Tumorigenic Process Research Articles

FBXO32 targets PHPT1 for ubiquitination to regulate the growth of EGFR mutant lung cancer.

Phosphohistidine phosphatase 1 (PHPT1) is an oncogene that has been reported to participate in multiple tumorigenic processes. As yet, however, the role of PHPT1 in lung cancer development remains uncharacterized. RNA sequencing assay and 18 pairs of tumor and normal tissues from patients were analyzed to reveal the upregulation of PHPT1 in lung cancer, followed by confirming the biological function in vitro and in vivo. Next, Gene Set Enrichment Analysis, lung cancer samples, apoptosis assay, mass spectrometry experiments and western blotting were used to investigate the molecular mechanism underlying PHPT1 driven progression in epidermal growth factor receptor (EGFR)-mutant lung cancer. Finally, we performed cellular and animal experiments to explore the tumor suppressive function of F-box protein 32 (FBXO32). We found that PHPT1 is overexpressed in lung cancer patients and correlates with a poor overall survival. In addition, we found that the expression of PHPT1 is elevated in EGFR-mutant lung cancer cells and primary patient samples. Inhibition of PHPT1 expression in EGFR mutant lung cancer cells significantly decreased their proliferation and clonogenicity, and suppressed their in vitro tumor growth. Mechanistic studies revealed that activation of the ERK/MAPK pathway is driven by PHPT1. PHPT1 is required for maintaining drug resistance to erlotinib in EGFR mutant lung cancer cells. We found that FBXO32 acts as an E3 ubiquitin ligase for PHPT1, and that knockdown of FBXO32 leads to PHPT1 accumulation, activation of the ERK/MAPK pathway and promotion of the proliferation, clonogenicity and growth of lung cancer cells. Our findings indicate that PHPT1 may serve as a biomarker and therapeutic target for acquired erlotinib resistance in lung cancer patients carrying EGFR mutations.

The Impact of Epithelial–Mesenchymal Transition and Metformin on Pancreatic Cancer Chemoresistance: A Pathway towards Individualized Therapy

Globally, pancreatic ductal adenocarcinoma remains among the most aggressive forms of neoplastic diseases, having a dismal prognostic outcome. Recent findings elucidated that epithelial–mesenchymal transition (EMT) can play an important role in pancreatic tumorigenic processes, as it contributes to the manifestation of malignant proliferative masses, which impede adequate drug delivery. An organized literature search with PubMed, Scopus, Microsoft Academic and the Cochrane library was performed for articles published in English from 2011 to 2021 to review and summarize the latest updates and knowledge on the current understanding of EMT and its implications for tumorigenesis and chemoresistance. Furthermore, in the present paper, we investigate the recent findings on metformin as a possible neoadjuvant chemotherapy agent, which affects EMT progression and potentially provides superior oncological outcomes for PDAC patients. Our main conclusions indicate that selectively suppressing EMT in pancreatic cancer cells has a promising therapeutic utility by selectively targeting the chemotherapy-resistant sub-population of cancer stem cells, inhibiting tumor growth via EMT pathways and thereby improving remission in PDAC patients. Moreover, given that TGF-β1-driven EMT generates the migration of tumor-initiating cells by directly linking the acquisition of abnormal cellular motility with the maintenance of tumor initiating potency, the chemoprevention of TGF-β1-induced EMT may have promising clinical applications in the therapeutic management of PDAC outcomes.

Epigenetic Regulation: A Link between Inflammation and Carcinogenesis.

