Vol.:(0123456789) 1 3 Clinical & Experimental Metastasis (2018) 35:393–402 https://doi.org/10.1007/s10585-018-9905-y RESEARCH PAPER Alternative splicing and cancer metastasis: prognostic and therapeutic applications Diego M. Marzese 1  · Ayla O. Manughian‑Peter 1  · Javier I. J. Orozco 1  · Dave S. B. Hoon 1,2 Received: 23 February 2018 / Accepted: 22 May 2018 / Published online: 29 May 2018 © Springer Science+Business Media B.V., part of Springer Nature 2018 Abstract Metastatic cells exhibit an extraordinary phenotypic plasticity, not only in adapting to unfamiliar microenvironments but also in surviving aggressive treatments and immune responses. A major source of phenotypic variability is alternative splicing (AS) of the pre-messenger RNA. This process is catalyzed by one of the most complex pieces of cellular molecular regula- tory events, the spliceosome, which is composed of ribonucleoproteins and polypeptides termed spliceosome factors. With strong evidence indicating that AS afects nearly all genes encoded by the human genome, aberrant AS programs have a signifcant impact on cancer cell development and progression. In this review, we present insights about the genomic and epigenomic factors afecting AS, summarize the most recent fndings linking aberrant AS to metastatic progression, and highlight potential prognostic and therapeutic applications. Keywords Cancer metastasis · Alternative splicing · Epigenetics · Prognostic · Therapeutics Introduction Metastatic tumor cells have an intrinsic phenotypic plastic- ity conveyed by genetic and epigenetic alterations allowing them to adapt to and survive variable regional and systemic impediments imposed by the immune system, therapeu- tic treatments, and unfamiliar micro-environments, inde- pendent of the tumor origin [1, 2]. Alternative pre-mRNA splicing (AS) is one of the major sources of protein vari- ability in human cells [3]. During the splicing process, specific non-coding sequences of precursor messenger RNAs (pre-mRNA) are recognized and removed to form a mature mRNA [3]. Thus, this fnely regulated process generates multiple mRNA transcripts and protein isoforms with related, distinct, or even opposing functions from a single gene unit [3]. The AS process is regulated by a com- plex molecular machine deemed the spliceosome, which is composed of nuclear ribonucleoproteins and polypeptides denominated spliceosome factors (SFs). Since AS controls almost all human genes, subtle alterations in this process have a signifcant impact on human diseases, such as the generation of tumor-promoting and metastasis-specific splice variants in cancer [4, 5]. From a holistic perspective, variations in the expression level of SFs leads to hyper-var- iability in the individual cell-type specifc splicing program. This often becomes even more pronounced in tumor cells that have a higher adaptation potential and dynamic phe- notype compared to their normal origin. The activation of AS programs of genes in a cancer cell can create aggressive tumor clones that allow them to survive and metastasize more efciently. Nonetheless, one of the most promising aspects of spliceosome alterations is that there are at least two major levels at which aberrant splicing can be modu- lated; frst is the design of splicing site-specifc antisense oligonucleotides (ASOs) that target abnormal exons in pre- spliced mRNA. This approach has demonstrated extraordi- nary results in patients with Duchenne muscular dystrophy (DMD) [6] and in patients with spinal muscular atrophy (SMA) [7]. The second level of splicing modulation has been translated into a new generation of antitumor drugs Presented at the 7th International Cancer Metastasis Symposium in San Francisco, CA from April 20–22, 2017 (www.cancermeta stasis.org). * Dave S. B. Hoon hoond@jwci.org 1 Department of Translational Molecular Medicine, John Wayne Cancer Institute, Santa Monica, CA, USA 2 Sequencing Center, John Wayne Cancer Institute, Santa Monica, CA, USA