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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.

Breast epithelial organoid

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.

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Model of associations between cell-of-origin and tumor type in breast cancer

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.

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Keratin 8 and 14 staining in a murine mammary gland during pregnancy.

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 Toftård’s laboratory as a postdoctoral fellow (2011 – 2017).

Pablo Fernández Pernas; Postdoctoral Fellow

Agneta Andersson, Biomedical Scientist

Maryam Saghafian, Senior Lab Manager (currently on maternity leave)

Xiaoze Li-Wang, Senior Lab Manager

Previous Members

Johanna Englund, PhD, 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  PhD students. We will assist you with grant applications and interim financial support.

We are also looking forward to applications from master (M.Sc.) students

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.

Leander Blaas

Assistant professor
Department of Biosciences and Nutrition (BioNut), H2