Simple SummaryEpigenetics encompasses all the modifications that occur within cells that are independent of gene mutations. The environment is the main influencer of these alterations. It is well known that a proinflammatory environment can promote and sustain the carcinogenic process and that this environment induces epigenetic alterations. In this review, we will report how a proinflammatory microenvironment that encircles the tumor core can be responsible for the induction of epigenetic drift.Epigenetics encompasses a group of dynamic, reversible, and heritable modifications that occur within cells that are independent of gene mutations. These alterations are highly influenced by the environment, from the environment that surrounds the human being to the internal microenvironments located within tissues and cells. The ways that pigenetic modifications promote the initiation of the tumorigenic process have been widely demonstrated. Similarly, it is well known that carcinogenesis is supported and prompted by a strong proinflammatory environment. In this review, we introduce our report of a proinflammatory microenvironment that encircles the tumor core but can be responsible for the induction of epigenetic drift. At the same time, cancer cells can alter their epigenetic profile to generate a positive loop in the promotion of the inflammatory process. Therefore, an in-depth understanding of the epigenetic networks between the tumor microenvironment and cancer cells might highlight new targetable mechanisms that could prevent tumor progression.

The microenvironment of pituitary adenomas: biological, clinical and therapeutical implications.

The microenvironment ofpituitary adenomas (PAs) includes a range of non-tumoral cells, such as immune and stromal cells, as well as cell signaling molecules such as cytokines, chemokines and growth factors, which surround pituitary tumor cells and may modulate tumor initiation, progression, invasion, angiogenesis and other tumorigenic processes. The microenvironment of PAs has been actively investigated over the last years, with several immune and stromal cell populations, as well as different cytokines, chemokines and growth factors being recently characterized in PAs. Moreover, key microenvironment-related genes as well as immune-related molecules and pathways have been investigated, with immune check point regulators emerging as promising targets for immunotherapy. Understanding the microenvironment of PAs will contribute to a deeper knowledge of the complex biology of PAs, as well as will provide developments in terms of diagnosis, clinical management and ultimately treatment of patients with aggressive and/or refractory PAs.

Gynecologic Cancer, Cancer Stem Cells, and Possible Targeted Therapies.

Gynecologic cancer is one of the main causes of death in women. In this type of cancer, several molecules (oncogenes or tumor suppressor genes) contribute to the tumorigenic process, invasion, metastasis, and resistance to treatment. Based on recent evidence, the detection of molecular changes in these genes could have clinical importance for the early detection and evaluation of tumor grade, as well as the selection of targeted treatment. Researchers have recently focused on cancer stem cells (CSCs) in the treatment of gynecologic cancer because of their ability to induce progression and recurrence of malignancy. This has highlighted the importance of a better understanding of the molecular basis of CSCs. The purpose of this review is to focus on the molecular mechanism of gynecologic cancer and the role of CSCs to discover more specific therapeutic approaches to gynecologic cancer treatment.

Abstract P2-05-02: Low molecular weight cyclin E facilitate replication stress tolerance in breast cancer development

