Introduction

We will consider a system consisting of a primary tumor and its metastases as well as an underlying structure of molecular pathways that contribute to tumor growth and progression. We plan to develop a mathematical approach allowing understanding tumor genome data in terms tumor phylogeny and progression. In parallel, we will investigate a system of equations describing dynamics of the epithelial-mesenchymal transition (EMT), which is one of the ways healthy cells are enrolled in tumor architecture as well as an important step of cancer progression.  

Goal

Aim 1 Develop and validate models of clonal evolution of cancer cell populations in the primary and secondary tumors. Validate the models using experimental data obtained from specimens of breast and head and neck cancers. Based on the same data and literature, propose a model of metastatic spread in these cancers. Aim 2 Develop a model of tumor progression, using the example of the epithelial-mesenchymal transition (EMT) and its interaction with innate immunity (the NF-κB) regulatory module. Validate the model using cell-line experimentation, In addition, employ the models to develop a systemic approach to anticancer agents which explore immune system-related effects.

Tasks

Generalize the Kimmel-Tavaré model of selective sweeps (see Preliminary Studies) in cancer to multiple sweeps. Employ birth-and-death process coalescent of Lambert to improve the study the patterns of tumor growth based on site frequency spectra.Compare cancer genomes in primary solid tumor and matched concurrent metastasis to regional lymph nodes. We expect to identify genetic heterogeneity between primary tumor and local metastases, and to model evolution of cancer genomes during cancer spread/progression to evaluate the role of selection and new mutations.Replicate and extend the NF-κB – EMT circuit experiments of Brasier laboratory using cell lines with breast cancer and head-and-neck cancer characteristics. Employ native-immunity modifying agents to further explore the connection between NF-κB – EMT and anti-EMT action of such agentsDevelop models of stimulation of the immune system for treatment of cancer, using literature data and own models of immune response and validate it based on data from Task 3Generalize the proof-of-concept model of maintenance therapy to include realistic patterns of competition, growth and killing of sensitive and resistant cells and validate it based on data from Task 3

Contractors

Project manager

Marek Kimmel

Contractors

Wojciech Bensz, Monika Kurpas, Roman Jaksik, Paweł Kuś

Results

Articles