall BC proliferation corresponding with a 2.6-fold reduction in the EpCAMpos/ITGA6 pos/CD24pos stem cell fraction; (c) LUSC donor cells demonstrated up to 2.8-fold increase in dysmorphic BCs; and (d) cells procured from LUAD patients displayed increased proliferation and S-phase cell cycle fractions. These differences corresponded with: (i) disparate NOTCH1/NOTCH2 transcript expression and altered expression of potential downstream (ii) E-cadherin (CDH1), tumor protein-63 (TP63), secretoglobin family 1a member 1 (SCGB1A1), and Hairy/enhancer-of-split related with YRPW motif 1 (HEY1); and (iii) reduced EPCAM and increased NK2 homeobox-1 (NKX2-1) mRNA expression in LUAD donor BCs.ConclusionsThese and other findings demonstrate impacts of donor age, smoking, and lung cancer case-control status on BC phenotypic and molecular traits and may suggest Notch signaling pathway deregulation during early human lung cancer pathogenesis.

Biomarkers of lung congestion and injury in acute heart failure.

Acute heart failure (AHF) classification and management are primarily based on lung congestion and/or hypoperfusion. The quantification of the vascular and tissue lung damage is not standard practice though biomarkers of lung injury may play a relevant role in this context. Haemodynamic stress promotes alveolar and vascular derangement with loss of functional units, impaired lung capillary permeability and fluid swelling. This culminates in a remodelling process with activation of inflammatory and cytokines pathways. Four families of lung surfactant proteins (i.e., SP-A, SP-B, SP-C, and SP-D), essential for the membrane biology and integrity are released by alveolar type II pneumocites. With deregulation of fluid handling and gas exchange pathways, SPs become sensitive markers of lung injury. We report the pathobiology of lung damage; the pathophysiological and clinical implications of alveolar SPs along with the newest evidence for some classical HF biomarkers that have also shown to reflect a vascular and/or a tissue lung-related activity.

Integrative Analysis of Multi-Omics Data to Identify Deregulated Molecular Pathways and Druggable Targets in Chronic Lymphocytic Leukemia.

Chronic Lymphocytic Leukemia (CLL) is the most common B-cell malignancy in the Western world, characterized by frequent relapses despite temporary remissions. Our study integrated publicly available proteomic, transcriptomic, and patient survival datasets to identify key differences between healthy and CLL samples. We exposed approximately 1000 proteins that differentiate healthy from cancerous cells, with 608 upregulated and 415 downregulated in CLL cases. Notable upregulated proteins include YEATS2 (an epigenetic regulator), PIGR (Polymeric immunoglobulin receptor), and SNRPA (a splicing factor), which may serve as prognostic biomarkers for this disease. Key pathways implicated in CLL progression involve RNA processing, stress resistance, and immune response deficits. Furthermore, we identified three existing drugs-Bosutinib, Vorinostat, and Panobinostat-for potential further investigation in drug repurposing in CLL. We also found limited correlation between transcriptomic and proteomic data, emphasizing the importance of proteomics in understanding gene expression regulation mechanisms. This generally known disparity highlights once again that mRNA levels do not accurately predict protein abundance due to many regulatory factors, such as protein degradation, post-transcriptional modifications, and differing rates of translation. These results demonstrate the value of integrating omics data to uncover deregulated proteins and pathways in cancer and suggest new therapeutic avenues for CLL.

Identification of resistance mechanisms to small-molecule inhibition of TEAD-regulated transcription

The Hippo tumor suppressor pathway controls transcription by regulating nuclear abundance of YAP and TAZ, which activate transcription with the TEAD1-TEAD4 DNA-binding proteins. Recently, several small-molecule inhibitors of YAP and TEADs have been reported, with some entering clinical trials for different cancers with Hippo pathway deregulation, most notably, mesothelioma. Using genome-wide CRISPR/Cas9 screens we reveal that mutations in genes from the Hippo, MAPK, and JAK-STAT signaling pathways all modulate the response of mesothelioma cell lines to TEAD palmitoylation inhibitors. By exploring gene expression programs of mutant cells, we find that MAPK pathway hyperactivation confers resistance to TEAD inhibition by reinstating expression of a subset of YAP/TAZ target genes. Consistent with this, combined inhibition of TEAD and the MAPK kinase MEK, synergistically blocks proliferation of multiple mesothelioma and lung cancer cell lines and more potently reduces the growth of patient-derived lung cancer xenografts in vivo. Collectively, we reveal mechanisms by which cells can overcome small-molecule inhibition of TEAD palmitoylation and potential strategies to enhance the anti-tumor activity of emerging Hippo pathway targeted therapies.

Emerging Role of Hippo-YAP (Yes-Associated Protein)/TAZ (Transcriptional Coactivator with PDZ-Binding Motif) Pathway Dysregulation in Renal Cell Carcinoma Progression.

Although Hippo-YAP/TAZ pathway involvement has been extensively studied in the development of certain cancers, the involvement of this cascade in kidney cancer progression is not well-established and, therefore, will be the focus of this review. Renal cell carcinoma (RCC), the most prevalent kidney tumor subtype, has a poor prognosis and a high mortality rate. Core Hippo signaling inactivation (e.g., LATS kinases) leads to the nuclear translocation of YAP/TAZ where they bind to co-transcriptional factors such as TEAD promoting transcription of genes which initiates various fibrotic and neoplastic diseases. Loss of expression of LATS1/2 kinase and activation of YAP/TAZ correlates with poor survival in RCC patients. Renal-specific ablation of LATS1 in mice leads to the spontaneous development of several subtypes of RCC in a YAP/TAZ-dependent manner. Genetic and pharmacological inactivation of YAP/TAZ reverses the oncogenic potential in LATS1-deficient mice, highlighting the therapeutic benefit of network targeting in RCC. Here, we explore the unique upstream controls and downstream consequences of the Hippo-YAP/TAZ pathway deregulation in renal cancer. This review critically evaluates the current literature on the role of the Hippo pathway in RCC progression and highlights the recent scientific evidence designating YAP/TAZ as novel therapeutic targets against kidney cancer.

Dual targeting of histone deacetylases and MYC as potential treatment strategy for H3-K27M pediatric gliomas.

Diffuse midline gliomas (DMGs) are aggressive and fatal pediatric tumors of the central nervous system that are highly resistant to treatments. Lysine to methionine substitution of residue 27 on histone H3 (H3-K27M) is a driver mutation in DMGs, reshaping the epigenetic landscape of these cells to promote tumorigenesis. H3-K27M gliomas are characterized by deregulation of histone acetylation and methylation pathways, as well as the oncogenic MYC pathway. In search of effective treatment, we examined the therapeutic potential of dual targeting of histone deacetylases (HDACs) and MYC in these tumors. Treatment of H3-K27M patient-derived cells with Sulfopin, an inhibitor shown to block MYC-driven tumors in vivo, in combination with the HDAC inhibitor Vorinostat, resulted in substantial decrease in cell viability. Moreover, transcriptome and epigenome profiling revealed synergistic effect of this drug combination in downregulation of prominent oncogenic pathways such as mTOR. Finally, in vivo studies of patient-derived orthotopic xenograft models showed significant tumor growth reduction in mice treated with the drug combination. These results highlight the combined treatment with PIN1 and HDAC inhibitors as a promising therapeutic approach for these aggressive tumors.