Systems Biology of Breast Cancer

Despite much progress in breast cancer research, 20 to 25 percent of all women diagnosed with breast cancer die from the disease. The researchers working on the MetastasiX MRD Project now plan to elucidate the cellular and molecular determinants of breast cancer growth and progression to metastases. Their aim is to find new targets for therapies for the remaining lethal cases.

Breast cancer-related deaths are mostly caused by cancer cells spreading to distant organs during cancer progression. At distant sites, these smallest units of cancer able to replicate independently can grow as metastases and eventually lead to fatal complications. Although progress has been made in recognizing different types of breast cancer, the cancer cells responsible for metastasis formation and treatment resistance, and the underlying mechanisms and dynamics of breast cancer progression, are still poorly understood. 

Modeling breast cancer progression

For the development of new therapies, a systems-level understanding of the multiple signaling pathways and their integration into regulatory networks underlying breast cancer progression is required. Therefore, the MetastasiX MRD Project team plans to use computational and mathematical modeling of these complex biological systems to unravel and integrate the cellular and molecular determinants of breast cancer metastasis. The scientists will use mouse models which preserve the heterogeneous and dynamic characteristics of human breast cancer during progression, and validate their findings using clinical specimens from patients with breast cancer and data on their clinical outcomes. 

Integrating different approaches toward new therapies

To reach their goals, the researchers involved in the project will apply four interwoven and complementary approaches: the first will use sophisticated molecular biology techniques such as transcriptomic, phosphoproteomic and single-cell mass-cytometry to identify signaling networks driving the different stages of breast cancer progression, and to assess the cellular heterogeneity in the various stages of metastasis. The second approach will elaborate on this by comparing the results to blood and cancer tissue from patients with associated clinical outcome data. The third approach will evaluate these datasets to mathematically model the molecular and cellular dynamics during tumor progression. This will identify candidate metastasis-initiating cells and their signaling networks, which will be used to generate hypotheses for testing in the final stage of the project. Here, proof-of-concept experiments using cellular systems in vitro and animal models in vivo will validate the predictions of the mathematical models. This way the researchers will test the merit of candidate pathways and molecules as targets for new therapies that will improve the clinical management of lethal breast cancer.

Updated June 2015