The Many Facets of Therapy Resistance and Tumor Recurrence in Glioblastoma

Glioblastoma (GBM) is the most lethal type of primary brain cancer. Standard care using chemo- and radio-therapy modestly increases the overall survival of patients; however, recurrence is inevitable, due to treatment resistance and lack of response to targeted therapies. GBM therapy resistance has been attributed to several extrinsic and intrinsic factors which affect the dynamics of tumor evolution and physiology thus creating clinical challenges. Tumor-intrinsic factors such as tumor heterogeneity, hypermutation, altered metabolomics and oncologically activated alternative splicing pathways change the tumor landscape to facilitate therapy failure and tumor progression. Moreover, tumor-extrinsic factors such as hypoxia and an immune-suppressive tumor microenvironment (TME) are the chief causes of immunotherapy failure in GBM. Amid the success of immunotherapy in other cancers, GBM has occurred as a model of resistance, thus focusing current efforts on not only alleviating the immunotolerance but also evading the escape mechanisms of tumor cells to therapy, caused by inter- and intra-tumoral heterogeneity. Here we review the various mechanisms of therapy resistance in GBM, caused by the continuously evolving tumor dynamics as well as the complex TME, which cumulatively contribute to GBM malignancy and therapy failure; in an attempt to understand and identify effective therapies for recurrent GBM

Human satellite-III non-coding RNAs modulate heat-shock-induced transcriptional repression

The heat shock response is a conserved defense mechanism that protects cells from physiological stress, including the thermal stress. Besides the activation of heat shock protein genes, the heat shock response is also known to bring about global suppression of transcription, the mechanism for which however is poorly understood. One of the intriguing aspects of the heat shock response in human cells is the transcription of Satellite-III (Sat3) long-noncoding RNAs and their association with nuclear stress bodies (nSBs) of unknown function. Besides the Sat3 transcript, the nSBs are also known to recruit transcription factors HSF1, and CREBBP, and several RNA binding proteins, including the splicing factor SRSF1. We demonstrate here that the recruitment of CREBBP and SRSF1 to nSBs is Sat3-dependent, and that loss of Sat3 transcripts relieves the heat shock-induced transcriptional repression of a few target genes. Conversely, forced expression of Sat3 transcripts results in the formation of nSBs and the transcriptional repression even without a heat shock. Our results thus provide a novel insight into the regulatory role for the Sat3 transcripts in the heat shock-dependent transcriptional repression

The Role of Non-Coding RNAs in Glioma

For decades, research in cancer biology has been focused on the protein-coding fraction of the human genome. However, with the discovery of non-coding RNAs (ncRNAs), it has become known that these entities not only function in numerous fundamental life processes such as growth, differentiation, and development, but also play critical roles in a wide spectrum of human diseases, including cancer. Dysregulated ncRNA expression is found to affect cancer initiation, progression, and therapy resistance, through transcriptional, post-transcriptional, or epigenetic processes in the cell. In this review, we focus on the recent development and advances in ncRNA biology that are pertinent to their role in glioma tumorigenesis and therapy response. Gliomas are common, and are the most aggressive type of primary tumors, which account for ~30% of central nervous system (CNS) tumors. Of these, glioblastoma (GBM), which are grade IV tumors, are the most lethal brain tumors. Only 5% of GBM patients survive beyond five years upon diagnosis. Hence, a deeper understanding of the cellular non-coding transcriptome might help identify biomarkers and therapeutic agents for a better treatment of glioma. Here, we delve into the functional roles of microRNA (miRNA), long non-coding RNA (lncRNA), and circular RNA (circRNA) in glioma tumorigenesis, discuss the function of their extracellular counterparts, and highlight their potential as biomarkers and therapeutic agents in glioma

Tumor microenvironment signaling and therapeutics in cancer progression

Abstract Tumor development and metastasis are facilitated by the complex interactions between cancer cells and their microenvironment, which comprises stromal cells and extracellular matrix (ECM) components, among other factors. Stromal cells can adopt new phenotypes to promote tumor cell invasion. A deep understanding of the signaling pathways involved in cell‐to‐cell and cell‐to‐ECM interactions is needed to design effective intervention strategies that might interrupt these interactions. In this review, we describe the tumor microenvironment (TME) components and associated therapeutics. We discuss the clinical advances in the prevalent and newly discovered signaling pathways in the TME, the immune checkpoints and immunosuppressive chemokines, and currently used inhibitors targeting these pathways. These include both intrinsic and non‐autonomous tumor cell signaling pathways in the TME: protein kinase C (PKC) signaling, Notch, and transforming growth factor (TGF‐β) signaling, Endoplasmic Reticulum (ER) stress response, lactate signaling, Metabolic reprogramming, cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) and Siglec signaling pathways. We also discuss the recent advances in Programmed Cell Death Protein 1 (PD‐1), Cytotoxic T‐Lymphocyte Associated Protein 4 (CTLA4), T‐cell immunoglobulin mucin‐3 (TIM‐3) and Lymphocyte Activating Gene 3 (LAG3) immune checkpoint inhibitors along with the C‐C chemokine receptor 4 (CCR4)‐ C‐C class chemokines 22 (CCL22)/ and 17 (CCL17), C‐C chemokine receptor type 2 (CCR2)‐ chemokine (C‐C motif) ligand 2 (CCL2), C‐C chemokine receptor type 5 (CCR5)‐ chemokine (C‐C motif) ligand 3 (CCL3) chemokine signaling axis in the TME. In addition, this review provides a holistic understanding of the TME as we discuss the three‐dimensional and microfluidic models of the TME, which are believed to recapitulate the original characteristics of the patient tumor and hence may be used as a platform to study new mechanisms and screen for various anti‐cancer therapies. We further discuss the systemic influences of gut microbiota in TME reprogramming and treatment response. Overall, this review provides a comprehensive analysis of the diverse and most critical signaling pathways in the TME, highlighting the associated newest and critical preclinical and clinical studies along with their underlying biology. We highlight the importance of the most recent technologies of microfluidics and lab‐on‐chip models for TME research and also present an overview of extrinsic factors, such as the inhabitant human microbiome, which have the potential to modulate TME biology and drug responses