Project title: Alternative Splicing in PNET: an Unexplored Source of Therapeutic Targets

Description

Kafasla and her research team will work to identify alternative forms of a given protein (called isoforms) that are specific and present in pancreatic tumor cells. The team will analyze alternative splicing events in pancreatic NET cells as well as normal cells.

What question will the researchers try to answer?

Different protein “versions” are produced when alternative splicing is deregulated in cancer cells. In many cases, these protein versions act as dominant drivers in the development of cancer cells. Furthermore, several subtypes of cancer depend on splicing function for cell survival. These are among the findings that led to a growing interest in targeting alternative splicing for cancer treatment. Many compounds targeting either the alternative splicing process or specific cancer-driving protein versions are in clinical trials. The role of alternative splicing in the pathogenesis of pancreatic NETs (PNETs) has not been investigated in the preliminary results of Dr. Kafasla’s research show that alternative splicing is highly affected in PNETs and her team will continue to explore this.

Why is this important?

Deregulated alternative splicing is a hallmark of cancers, affecting many characteristics of cancer cells. Cancer cells alter the alternative splicing process to favor their survival and growth, and several molecular subtypes of cancer depend on such altered alternative splicing for cell survival. As a result, alternative splicing has been characterized as the Achilles’ heel of cancer, making cancer cells more vulnerable to splicing-targeting drugs than normal cells. A better understanding of these changes in alternative splicing in cancer cells can become a tool to use in the fight against PNETs.

What will researchers do?

Her team will analyze publicly available datasets for alternative splicing changes between normal and cancer tissues from patients. They aim to detect splicing changes – protein “versions” that are increased or decreased during tumorigenesis or that are functionally altered in cancer cells. These changes will be validated in human cells and in mouse models of NETs and then correlated with specific cancer cell characteristics and with distinct states of PNET development.

How might this improve the treatment of NETs?

The models used for these studies are commonly used by PNET researchers, but the contribution of alternative splicing in tumor characteristics is still a black box. The detailed analysis of these models by their team will advance the research field enormously. Alternative splicing has been targeted successfully in other disease settings and many drugs targeting alternative splicing are already in clinical trials for different types of cancer. Our work aims to pave the way for implementation of such targeting in PNETs.

What is the next step?

Once the alternative splicing changes in PNETs is characterized, their studies will be extended to patient-derived animal and cellular models of the disease. They will not only target general splicing functions but also disease-specific molecules at different stages from early development to final tumorigenesis. 

Outcomes:

Alternative Splicing (AS) is what cells employ to enrich the vast repertoire of their proteins, the functional molecules in a cell. A protein variant deriving from AS of an RNA can be potentially inhibited by a specific drug while another variant of the same protein that is generated by changed AS is not. AS is deregulated in cancer: it generates many protein variants that are tumor specific and help tumours grow and expand. In many instances, cancer cells alter the AS in order to escape therapies. This is often due to the fact that cancer cells produce too much of certain molecules that decide on the outcome of AS, the so-called splicing factors. Thus, there has been intense research on the development of drugs that can alter the AS outcome in cells. Such an approach has been successfully used to treat spinal muscular atrophy and other diseases that originate from mis-splicing. Following that, similar approaches for treatment of different cancers are on clinical trials. However, to target AS for therapeutic purposes, we need to know details on the AS deregulation during PNET development.

When we started working on the proposed research, the role of AS in the pathogenesis of Pancreatic Neuroendocrine tumors (PNETs) had not been investigated. Our aim was to identify novel protein variants that are characteristic for PNETs and drive its progress and also to define the splicing factors that are responsible for the generation of these novel variants. For this purpose, we used publicly available data from PNET patients and analyzed them bioinformatically to detect changes in AS between PNET patients and normal pancreatic cells. We identified a large number of AS differences between PNETs and normal samples. We have identified novel protein variants that appear in PNETs and not in normal pancreatic cells. Importantly, we discovered a new group of molecules that appear deregulated in PNETs because of changes in AS, and they are a group of proteins that are responsible for the hormone secreting function of the PNETs. Due to changes of AS, the variants of these proteins that are being produced are not the normal, properly functioning ones. We have also identified the splicing factor that is responsible for these changes. Importantly, we also verified that these proteins are problematic due to AS changes using experimental laboratory systems (animal and cellular models of PNETs) and verified that they regulate tumor growth and expansion in these experimental systems.

It is important to note that no previous studies have revealed this group of proteins as dysfunctional in PNETs, and this knowledge opens new possibilities for therapy development. On our side, we will continue working on finding the right molecules to target these AS changes as a therapeutic approach in PNET.

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