Project title: Tumor xenografts in zebrafish: a new in vivo model for lung carcinoids

Description

Vitale will develop a new laboratory model of lung NETs using zebrafish embryos to study in real time the development of the blood network that supports these tumors. With an established model, researchers will also test responses to targeted therapies.

What question will the researchers try to answer?

Can zebrafish serve as an accurate, effective, and reliable laboratory model of lung NETs to advance our knowledge of tumor biology and serve as a platform for preclinical drug screening?

Why is this important?

The lack of valid laboratory models is a critical obstacle in developing curative therapies for advanced lung carcinoid tumors. Zebrafish embryos are transparent, allowing the examination of important processes (such as the development of tumor blood vessels) to occur in near real-time. The permeability of zebrafish embryos can also support the testing of several antitumor drugs. For these reasons, Vitale hopes to use zebrafish models as an innovative and fast way to test lung NET treatments.

What will researchers do?

Researchers will study tumor cells’ supply system of nutrients and oxygen using fluorescent dye in translucent zebrafish embryos to understand how lung NETs form, grow and spread. Once the zebrafish model of lung NETs is established, researchers will then run experiments to test new targeted therapies to see their effect on cancer cells.

How might this improve the treatment of NETs?

Laboratory models like this help scientists identify and test cancer treatments quickly and easily in the laboratory. Having a zebrafish model of lung NETs could accelerate the search for effective treatments and even generate information to help doctors personalize care for individuals.

What is the next step?

Vitale will publish complete descriptions of the new methodology to develop this innovative zebrafish model in a peer-reviewed scientific journal so that other scientists all over the world can replicate it.

Outcomes:

Pulmonary carcinoids are well-differentiated neuroendocrine tumors (NETs) and include typical (TC) and atypical carcinoids (AC). Patients with TC or AC develop distant metastases in 25-30% of cases. Despite the development of novel drugs in cancer research over the last decade, there are no curative therapies for advanced lung carcinoid tumors. A key factor that has hindered clinical therapeutic progress is the lack of valid animal models for studying the tumor biology and for preclinical drug screening.

In the present project, we developed an innovative model based on the implantation of lung NET cells in zebrafish embryos. Zebrafish embryos are transparent, allowing examination of the engrafted tumor cells in vivo and evaluation of several important cancer processes, such as the tumor-induced angiogenesis (formation of new blood vessels contributing to the dissemination of tumor cells and supplying nutrients and oxygen for cancer growing) and the development of metastasis. Through the implantation of human carcinoid tumor cells in zebrafish embryos, we are able to study most of these events in real time and in a short period (5 days). This allows us to implant tumor tissue directly from patients after surgical procedure (patient-derived xenograft, PDX) in zebrafish embryos.

Emerging data show that PDX models of cancer accurately reflect clinical responses when treated with antitumor agents, representing a powerful tool for selecting the most appropriate treatment for each patient (personalized therapy). We observed that the injection of both immortalized cell lines and PDXs of TC and AC in zebrafish embryos quickly stimulated the formation of the tumor vascular network within 24-48 hours after the implantation. In the same time window, injected cells spread through the embryo body with the development of metastases. In addition, zebrafish embryos have high permeability to small molecules, such as several antitumor drugs. This allowed us to easily test the antitumor activity of several compounds. We found a significant inhibition of tumor-induced angiogenesis in zebrafish after treatment with tyrosine kinase inhibitors (axitinib, cabozantinib and sulfatinib). Cabozantinib was also able to inhibit the formation of metastases in this model.

In conclusion, this NET xenograft/zebrafish model appears to be a cheap and fast platform for studying tumor-induced angiogenesis and tumor cell dissemination of lung carcinoids and an innovative tool for drug screening. The possibility to implant PDXs opens a promising scenario for the identification of personalized therapies in patients with advanced lung carcinoid tumors.

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