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Micro colonisation and chemotherapy response of high-risk neuroectodermal tumours

We are interested in mechanisms for the progression of tumour cell subpopulations leading to refractory disease. Our research focuses on tumours of the central or peripheral nervous system in young children

Background

Cancers diagnosed very early in life show general disparities to most common solid tumours in adults with differences in their cancer-causing genetics, most conspicuously by a shorter time window with the accumulation of relatively few DNA mutations. Notably, embryonic solid tumours differ from adult tumours also with regard to their immediate microenvironment, which in turn may affect growth promoting signalling and the emergence of dominant clones.

Embryonic neuroectodermal tumours comprises a spectrum of inter- and intra-tumour heterogeneities with abilities to progress into high-risk phenotypes. The mechanisms underlying these outcomes are largely unknown. However, information are emerging on how both genetic and non-genetic mechanisms are influenced by the local microenvironment.

Cells with tumour-initiating capacity (TIC) have during the last half century been intensively studied using animal models and massive knowledge has been gathered. The clinical value has significantly increased with the use of orthotropic animal models; inoculation of fresh patient tumour material (PDX); and also models with “humanised” mice.

Our strategy

We have used an in vivo surrogate human embryonic set up derived from pluripotent stem cells, originally described by by Tzukerman et al 2006, and adapted this for neuroblastoma (NB) micro-colonisation; the NB-PSCT transplantation model (Jamil et al 2013, 2014). Here, a chaotic mix of developing human early components provides experimental conditions for micro colonization, including also tissue tropism guided from a homologous setting (Jamil et al 2013, 2014).

Schematic illustration of the PSCT model with tumour micro colonization

Specific Aims

1. To investigate clonogenic regrowth from patient biopsies using combinations of in vivo and in vitro models.

Following chemotherapy;

2. To perform single cell analysis of chemotherapy-resistant subpopulatios.
3. To identify the survival mechanisms of chemotherapy-resistant single cells.
4. To develop strategies for re-sensitising chemotherapy-resistant single cells to therapy.

Group members

Shahrzad Shirazi Fard, PhD, Port doc
Lars Ährlund-Richter, PhD, Professor emeritus
Linnea Ödborn Jönsson, Master Thesis Project (spring 2019)

Publications (PUBMED)

S Shirazi Fard
Lars Ährlund-Richter