Dormancy in Breast Cancer, the Role of Autophagy, lncRNAs, miRNAs and Exosomes.

Breast cancer (BC) is the most frequently diagnosed cancer in women for which numerous diagnostic and therapeutic options have been developed. Namely, the targeted treatment of BC, for the most part, relies on the expression of growth factors and hormone receptors by these cancer cells. Despite this, close to 30% of BC patients may experience relapse due to the presence of minimal residual disease (MRD) consisting of surviving disseminated tumour cells (DTCs) from the primary tumour which can colonise a secondary site. This can lead to either detectable metastasis or DTCs entering a dormant state for a prolonged period where they are undetectable. In the latter, cells can re-emerge from their dormant state due to intrinsic and microenvironmental cues leading to relapse and metastatic outgrowth. Pre- and clinical studies propose that targeting dormant DTCs may inhibit metastasis, but the choice between keeping them dormant or forcing their "awakening" is still controversial. This review will focus on cancer cells' microenvironmental cues and metabolic and molecular properties, which lead to dormancy, relapse, and metastatic latency in BC. Furthermore, we will focus on the role of autophagy, long non-coding RNAs (lncRNAs), miRNAs, and exosomes in influencing the induction of dormancy and awakening of dormant BC cells. In addition, we have analysed BC treatment from a viewpoint of autophagy, lncRNAs, miRNAs, and exosomes. We propose the targeted modulation of these processes and molecules as modern aspects of precision medicine for BC treatment, improving both novel and traditional BC treatment options. Understanding these pathways and processes may ultimately improve BC patient prognosis, patient survival, and treatment response.

The Contribution of Autophagy and LncRNAs to MYC-Driven Gene Regulatory Networks in Cancers.

MYC is a target of the Wnt signalling pathway and governs numerous cellular and developmental programmes hijacked in cancers. The amplification of MYC is a frequently occurring genetic alteration in cancer genomes, and this transcription factor is implicated in metabolic reprogramming, cell death, and angiogenesis in cancers. In this review, we analyse MYC gene networks in solid cancers. We investigate the interaction of MYC with long non-coding RNAs (lncRNAs). Furthermore, we investigate the role of MYC regulatory networks in inducing changes to cellular processes, including autophagy and mitophagy. Finally, we review the interaction and mutual regulation between MYC and lncRNAs, and autophagic processes and analyse these networks as unexplored areas of targeting and manipulation for therapeutic gain in MYC-driven malignancies.

Exosomes in Neuroblastoma Biology, Diagnosis, and Treatment.

Neuroblastoma is an extracranial solid tumour of the developing sympathetic nervous system accounting for circa 15% of deaths due to cancer in paediatric patients. The clinical course of this cancer may be variable, ranging from aggressive progression to regression, while the amplification of MYCN in this cancer is linked to poor patient prognosis. Extracellular vesicles are a double membrane encapsulating various cellular components including proteins and nucleic acids and comprise exosomes, apoptotic bodies, and microvesicles. The former can act as mediators between cancer, stromal and immune cells and thereby influence the tumour microenvironment by the delivery of their molecular cargo. In this study, the contribution of extracellular vesicles including exosomes to the biology, prognosis, diagnosis and treatment of neuroblastoma was catalogued, summarised and discussed. The understanding of these processes may facilitate the in-depth dissection of the complexity of neuroblastoma biology, mechanisms of regression or progression, and potential diagnostic and treatment options for this paediatric cancer which will ultimately improve the quality of life of neuroblastoma patients.

Deep analysis of neuroblastoma core regulatory circuitries using online databases and integrated bioinformatics shows their pan-cancer roles as prognostic predictors.

AIM: Neuroblastoma is a heterogeneous childhood cancer derived from the neural crest. The dual cell identities of neuroblastoma include Mesenchymal (MES) and Adrenergic (ADRN). These identities are conferred by a small set of tightly-regulated transcription factors (TFs) binding super enhancers, collectively forming core regulatory circuitries (CRCs). The purpose of this study was to gain a deep understanding of the role of MES and ADRN TFs in neuroblastoma and other cancers as potential indicators of disease prognosis, progression, and relapse. METHODS: To that end, we first investigated the expression and mutational profile of MES and ADRN TFs in neuroblastoma. Moreover, we established their correlation with neuroblastoma risk groups and overall survival while establishing their extended networks with long non-coding RNAs (lncRNAs). Furthermore, we analysed the pan-cancer expression and mutational profile of these TFs and their correlation with patient survival and finally their network connectivity, using a panel of bioinformatic tools including GEPIA2, human pathology atlas, TIMER2, Omicsnet, and Cytoscape. RESULTS: We show the association of multiple MES and ADRN TFs with neuroblastoma risk groups and overall survival and find significantly higher expression of various MES and ADRN TFs compared to normal tissues and their association with overall survival and disease-free survival in multiple cancers. Moreover, we report the strong correlation of the expression of these TFs with the infiltration of stromal and immune cells in the tumour microenvironment and with stemness and metastasis-related genes. Furthermore, we reveal extended pan-cancer networks comprising these TFs that influence the tumour microenvironment and metastasis and may be useful indicators of cancer prognosis and patient survival. CONCLUSION: Our meta-analysis shows the significance of MES and ADRN TFs as indicators of patient prognosis and the putative utility of these TFs as potential novel biomarkers.

The Role of Autophagy and lncRNAs in the Maintenance of Cancer Stem Cells.

Cancer stem cells (CSCs) possess properties such as self-renewal, resistance to apoptotic cues, quiescence, and DNA-damage repair capacity. Moreover, CSCs strongly influence the tumour microenvironment (TME) and may account for cancer progression, recurrence, and relapse. CSCs represent a distinct subpopulation in tumours and the detection, characterisation, and understanding of the regulatory landscape and cellular processes that govern their maintenance may pave the way to improving prognosis, selective targeted therapy, and therapy outcomes. In this review, we have discussed the characteristics of CSCs identified in various cancer types and the role of autophagy and long noncoding RNAs (lncRNAs) in maintaining the homeostasis of CSCs. Further, we have discussed methods to detect CSCs and strategies for treatment and relapse, taking into account the requirement to inhibit CSC growth and survival within the complex backdrop of cellular processes, microenvironmental interactions, and regulatory networks associated with cancer. Finally, we critique the computationally reinforced triangle of factors inclusive of CSC properties, the process of autophagy, and lncRNA and their associated networks with respect to hypoxia, epithelial-to-mesenchymal transition (EMT), and signalling pathways.