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
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.
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
- Breast Tumor Heterogeneity: Source of Fitness, Hurdle for Therapy. (Koren and Bentires-Alj, Molecular Cell 2016)
- PIK3CAH1047R induces multipotency and multi-lineage mammary tumors (Koren et al., Nature 2015).
- Expression of the human oncogenes PIK3CA H1047R and E545K in mammary epithelium of mice evokes heterogeneous tumors (Meyer, Cancer Res 2011; Koren, FEBS J 2013; and Meyer, Oncogenesis 2014).
- Effects of early pregnancy on mammary epithelial cell fate (Meier-Abt, Breast Cancer Res. 2013, 2014 and Trends in Molecular Medicine 2014).
- Mesenchymal precursor cells maintain the differentiation and proliferation potential of human breast epithelial cells (Duss, Breast Cancer Res. 2014 and 1 patent).
- SHP2 promotes breast cancer progression and maintains the tumor-initiating cell population (Aceto, Nature Medicine 2012; Aceto, Oncotarget 2012; and 2 patents).
CELL-AUTONOMOUS MECHANISMS CONTROLLING RESISTANCE AND METASTASIS
- Mechanism-based cancer therapy: resistance to therapy, therapy for resistance. (Ramos and Bentires-Alj, Oncogene 2015)
- Activation of IGF1R/p110β/mTOR confers resistance to α-specific PI3K inhibition (Leroy et al., Breast Cancer Res 2016).
- Tyrosine phosphatase SHP2 increases cell motility in triple-negative breast cancer through the activation of SRC-family kinases. (Sausgruber et al., Oncogene 2015).
JAK2/STAT5 inhibition circumvents resistance to PI3K/mTOR blockade: a rationale for co-targeting these pathways in metastatic breast cancer (Britschgi, Cancer Cell 2012, Drug Resistance Updates 2014 and 2 patents).
- The identification and validation of the effects of PTP1B, PTPα, PTP-PEST, delta-HER2 and ANO1 in breast cancer (Blakatraman et al., Mol Cancer Res 2011, Meyer et al., Oncogene 2014, Aceto et al., Cell 2011, Alajati et al., Cancer res 2013, Britschgi et al., PNAS 2013).
NON-CELL-AUTONOMOUS MECHANISMS CONTROLLING RESISTANCE AND METASTASIS
- Discontinuation of CCL2 inhibition accelerates breast cancer metastasis by promoting angiogenesis (Bonapace et al., Nature 2014).
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).