Abstract Low Molecular Weight Cyclin E (LMW-E) are the tumor specific, oncogenic forms of cyclin E that are post translationally generated by neutrophil elastase (NE) mediated cleavage of the 50 KDa full-length cyclin E1 (FL-cycE, encoded by CCNE1 gene). While FL-cycE localizes mainly to the cell nucleus, LMW-E lack the N-terminus nuclear localization signal and are detected in both the nucleus and cytoplasm. Compared to FL-cycE, LMW-E exhibit longer half-life and higher affinity to their kinase partner CDK2 and are resistant to natural CDK inhibitors such as p21 and p27. It is currently assumed that LMW-E drive the tumorigenic process by promoting G1/S cell cycle transition and accelerating mitotic exit. Here we report that LMW-E overexpression also promotes genomic instability by deregulating DNA replication in a CDC6 dependent manner. To this end, we developed an immunohistochemistry (IHC) assay with a cyclin E antibody that can identify LMW-E expressing tumors and examined the association of genetic instability of each tumor with LMW-E status in 2 different cohorts of breast cancer patients. Cohort 1 is a retrospective cohort of 725 patients with stage I-II breast cancer treated at MD Anderson (Houston, TX) between 1985 and 1999. Cohort 2 is a prospective cohort of 85 patients with stage I-II breast cancer who enrolled in our study at MD Anderson between January 2000 and June 2010. Our results show that positive LMW-E status in stage 1 or 2 breast cancer patients correlates with increasing copy number variations, as identified by Molecular Inversion Probe (MIP) in cohort 1 and somatic mutations, as identified by Whole Exome Sequencing (WES) in cohort 2. Second, using immortalized human mammary epithelial cells (hMECs) engineered to express doxycycline inducible LMW-E or FL-cycE in CCNE1 knock-out background, we found that FL-cycE over-expression leads to DNA damage, cell cycle arrest and cell death. LMW-E overexpression, on the other hand, facilitates cell proliferation with damaged DNA, resulting in multi-nuclei and micro-nuclei formation in daughter cells. Third, overexpression of FL-cycE reduces chromatin bound MCM complex, while LMW-E overexpression promotes the chromatin loading of pre-replication complex including MCMs. Lastly, we show that LMW-E but not FL-cycE is the major form of cyclin E that binds to the chromatin. Specifically, in both LMW-Einducible hMECs and LMW-Ehighbreast tumor cell lines, CDC6 is required for the nuclear translocation and chromatin loading of LMW-E. Our findings have revealed the unique oncogenic function of LMW-E in deregulating replication licensing, promoting replication stress tolerance and genomic instability that fuels tumor development. These findings also provide potential novel therapeutic strategies for treating LMW-Ehigh breast tumors, who do not respond to the current standard of care therapies. Citation Format: Mi Li, Kwang Huei Low, Tuyen Bui, Kelly K Hunt, Khandan Keyomarsi. Low molecular weight cyclin E facilitate replication stress tolerance in breast cancer development [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-05-02.

MicroRNA Interrelated Epithelial Mesenchymal Transition (EMT) in Glioblastoma.

MicroRNAs (miRNA) are small non-coding RNAs that are 20–23 nucleotides in length, functioning as regulators of oncogenes or tumor suppressor genes. They are molecular modulators that regulate gene expression by suppressing gene translation through gene silencing/degradation, or by promoting translation of messenger RNA (mRNA) into proteins. Circulating miRNAs have attracted attention as possible prognostic markers of cancer, which could aid in the early detection of the disease. Epithelial to mesenchymal transition (EMT) has been implicated in tumorigenic processes, primarily by promoting tumor invasiveness and metastatic activity; this is a process that could be manipulated to halt or prevent brain metastasis. Studies show that miRNAs influence the function of EMT in glioblastomas. Thus, miRNA-related EMT can be exploited as a potential therapeutic target in glioblastomas. This review points out the interrelation between miRNA and EMT signatures, and how they can be used as reliable molecular signatures for diagnostic purposes or targeted therapy in glioblastomas.

Genome-Wide Methylation Profiling of lncRNAs Reveals a Novel Progression-Related and Prognostic Marker for Colorectal Cancer.

Sporadic colorectal cancer (CRC) develops principally through the adenoma-carcinoma sequence. Previous studies revealed that DNA methylation alterations play a significant role in colorectal neoplastic transformation. On the other hand, long noncoding RNAs (lncRNAs) have been identified to be associated with some critical tumorigenic processes of CRC. Accumulating evidence indicates more intricate regulatory relationships between DNA methylation and lncRNAs in CRC. Nevertheless, the methylation alterations of lncRNAs at different stages of colorectal carcinogenesis based on a genome-wide scale remain elusive. Therefore, in this study, we first used an Illumina MethylationEPIC BeadChip (850K array) to identify the methylation status of lncRNAs in 12 pairs of colorectal cancerous and adjacent normal tissues from cohort I, followed by cross-validation with The Cancer Genome Atlas (TCGA) database and the Gene Expression Omnibus (GEO) database. Then, the abnormal hypermethylation of candidate genes in colorectal lesions was successfully confirmed by MassARRAY EpiTYPER in cohort II including 48 CRC patients, and cohort III including 286 CRC patients, 81 advanced adenoma (AA) patients and 81 nonadvanced adenoma (NAA) patients. DLX6-AS1 hypermethylation was detected at all stages of colorectal neoplasms and occurred as early as the NAA stage during colorectal neoplastic progression. The methylation levels were significantly higher in the comparisons of CRC vs. NAA (P < 0.001) and AA vs. NAA (P = 0.004). Moreover, the hypermethylation of DLX6-AS1 promoter was also found in cell-free DNA samples collected from CRC patients as compared to healthy controls (P adj = 0.003). Multivariate Cox proportional hazards regression analysis revealed DLX6-AS1 promoter hypermethylation was independently associated with poorer disease-specific survival (HR = 2.52, 95% CI: 1.35-4.69, P = 0.004) and overall survival (HR = 1.64, 95% CI: 1.02-2.64, P = 0.042) in CRC patients. Finally, a nomogram was constructed and verified by a calibration curve to predict the survival probability of individual CRC patients (C-index: 0.789). Our findings indicate DLX6-AS1 hypermethylation might be an early event during colorectal carcinogenesis and has the potential to be a novel biomarker for CRC progression and prognosis.

