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Interplay within tumor microenvironment orchestrates neoplastic RNA metabolism and transcriptome diversity

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Abstract The heterogeneous population of cancer cells within a tumor mass interacts intricately with the multifaceted aspects of the surrounding microenvironment. The reciprocal crosstalk between cancer cells and the tumor microenvironment (TME) shapes the cancer pathophysiome in a way that renders it uniquely suited for immune tolerance, angiogenesis, metastasis, and therapy resistance. This dynamic interaction involves a dramatic reconstruction of the transcriptomic landscape of tumors by altering the synthesis, modifications, stability, and processing of gene readouts. In this review, we categorically evaluate the influence of TME components, encompassing a myriad of resident and infiltrating cells, signaling molecules, extracellular vesicles, extracellular matrix, and blood vessels, in orchestrating the cancer‐specific metabolism and diversity of both mRNA and noncoding RNA, including micro RNA, long noncoding RNA, circular RNA among others. We also highlight the transcriptomic adaptations in response to the physicochemical idiosyncrasies of TME, which include tumor hypoxia, extracellular acidosis, and osmotic stress. Finally, we provide a nuanced analysis of existing and prospective therapeutics targeting TME to ameliorate cancer‐associated RNA metabolism, consequently thwarting the cancer progression. This article is categorized under: RNA Processing > Splicing Regulation/Alternative Splicing RNA Turnover and Surveillance > Regulation of RNA Stability RNA in Disease and Development > RNA in Disease
Cellular components of the TME. The TME is a complex ecosystem that nurtures and sustains tumor growth. Various cellular entities present in the TME include immune cells: TAMs, Tregs, dendritic cells, MSDCs, stromal cells: endothelial cells, MSCs, and CAFs. Each of these cell populations contributes to tumor progression in unique ways
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Extracellular vesicle‐mediated communication in shaping the tumor transcriptome. EVs manufactured in tumor cells are packed with mRNAs miRNAs, circRNA, lncRNA, RNA binding proteins, and other components to be transferred into the TME. Thus, EVs mediate intercellular communication within the tumor milieu. The mRNAs transported are further translated by the recipient cell's translation machinery to generate functional proteins, whereas the miRNAs, circRNA, and lncRNA promote migration and angiogenesis. The RNA components are maintained by the RNA binding proteins within the EVs. Other RNA binding proteins such and splicing factors and snRNAs are also present and modulate the alternative splicing events within the recipient cells
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Extracellular matrix‐mediated regulation of tumor transcriptome. An increase in collagen density leads to the elevation of matrix stiffness. These mechanical forces influence integrin signaling and also activates a cascade of downstream phosphorylation events. The resultant activation of the ERK pathway via a Rho/ROCK signaling axis as well as the influx of Ca2+ in response to mechanical stimulation differentially regulates miRNA production. Whereas, PI3K‐AKT pathways regulate alternative splicing events in the presence of a stiffer ECM by phosphorylating and controlling the functioning of splicing factors (SF)
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Hypoxia‐elicited regulation of RNA metabolism. Cancer cells at the core of the tumor tissues experience severe oxygen deprivation. In response to this hypoxic tumor milieu, cancer cells undergo a dramatic reprogramming in their RNA metabolism and diversity. These transcriptomic changes include selective mRNA stabilization, global mRNA destabilization, upregulation of pro‐tumorigenic miRNAs, downregulation of anti‐tumorigenic miRNA, selective mRNA translation, and induction of pro‐tumorigenic alternative splicing
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Cellular components of TME and RNA metabolism. (a) Exosomes released from tumor cells containing lncRNA are taken up by naïve T‐cells. They act as miRNA sponges to activate the Hippo signaling pathway leading to the differentiation of naïve T‐cells to Tregs. (b) miRNAs and lncRNAs promote M1 to M2 macrophage polarization and the reverse process. (c) Alternative pre‐mRNA splicing in cancer cells leads to the generation of neoantigens which are taken up by dendritic cells, subsequently activating T‐cells. (d) miRNA‐mediated inhibition of SOCS3 activates the JAK/STAT pathway leading to increased production of immunosuppressive cytokine Arg1 in MSDCs. (e) Alternative polyadenylation events can promote tumor infiltration and proliferation either by 3′US or 3′UL, affecting miRNA binding sites
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RNA in Disease and Development > RNA in Disease
RNA Turnover and Surveillance > Regulation of RNA Stability
RNA Processing > Splicing Regulation/Alternative Splicing

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