# Pilot study: transduction of primary paraganglioma chromaffin tumour cells with inducible c-MYC drives cell proliferation

## TL;DR

This study shows that primary paraganglioma tumor cells can be made to proliferate in the lab using a controllable gene system.

## Contribution

The first demonstration of inducible proliferation in primary paraganglioma chromaffin tumor cells using c-MYC.

## Key findings

- Primary paraganglioma cells were successfully transduced with an inducible c-MYC system.
- Proliferation was achieved even in later passage cultures with over 80% chromaffin tumor cells.
- This method offers a promising alternative to current inadequate models for SDH-related tumors.

## Abstract

Succinate dehydrogenase (SDH) gene variants are the most common cause of the
neuroendocrine tumour hereditary paraganglioma, which is associated with an
over 20% metastasis risk as well as significant morbidity. There are
currently no relevant human tumour cell lines or mouse models, and molecular
understanding of downstream tumourigenic pathways is still rudimentary
despite over two decades of concerted effort worldwide. These tumours
generally show extremely slow in vivo doubling times (4–12 years),
presumably existing in a primarily semi-quiescent state with little cell
cycling or DNA replication. This characteristic makes deriving a useful
tumour cell line impractical. A better alternative would be a cell line in
which cell proliferation can be turned on and off at will, allowing
expansion to generate sufficient cell numbers and experimentation once
tumour cells have returned to their natural semi-quiescent state. The
closest models currently available, highly-proliferating rat and mouse
adrenal paraganglioma cell lines, are molecularly unrelated to SDH tumours.
In this pilot study, we investigated whether primary SDH-derived
paraganglioma tumour cells can be made to proliferate in vitro. We
successfully transduced primary paraganglioma tumour cells with a lentiviral
construct, using the proven strategy of c-MYC¬T58A (c-MYC) controlled by a
Tet-On doxycycline-inducible expression system. We present the first
evidence that primary paraganglioma chromaffin cells can be induced to
proliferate in vitro, even in later passage cultures. Without any prior
selection for chromaffin tumour cells, passaged cultures were obtained with
over 80% synaptophysin-expressing chromaffin tumour cells, suggesting that
this highly promising strategy deserves further exploration.