P53-Induced LINC00893 Regulates RBFOX2 Stability to Suppress Gastric Cancer Progression.

Long noncoding RNAs (lncRNAs) have been reported to regulate diverse tumorigenic processes. However, little is known about long intergenic non-protein coding RNA 00893 (LINC00893) and its role in gastric cancer (GC). Herein we investigated its biological functions and molecular mechanism in GC. LINC00893 was decreased in GC tissues but significantly elevated in AGS cells after treatment with Nutlin-3. In GC patients, it was found that low expression of LINC00893 was correlated with tumor growth, metastasis and poor survival. Functionally, overexpression of LINC00893 suppressed the proliferation, migration and invasion of GC cells. Mechanistically, LINC00893 regulated the expression of epithelial-mesenchymal transition (EMT)-related proteins by binding to RNA binding fox-1 homolog 2 (RBFOX2) and promoting its ubiquitin-mediated degradation, thus suppressing the EMT and related functions of GC. In addition, the transcription factor p53 can regulate the expression of LINC00893 in an indirect way. Taken together, these results suggested that LINC00893 regulated by p53 repressed GC proliferation, migration and invasion by functioning as a binding site for RBFOX2 to regulate its stability and the expression of EMT-related proteins. LINC00893 acts as a tumor-inhibiting lncRNA that is induced by p53 in GC and regulates EMT by binding to RBFOX2, thus providing a novel experimental basis for the clinical treatment of GC.

Decellularized Colorectal Cancer Matrices as Bioactive Scaffolds for Studying Tumor-Stroma Interactions.

Simple SummaryColorectal cancer is an increasingly prevalent disease that accounts for substantial mortality and morbidity and is responsible for an impaired quality of life. This scenario highlights the urgent need to better understand the biological mechanisms underlying colorectal cancer onset, progression and spread to improve diagnosis and establish tailored therapeutic strategies. Therefore, understanding tumor microenvironment dynamics could be crucial, since it is where the tumorigenic process begins and evolves under the heavy influence of the complex crosstalk between all elements: the cellular component (cancer cells and the non-malignant stromal cells), the non-cellular component (extracellular matrix) and the interstitial fluids. Bioengineered models that can accurately mimic the tumor microenvironment are the golden key to comprehending disease biology. Therefore, the focus of this review addresses the advanced 3D-based models of the decellularized extracellular matrix as high-throughput strategies in colorectal cancer research that potentially fill some of the gaps between in vitro two-dimensional and in vivo models.More than a physical structure providing support to tissues, the extracellular matrix (ECM) is a complex and dynamic network of macromolecules that modulates the behavior of both cancer cells and associated stromal cells of the tumor microenvironment (TME). Over the last few years, several efforts have been made to develop new models that accurately mimic the interconnections within the TME and specifically the biomechanical and biomolecular complexity of the tumor ECM. Particularly in colorectal cancer, the ECM is highly remodeled and disorganized and constitutes a key component that affects cancer hallmarks, such as cell differentiation, proliferation, angiogenesis, invasion and metastasis. Therefore, several scaffolds produced from natural and/or synthetic polymers and ceramics have been used in 3D biomimetic strategies for colorectal cancer research. Nevertheless, decellularized ECM from colorectal tumors is a unique model that offers the maintenance of native ECM architecture and molecular composition. This review will focus on innovative and advanced 3D-based models of decellularized ECM as high-throughput strategies in colorectal cancer research that potentially fill some of the gaps between in vitro 2D and in vivo models. Our aim is to highlight the need for strategies that accurately mimic the TME for precision medicine and for studying the pathophysiology of the disease.

