Metastatic colonisation and chemotherapy response in perinatal neuroectoderm high-risk tumours

Background

Cancers diagnosed very early in life generally show discrepancies to most common tumours in adults; by the accumulation of relatively few DNA mutations, the time frame before diagnosis, and notably also with regard to the local microenvironment.

This may in turn affect emergence of dominant tumour clones as well as the process of metastatic colonization, the main topics addressed in this project.

In histological terms, neuroectodermal tumours comprises tumours of both the central or the peripheral nervous systems. These show a spectrum of inter- and intra-tumour heterogeneities regarding abilities to develop into high-risk phenotypes with increased resistance to therapy and metastatic behaviour.

The primary tumour mass has been shown to include cells with an extraordinary capacity for regrowth (often referred to as tumour-initiating cells; “TICs”). Experimentally, the options for in vivo studies of regrowth from such cells (with or without therapeutic intervention), have been limited to xenograft models.

The more recent introduction of orthotropic models, and the use of primary patient tumour material (PDX) have significantly increased the clinical value of such studies. However, a by now well recognised occurrence of a dynamic interplay between tumour cells and their microenvironment leads to a theoretical drawback in attempts to extrapolate results obtained in a non-homologous environment (i.e. studies of a human tumour in a non-human microenvironment), particularly during tumour micro colonisation at secondary site (metastatic colonisation).

Strategy

We combine conventional in vitro approaches with an human surrogate experimental platform, pluripotent stem cell induced teratoma (PSCT) derived from diploid human pluripotent stem cells, an approach originally described by by Tzukerman et al 2006 (Proc Natl Acad Sci U S A 2003;100:13507–12) .

In this experimental in vivo platform, a chaotic but benign mix of human early components (Gertow et al 2004), and for this project of particular interest a protuberant embryonic neural development (Gertow et al 2011), provide unparalleled experimental conditions for in vivo microcolonization (metastatic colonisation) of neuroectodermal tumours in a human homologous setting, (Jamil/Cedervall et al 2013, Jamil et al 2014).

Specific Aims

1. Investigate metastatic colonisation from patient biopsies using the novel human surrogate in vivo model.

2. Single cell analysis of chemotherapy resistant subpopulations in vivo and in vitro.
3. Investigate survival mechanisms of chemotherapy resistant single cells.
4. Explore strategies to re-sensitize chemotherapy resistant cells to therapy.

Illustrations

Figure 1 - Schematic illustration of the NB-PSCT model