Neuroblastoma micro colonisation and chemotherapy response/resistance
Research group leader:
Childhood cancers show fundamental differences to most common adult solid tumours in their cancer-causing genetics, cell biology and their local tissue microenvironment. Relatively few DNA mutations have been revealed compared with adult cancers.
Neuroectodermal tumours include some of the most common and deadly malignancies of children. Relapse is the main cause of death and the outmost challenge in cancer treatment is to inhibit continued growth and spread.
Neuroblastoma generally shows a high degree of inter- and intra-tumoural heterogeneity on the genetic as well as phenotypic levels, and unique abilities to spontaneously regress/differentiate or develop aggressive metastatic phenotypes. Here, analysis of therapy resistance is central.
Chemotherapy is predominant in first line therapy of high-risk neuroblastoma and response to treatment is associated with outcome. While large efforts are undertaken globally to identify new better alternatives, first line therapy is generally not open to wide selection of alternatives. Second or third line therapy in patients with recurrent or refractory disease where prognosis is poor leaves more room for individual alternatives and this is the main target of our research.
The microenvironment most likely contributes to clonal dominance and to the disparity between primary and metastatic tumours seen in many patients, as well as to inter-
tumour heterogeneity between patients with the same tumour type. Furthermore, response to chemotherapy is likely influenced by the local microenvironment. When modelling the relevant signalling of childhood cancer, it is critical to consider species and developmental aspects.
The analysis of rare cells in the original tumour specimen of solid tumours is a meticulous challenge and the possibilities to study clinically relevant repopulation in human tumours after chemotherapy have so far been more limited, with mainly evaluation from biopsy samples taken at various intervals after the last round of chemotherapy. Our group has explored a complementary possibility with in vivo expansion of rare clones into identifiable micro colonies developing in a human homologous experimental set up, suitable for transplantation of embryonic tumours (Gertow et al 2004, 2007, 2011, Cedervall et al 2011, Jamil 2013, reviewed by Hultman et al 2014).
Human diploid bona fide pluripotent stem cells (PSC) are known to develop into experimental benign teratomas (PSCT); mimicking development of embryonic tissues (e.g. Gertow et al 2004, 2007). The benign 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, reviewed by Hultman et al 2014). 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.
We have demonstrated that random injection/transplantation of neuroblastoma into the rich mixture of human embryonic tissue-compartments present in PSCT results in non-random micro colonization; exclusively initiated in tissue compatible with loose mesenchyme (Jamil et al 2013, 2014). This tropism, detected in homologous microenvironment, is an important complement to PDX modelling using non-homologous mouse orthotropic tissue.
Micro colonisation of neuroblastoma is studied in PDX and PSCT models. Following chemotherapy, we use single cell, high throughput high content analysis (laser scanning; and Metafer system) to visualise and quantitatively measure early outcome therapy response parameters.
Neuroectodermal tumours, human model, colonisation, progression, therapy resistance.
Martin Norin, PhD