Altered BMP2/4 Signaling in Stem Cells and Their Niche: Different Cancers but Similar Mechanisms, the Example of Myeloid Leukemia and Breast Cancer.

Understanding mechanisms of cancer development is mandatory for disease prevention and management. In healthy tissue, the microenvironment or niche governs stem cell fate by regulating the availability of soluble molecules, cell-cell contacts, cell-matrix interactions, and physical constraints. Gaining insight into the biology of the stem cell microenvironment is of utmost importance, since it plays a role at all stages of tumorigenesis, from (stem) cell transformation to tumor escape. In this context, BMPs (Bone Morphogenetic Proteins), are key mediators of stem cell regulation in both embryonic and adult organs such as hematopoietic, neural and epithelial tissues. BMPs directly regulate the niche and stem cells residing within. Among them, BMP2 and BMP4 emerged as master regulators of normal and tumorigenic processes. Recently, a number of studies unraveled important mechanisms that sustain cell transformation related to dysregulations of the BMP pathway in stem cells and their niche (including exposure to pollutants such as bisphenols). Furthermore, a direct link between BMP2/BMP4 binding to BMP type 1 receptors and the emergence and expansion of cancer stem cells was unveiled. In addition, a chronic exposure of normal stem cells to abnormal BMP signals contributes to the emergence of cancer stem cells, or to disease progression independently of the initial transforming event. In this review, we will illustrate how the regulation of stem cells and their microenvironment becomes dysfunctional in cancer via the hijacking of BMP signaling with main examples in myeloid leukemia and breast cancers.

Mitochondrial 1555 G>A variant as a potential risk factor for childhood glioblastoma.

BackgroundChildhood glioblastoma multiforme (GBM) is a highly aggressive disease with low survival, and its etiology, especially concerning germline genetic risk, is poorly understood. Mitochondria play a key role in putative tumorigenic processes relating to cellular oxidative metabolism, and mitochondrial DNA variants were not previously assessed for association with pediatric brain tumor risk.MethodsWe conducted an analysis of 675 mitochondrial DNA variants in 90 childhood GBM cases and 2789 controls to identify enrichment of mitochondrial variant associated with GBM risk. We also performed this analysis for other glioma subtypes including pilocytic astrocytoma. Nuclear-encoded mitochondrial gene variants were also analyzed.ResultsWe identified m1555 A>G was significantly associated with GBM risk (adjusted OR 29.30, 95% CI 5.25–163.4, P-value 9.5 X 10–4). No association was detected for other subtypes. Haplotype analysis further supported the independent risk contributed by m1555 G>A, instead of a haplogroup joint effect. Nuclear-encoded mitochondrial gene variants identified significant associations in European (rs62036057 in WWOX, adjusted OR = 2.99, 95% CI 1.88–4.75, P-value = 3.42 X 10–6) and Hispanic (rs111709726 in EFHD1, adjusted OR = 3.57, 95% CI 1.99–6.40, P-value = 1.41 X 10–6) populations in ethnicity-stratified analyses.ConclusionWe report for the first time a potential role played by a functional mitochondrial ribosomal RNA variant in childhood GBM risk, and a potential role for both mitochondrial and nuclear-mitochondrial DNA polymorphisms in GBM tumorigenesis. These data implicate cellular oxidative metabolic capacity as a contributor to the etiology of pediatric glioblastoma.

