Abstract
During tumor progression, hypoxia, nutrient deprivation or changes in the extracellular environment (i.e., induced by anti-cancer drugs) elicit adaptive responses in cancer cells. Cellular plasticity increases the chance that tumor cells may survive in a challenging microenvironment, acquire new mechanisms of resistance to conventional drugs, and spread to distant sites. Re-activation of stem pathways appears as a significant cause of cellular plasticity because it promotes the acquisition of stem-like properties through a profound phenotypic reprogramming of cancer cells. In addition, it is a major contributor to tumor heterogeneity, depending on the coexistence of phenotypically distinct subpopulations in the same tumor bulk. Several cellular mechanisms may drive this fundamental change, in particular, high-throughput sequencing technologies revealed a key role for alternative splicing (AS). Effectively, AS is one of the most important pre-mRNA processes that increases the diversity of transcriptome and proteome in a tissue- and development-dependent manner. Moreover, defective AS has been associated with several human diseases. However, its role in cancer cell plasticity and tumor heterogeneity remains unclear. Therefore, unravelling the intricate relationship between AS and the maintenance of a stem-like phenotype may explain molecular mechanisms underlying cancer cell plasticity and improve cancer diagnosis and treatment.
Highlights
Tumorigenesis is a multistep process requiring the ability of cancer cells to survive in a challenging microenvironment
Maturation of its mRNA is tightly regulated by polypyrimidine tract-binding protein 1 (PTBP1) and serine/arginine repetitive matrix protein 4 (SRRM4), two RNA-binding proteins (RBPs) differentially expressed during neurogenesis
There is increasing evidence that, during tumor progression, cell subpopulations with distinct genomic alterations arise within the same tumor bulk, a phenomenon termed intratumor heterogeneity
Summary
Tumorigenesis is a multistep process requiring the ability of cancer cells to survive in a challenging microenvironment. Tumor heterogeneity is considered the main cause of therapy failure and cancer progression towards worse outcomes [12] In this scenario, it is not surprising that defects in mechanisms controlling gene expression might have a pivotal role in cancer cell plasticity. It is well known that AS regulates several biological processes such as proliferation, cell death, migration, and angiogenesis because it controls gene expression at the transcriptional level It increases the diversity of transcriptome and proteome in human cells, its deregulation may greatly contribute to tumor plasticity [13,14]. AS plays a key role in the regulation of the balance between pluripotency and differentiation of human embryonic stem cells (hESCs) during embryogenesis and tissue differentiation This consists in a proof-of-concept where defective AS machinery could sustain the acquisition of phenotypic plasticity in a pathological context [15].
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