Breast cancer cells-of-origin and tumor heterogeneity - Leander Blaas
Breast cancer is the most common cancer type in women and shows remarkable genetic and phenotypic heterogeneity. This diversity partly originates from mutations in different stem cells or progenitor cells, such that transformation of a mammary stem cell results in a different tumour phenotype than transformation of committed progenitor or differentiated cells. The identities of these peculiar progenitor cell populations and their tumor forming capabilities are incompletely understood.
Plasticity of human breast epithelial cells
My research focuses on studying the cellular and genetic determinants underlying human breast tumour heterogeneity.
Luminal breast tumors consist mostly of cells that resemble those found in the inner lining of the breast ducts (luminal mammary gland cells), whereas other tumors can have cells more similar to the outer layer of the breast epithelium (basal cells). Strikingly, the majority of human breast cancers develop from luminal breast epithelial cells, whereas only few tumor types derive from basal cells. In our group, we study the biology of breast epithelial cells and how transforming mutations affect their lineage-restriction and plasticity. To this end, we are developing genome-engineered human breast organoids to analyze how mutational events turn healthy cells into different types of breast tumors.
Cells-of-origin for breast cancer subtypes
Human breast cancers can be loosely grouped into luminal (luminalA and B), baso-luminal (Her2 – enriched), and basal subtypes (basal-like, claudin - low, and normal - like tumors), based on gene expression and histological characteristics. The phenotype of a given breast tumour is partly impacted by the normal precursor (‘‘cell-of-origin’’) subjected to neoplastic transformation. Growing evidence suggests that a basal or luminal tumour phenotype also depends on the nature of tumour-driving mutations. However, only little knowledge exists about which mutations have to occur in exactly what breast epithelial cell type(s) in order to form a distinct breast tumour subtype.
Therefore, we are analysing the impact of mutational events on distinct populations of breast epithelial cells and how they contribute to breast cancer inter- and intra-tumoural heterogeneity.
We are applying CRRISPR/Cas9 – mediated genome engineering to primary breast epithelial cells and together with advanced organoid technology, genetic lineage tracing, and xenotransplantation studies, we aim to identify the cells-of-origin for different breast cancers.
LGR6 expressing cells in normal breast development and breast cancer
We have recently discovered rare mammary epithelial progenitor cells expressing the G-protein-coupled receptor Lgr6. These lineage-committed progenitors contribute to mammary gland development and are potent cells-of-origin for mammary gland tumors. However, the exact identity of these cells and signalling mechanisms downstream of Lgr6 remain unclear.
We are investigating the identity and function of Lgr6 expressing human mammary epithelial cells and their role in breast tumour development in-depth, as well as Lgr6-mediated signalling and its effects on the biology of progenitor cells.
Group members
Leander Blaas, PI / Assistant Professor
I currently hold a position of assistant professor funded by Karolinska Institutet’s Board of Research (“KI FoAss”, since 2018) and lead my own line of research as principal investigator in the laboratory of Prof. Rune Toftgård.
I performed my PhD work at the Ludwig Boltzmann Institute for Cancer Research, Vienna/Austria, and received my PhD from the Medical University of Vienna in 2010 before joining Rune Toftgård’s laboratory as a postdoctoral fellow (2011 – 2017).
Pablo Fernández Pernas; Postdoctoral Fellow
Previous Members
Johanna Englund, PhD, Guest Researcher
Anne-Franziska Guthörl, Master student
Matilda Holm, guest researcher
Collaborations
National
Pekka Katajisto, Department of Biosciences and Nutrition, KI
Carina Strell/Arne Östman, Department of Oncology-Pathology, KI
Iyadh Douagi, Department of Medicine, KI
Linda Lindström, Department of Biosciences and Nutrition, KI
International
Emilio Casanova, Ludwig Boltzmann Inst. for Cancer Research, Vienna, Austria
Monica Musteanu/Mariano Barbacid. CNIO, Madrid, Spain
Johanna Englund, Institute of Biotechnology, University of Helsinki, Finland
Current Funding
Vetenskapsrådet: Etableringsbidrag/Starting grant (2018 - 2021)
Karolinska Institutet’s board of research: FoAss position (2018 – 2021)
Previous Funding
Marie Curie Intra-European fellowship
Wenner-Gren Foundation postdoctoral fellowship
Join the Group!
If you are excited about studying the mechanisms behind breast cancer heterogeneity, we are happy to receive tailored applications and expressions of interest from potential postdocs or master (M.Sc.) students. We will assist you with grant applications and interim financial support.
In case you are interested in joining our lab please send a letter of motivation and 2-3 academic referees to leander.blaas@ki.se.