Abstract P040: Harness the immune-modulatory activities of Toxoplasma gondii to improve lymphocyte infiltration into brain tumors

Abstract While checkpoint inhibitors carry great promises for T-cells-based immunotherapy for brain tumors, the presence of abundant T cells supported by the tumor microenvironment (TME) is a prerequisite for it to be effective. Our lab and others' work using mouse models and patient samples demonstrated that, Shh-subtype medulloblastoma, a well-studied pediatric brain tumor, lacks both T cell infiltration and a supportive TME, posing a critical barrier for immunotherapy. I envision that the protozoans Toxoplasma gondii (T.gondii) as a biological agent could provide a unique solution, because T.gondii can naturally disseminate to the brain and induce significant infiltration and activation of T cells asymptomatically. We hypothesize that T.gondii could attract T cells into brain tumors while at the same time convert the non-supportive TME into one that is conducive for T cells. Using a mouse model for medulloblastoma based on a genetic system called Mosaic Analysis with Double Markers (MADM) that recapitulates the tumorigenic process in human by producing few and precisely labeled mutant cells, I was able to assess the immuno-modulatory potential of T.gondii in the context of an intact immune system and endogenous TME. Our preliminary data revealed three exciting facets about T.gondii's immunotherapeutic potential. Via histological assessment and flow cytometry, we found that at 24 days post infection, abundant T cells are recruited into TME. Correspondingly, we detected significant elevation of IFNg and IFNg-driven genes in the tumors, suggesting Th-1 immunity presence in TME. Lastly, we found that T.gondii challenge is associated with reduced tumor incidence. These results indicates T.gondii holds potent immuno-modulatory capability and potentially anti-tumoral functions. My follow-up studies with dive more deeply into three aspects: 1) determine whether T. gondii can sustainably recruit functional T cells into the tumor mass; 2) determine whether T. gondii can help shape a T cell-supportive TME, especially through activating Th1-immune response in innate immune cells; and 3) identify the underlying mechanisms for T.gondii to exert tumor-suppressing activities. Citation Format: Yen Nguyen, Xiaoyu Zhao, Sarah Ewald, Tajie Harris, Hui Zong. Harness the immune-modulatory activities of Toxoplasma gondii to improve lymphocyte infiltration into brain tumors [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2021 Oct 5-6. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(1 Suppl):Abstract nr P040.

Alternative RNA splicing in tumour heterogeneity, plasticity and therapy.

ABSTRACTAlternative splicing is a process by which a single gene is able to encode multiple different protein isoforms. It is regulated by the inclusion or exclusion of introns and exons that are joined in different patterns prior to protein translation, thus enabling transcriptomic and proteomic diversity. It is now widely accepted that alternative splicing is dysregulated across nearly all cancer types. This widespread dysregulation means that nearly all cellular processes are affected – these include processes synonymous with the hallmarks of cancer – evasion of apoptosis, tissue invasion and metastasis, altered cellular metabolism, genome instability and drug resistance. Emerging evidence indicates that the dysregulation of alternative splicing also promotes a permissive environment for increased tumour heterogeneity and cellular plasticity. These are fundamental regulators of a patient's response to therapy. In this Review, we introduce the mechanisms of alternative splicing and the role of aberrant splicing in cancer, with particular focus on newfound evidence of alternative splicing promoting tumour heterogeneity, cellular plasticity and altered metabolism. We discuss recent in vivo models generated to study alternative splicing and the importance of these for understanding complex tumourigenic processes. Finally, we review the effects of alternative splicing on immune evasion, cell death and genome instability, and how targeting these might enhance therapeutic efficacy.

Highly diluted compounds effects on B16-F10 melanogenesis, reactive oxygen species (ROS) production and tumorigenesis.

