Project Details
Projekt
Cell lineage analysis of metastatic desease
Applicant
Professor Dr. Ehud Shapiro
Subject Area
Pathology
Term
from 2014 to 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 242727105
The cellular dynamics of human cancers are generally unknown and many questions regarding the relations between primary tumour cells and metastases are open, most importantly the origin and nature of metastasis-generating cells, and the genetic diversity of both primary tumours and metastasis that contributes to functional heterogeneity. To address these questions our team has previously developed a method for cell lineage tree reconstruction utilizing random somatic mutations of microsatellites (MS) accumulated during cell divisions. This retrospective method is based on the concept that somatic mutations, which have accumulated during cell divisions, endow each cell with a genomic signature that, with very high probability, is unique. The distances between the genomic signatures of different cells, as measured using mathematical methods, can then be used to reconstruct a cell lineage tree. Applying cell lineage analysis to metastasis research enables to follow cancer cell subpopulations in their natural environment over a relevant time scale (before and after the creation of metastases) and to pinpoint changes in diversity and environment contributing to metastasis formation. It is currently unknown which subpopulation of cells are able to found metastases. There is neither proof for a cancer stem cell concept nor for a stochastic model to metastasis formation. By applying lineage analysis to individual cancer cells before and after metastasis formation and to cells from different metastases within the same individual we aim to identify the subpopulation of the tumour that generated the metastatic clones, and then characterize them in depth. Furthermore, substructure of the metastasis itself and the evolution of multiple metastases will be further explored in order to resolve questions such as the contribution of specific metastases to generalized disease. The correlation between the lineage tree attributes and other data that will be produced by the consortium will be combined in order to get a better understanding on the mechanisms of metastasis formation.
DFG Programme
Research Units
International Connection
Israel
