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H2020Individual fellowship2017–2019

SPLICANCER · Regulation and reprogramming of alternative splicing in cellular transformation

Horizon 2020 — Marie Skłodowska-Curie Actions

Duration
2017-07-01 → 2019-06-30
EU contribution
€168,277
Participants
1
Scheme
MSCA-IF-EF-ST

Lines connect the coordinator with its partners.

Results in brief

Regulation and reprogramming of alternative splicing in cellular transformation

The human genome contains all the information that a human cell requires to survive and develop healthy and functionally. This information is present in the genome as subunits called genes, which are read by the cell thanks to specialized biological machineries. Genes are first transcribed in the cell nucleus as messenger RNAs (mRNA), which are then exported to the cytoplasm where they are finally translated into proteins. This linear sequence of events is complicated by additional regulatory steps that occur during the process. Indeed, genes are first transcribed as immature precursor mRNAs (pre-mRNAs) that contain both coding (exons) and non-coding segments (introns). In following steps, then, introns are removed and exons are joined together by a process called “splicing” to ultimately obtain a mature mRNA. During splicing, some exons (alternative exons) can be occasionally included from pre-mRNAs, thus generating different mature mRNAs and, as a consequence, different protein isoforms. This process is known as alternative splicing (AS) and it amplifies the protein-coding capacity of the human genome by generating multiple protein isoforms, each with different functions, from a single gene. Alterations during the process of AS can be detrimental for cells, leading to diseases including cancer. Indeed, the identification of mutations in genes coding for AS regulators in tumors highlighted the effects of AS dysfunction in cancer progression. The aim of this project was to study the physiological mechanism behind alternative splicing of myosin VI in order to understand its de-regulation in tumors and cancer progression.

Data: CORDIS, © European Union

Project objective

Alternative splicing (AS), by affecting nearly 90 percent of human genes, is the major contributor to protein diversity. Mutations that disrupt AS regulatory sequences are a widespread source of human diseases. Various evidences suggest that an AS reprogramming is critical in cell adaptation during cancer development. In spite of increasing interest in the potential oncogenic role of AS, little is known about the molecular mechanisms behind its deregulation during the somatic to the cancer cell transformation. Our aim is to contribute to the characterisation of AS reprogramming during the somatic to the proliferative cancer cell transformation using myosin VI as model system. Recent studies from the host lab reported how myosin VI AS modulates its interactome leading to different cellular functions (endocytosis for the long isoform and cell migration for the short one). The lab found that alternative myosin VI splicing is aberrantly regulated in cancer, where exon skipping dictates cell addiction to myosin VIshort for tumour cell migration.In this proposal, we intends to 1) Identify the myosin VI’s alternative splicing regulators and define their role in vitro, 2) identify common splicing-regulated events that occur during the establishment of a fully polarized epithelial architecture and that are possibly deregulated in cancer (AS reprogramming), 3) assess whether cancer stem cells express a specific set of the identified AS genes.Preliminary results revealed that myosin VI isoforms expression can be switch on/off in selective culture conditions. We will take advantage of this beahviour to set up our analysis based on a multidisciplinary approach that includes biochemical, mass spectrometry and cellular biological assayes. The new set of information will gained with this proposal will be instrumental to understanding the molecular mechanism at the basis of AS (de)regulation for myosin VI and more in general for cell transformation during cancer progression.

Original text from CORDIS.

Participants

  • IFOM-ISTITUTO FONDAZIONE DI ONCOLOGIA MOLECOLARE ETS · MilanoCoordinatorItaly

Links

Data: CORDIS, © European Union