Background: Cutaneous melanoma is a highly malignant tumor derived from pigment-producing (melanin) melanocytes of skin epidermis. Cutaneous pigmentation is described as the major physiologic defense against UV radiation. During melanin biosynthesis and other tumorigenic process, reactive oxygen species (ROS) are produced and might be critically involved in several melanomagenesis stages. ROS play key roles on regulation of many types cell proliferation, including melanoma cells. Aims: In this work we evaluated the effects of highly diluted compounds on melanogenesis and changes in reactive oxygen species after 96 hours of treatment and possible involvement in tumorigenesis. Methodology: Melanin content was measured in B16-F10 cells after 96 hours of treatment with highly diluted compounds, as well as the superoxide anion, hydrogen peroxide and nitric oxide. Furthermore, the effects of highly diluted compounds on cell proliferation were investigated by trypan blue exclusion method after 48 hours of treatment. Results: Treatment led to an increase in B16-F10 melanin content and a decrease in nitrite concentration, an intermediate product of nitric oxide. We also observed a decrease in cell proliferation after treatment. It is well recognized that nitric oxide (NO) is involved in tumor progression, including melanoma. Several articles show that NO treated B16-F10 cells exhibited higher metastatic capacity. Thereby, reduction in cell proliferation can be due to low NO levels. It is speculated that melanocytes are programmed to survive in order to preserve their photoprotective role, thus in a compensatory manner the cell may be synthesizing melanin in response to cell proliferation reduction. Conclusions: These results suggest that treatment may be reducing tumorigenic capacity via ROS reduction. However further studies are need to better understand highly diluted compounds mechanisms of action.

Unraveling unique and common cell type-specific mechanisms in glioblastoma multiforme

Glioblastoma multiforme persists to be an enigmatic distress in neuro-oncology. Its untethering capacity to thrive in a confined microenvironment, metastasize intracranially, and remain resistant to the systemic treatments, renders this tumour incurable. The glial cell type specificity in GBM remains exploratory. In our study, we aimed to address this problem by studying the GBM at the cell type level in the brain. The cellular makeup of this tumour is composed of genetically altered glial cells which include astrocyte, microglia, oligodendrocyte precursor cell, newly formed oligodendrocyte and myelinating oligodendrocyte. We extracted cell type-specific solid tumour as well as recurrent solid tumour glioma genes, and studied their functional networks and contribution towards gliomagenesis. We identified the principal transcription factors that are found to be regulating vital tumorigenic processes. We also assessed the protein–protein interaction networks at their domain level to get a more microscopic view of the structural and functional operations that transpire in these cells. This yielded the eminent protein regulators exhibiting their regulation in signaling pathways. Overall, our study unveiled regulatory mechanisms in glioma cell types that can be targeted for a more efficient glioma therapy.

Extracellular Vesicles in Lung Cancer Metastasis and Their Clinical Applications.

Simple SummaryCancer cells are known to interact with the surrounding extracellular environment to facilitate tumorigenic processes. One mechanism by which cancer cells communicate with each other and their environment is through extracellular vesicles. These vesicles contain various biological molecules that are secreted by parental cells for delivery to target recipient cells. Over the past several decades, knowledge of the structure and contents of extracellular vesicles has provided valuable insight into tumor biology. Considering this information, researchers have begun examining the potential of these vesicles for developing novel biomarker classifiers as well as therapeutic strategies.Extracellular vesicles (EVs) are heterogenous membrane-encapsulated vesicles secreted by every cell into the extracellular environment. EVs carry bioactive molecules, including proteins, lipids, DNA, and different RNA forms, which can be internalized by recipient cells, thus altering their biological characteristics. Given that EVs are commonly found in most body fluids, they have been widely described as mediators of communication in several physiological and pathological processes, including cancer. Moreover, their easy detection in biofluids makes them potentially useful candidates as tumor biomarkers. In this manuscript, we review the current knowledge regarding EVs and non-coding RNAs and their role as drivers of the metastatic process in lung cancer. Furthermore, we present the most recent applications for EVs and non-coding RNAs as cancer therapeutics and their relevance as clinical biomarkers.

