INTRODUCTION

Breast cancer is diagnosed in ~1.4 million women worldwide and ~500,000 lives are lost to the disease annually, the vast majority due to metastasis. Curing metastatic breast cancer clearly represents an unmet medical need. Patients may do well after surgery and adjuvant treatment but drug-resistant, fatal metastases often develop. Critical to the phenomenon of resistance is tumor heterogeneity (Ramos and Bentires-Alj, Oncogene 2015, Koren and Bentires-Alj, Molecular Cell 2016) and this is the thread connecting the research in our
lab.

Tumor heterogeneity impinges on prognosis, response to therapy, and metastasis and is one of the most important and clinically relevant areas of cancer research. Heterogeneity results from genetic and epigenetic alterations that enhance the plasticity and fitness of cancer cells in the face of hurdles such as the metastatic cascade and anti-cancer therapies. At the molecular, cellular, and whole organism levels, we assess mechanisms that influence normal and neoplastic breast stem cells, metastasis, and resistance to targeted therapies.

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We explore both cell autonomous (genetics, epigenetics, and proteomics) and non-cell autonomous mechanisms (immune cells, adipcoytes, and other stromal factors). We use systems medicine quantitative methods, synthetic lethal screens, unbiased pooled shRNA, CRISPR, transposon-based screens, and hypothesis-driven approaches. Computational biology is a very important part of our research. Moreover, we use multiphoton intravital imaging to assess the interactions between cancer cells and immune cells.

These interdisciplinary projects seek to elucidate the integrated effects of signaling pathways and epigenetics on breast cell fate and tumor heterogeneity, and to leverage this mechanistic understanding into therapy. To this end, we collaborate with clinicians and have built a Breast Cancer Personalized Medicine Team which should ultimately improve treatment for patients in Basel and throughout the world.


MOLECULAR MECHANISMS CONTROLLING NORMAL AND NEOPLASTIC BREAST CELL STATES


CELL-AUTONOMOUS MECHANISMS CONTROLLING RESISTANCE AND METASTASIS 


NON-CELL-AUTONOMOUS MECHANISMS CONTROLLING RESISTANCE AND METASTASIS


Novel technologies and model systems

We have developed novel technologies and original tools to study the molecular mechanisms of stem cells, metastasis and resistance. These include novel 3D culture conditions of human breast epithelial cells (Duss et al., BCR), invasive 3D cultures of transformed breast cells (Aceto et al BCR; Alajati et al, Cancer Res), conditional knockouts and transgenic mice (Meyer et al, Cancer Res; Koren S., FEBS J), primary derived xenograft models of breast cancer and a multiphoton intravital microscope for studying tumor stroma interactions and metastasis in 4D and at a single-cell level (Bonapace et al, JMGBN and Nature).