Micro colonisation and chemotherapy response of high-risk neuroblastoma
We are interested in the evolution of tumour subpopulations leading to relapse, metastasis, and the development of therapy-resistance. Our research focuses on pre-clinical evaluation of tumour interventions
Research group leader:
Childhood cancers show fundamental differences to most common adult solid tumours in their cancer-causing genetics, cell biology, and also their local tissue microenvironment. The current paradigm in child cancer research predicts that effective treatments will be attainable when the molecular events that are specific to childhood tumorigenesis are better understood. In many paediatric solid tumours, complete clinical remission can be achieved, but metastasis and relapse are the main causes of death, which make it imperative to understand intra-tumour variations for therapy responsiveness. Modelling of tumour micro colonisation reflects in this context the ability of cell subpopulations to comply or adapt to new environments (i.e. subsets of cells either present in a minority at diagnosis or develop during therapy), a feature with great impact on metastasis and clinical prognosis. Here, the local microenvironment likely contributes to clonal dominance and the disparity between primary and metastatic tumours seen in many patients.
Neuroblastoma is the most common cancer during infancy, half of which are clinically manifested before the age of 18 months. Together with the demonstration of prevalent appearance of tumour-like neuroblastoma in situ there is strong support for the notion of an origin already during the prenatal phase. The diagnosis comprises a spectrum of embryonic tumours of the peripheral sympathetic nervous system with a high degree of inter- and intra-tumour heterogeneity.
The analysis of rare cells in solid human tumours is a meticulous challenge and experimental possibilities to study clinically relevant regrowth following chemotherapy have so far been limited, resorting to xenografts as the main alternative. Our group has explored a possibility with expansion of rare tumour cell clones into identifiable micro colonies in a human homologous experimental in vivo (Gertow et al 2004, 2007, 2011, Cedervall et al 2011, Jamil et al 2013, 2014, reviewed by Hultman et al 2014).
Xenografts of human diploid bona fide pluripotent stem cells (PSC) are known to develop into experimental teratoma (PSCT), showing chaotic but benign components mimicking development of embryonic tissues (e.g. Gertow et al 2004, 2007). The PSCT-microenvironment includes abundant embryonic neural components, developmentally overlapping with gestation stages immediately preceding the positioning of adrenal sympatical progenitors in embryonic mesenchyme (Gertow 2011).
Neuroblastoma is considered to originate from stages along the differentiating sympathoadrenal lineage. Thus, the embryonic nature and particularly the presence of matching early neural components suggest the model to be uniquely suited for studies on early childhood tumours of neuroectodermal origin, such as neuroblastoma (Jamil et al 2013, 2014).
We have demonstrated that random injections of neuroblastoma into the diversity of human embryonic tissue/organoid-like compartments in PSCT results in non-random microcolonization initiated in tissue compatible with loose mesenchyme (Jamil et al 2013, 2014). Tropism in homologous microenvironment in the PSCT model provides a valuable complement to current PDX-modelling comprising non-homologous orthotropic mouse environment.
Microcolonisation of neuroblastoma is studied in PDX and PSCT models. Following chemotherapy, we use single cell, high throughput high content analysis (laser scanning; and Metafer systems) to visualise and quantitatively measure early outcome therapy response parameters.
Neuroectodermal tumours, human model, colonisation, progression, therapy resistance.
Martin Norin, PhD