Epigenetically associated CCL20 upregulation correlates with esophageal cancer progression and immune disorder

Chemokines have distinct effects on tumor progression by affecting cancer immunity and tumorigenesis. However, the characteristic chemokine profiles and their roles in immune cell recruitment and cancer cell biology are not entirely understood in esophageal cancer. Here, we scrutinized chemokine's expression profiles in independent esophageal cancer cohorts and identified the elevated CCL20 as a risk factor to predict patients' prognosis regardless of histology subtypes. Enhanced CCL20 expression was also associated with the acquisition of metastatic potential. Mechanistically, the upregulation of CCL20 in tumor cells was associated with promoter hypomethylation. Furthermore, by analyzing single-cell RNA sequencing data of a mouse model mimicking human ESCC development, we observed an imbalance among CD4+ T subtypes in the tumor microenvironment, namely Ccr6+ Th17 and Treg cells infiltration alongside the elevated Ccl20 expression in abnormal epithelial cells during the tumorigenic process. Together, these results reveal that hypomethylation-induced CCL20 promotes esophageal cancer progression and immune disorder. Targeting CCL20 might be a promising therapeutic approach in esophageal cancer.

Effect of Invasion of Borrelia burgdorferi in Normal and Neoplastic Mammary Epithelial Cells.

Borrelia burgdorferi, the causative agent of Lyme Disease, is known to be able to disseminate and colonize various organs and tissues of its hosts, which is very crucial for its pathogenicity and survival. Recent studies have shown the presence of B. burgdorferi DNA in various breast cancer tissues, in some with poor prognosis, which raises the question about whether B. burgdorferi can interact with mammary epithelial cells and could have any effect on their physiology, including tumorigenic processes. As the model in this study, we have used MCF 10A normal and MDA-MB-231 tumorigenic mammary epithelial cells and infected both cell lines with B. burgdorferi. Our immunofluorescence and confocal microscopy results showed that B. burgdorferi is capable of invading normal epithelial and breast carcinoma cell lines within 24 h; however, the infection rate for the breast carcinoma cell lines was significantly higher. While the infection of epithelial cells with B. burgdorferi did not cause any changes in cell proliferation rates, it showed a significant effect on the invasion and migratory capacity of the breast cancer cells, but not on the normal epithelial cells, as determined by Matrigel invasion and wound healing assays. We have also found that the levels of expression of several epithelial–mesenchymal transition (EMT) markers (fibronectin, vimentin, and Twist1/2) changed, with a significant increase in tissue remodeling marker (MMP-9) in MDA-MB-231 cells demonstrated by quantitative Western blot analyses. This observation further confirmed that B. burgdorferi infection can affect the in vitro migratory and invasive properties of MDA-MB-231 tumorigenic mammary epithelial cells. In summary, our results suggest that B. burgdorferi can invade breast cancer tumor cells and it can increase their tumorigenic phenotype, which urges the need for further studies on whether B. burgdorferi could have any role in breast cancer development.

Epigenetic Signaling of Cancer Stem Cells During Inflammation.

Malignant tumors pose a great challenge to human health, which has led to many studies increasingly elucidating the tumorigenic process. Cancer Stem Cells (CSCs) have profound impacts on tumorigenesis and development of drug resistance. Recently, there has been increased interest in the relationship between inflammation and CSCs but the mechanism underlying this relationship has not been fully elucidated. Inflammatory cytokines produced during chronic inflammation activate signaling pathways that regulate the generation of CSCs through epigenetic mechanisms. In this review, we focus on the effects of inflammation on cancer stem cells, particularly the role of signaling pathways such as NF-κB pathway, STAT3 pathway and Smad pathway involved in regulating epigenetic changes. We hope to provide a novel perspective for improving strategies for tumor treatment.