The NCI Center for Modeling Cancer Development (CMCD) focuses on the analysis of cancer as a complex biological system. This center is part of the National Cancer Institute Integrative Cancer Biology Program (ICBP), which is a cornerstone in the development and implementation of computational models of processes relevant to cancer prevention, diagnostics and therapeutics. The integration of experimental biology with computational biology will result in new insights in cancer and new approaches to effective treatments.
This center brings clinical and basic cancer researchers together with researchers from mathematics, physics, information technology, imaging sciences and computer science to work on key challenges in cancer biology.
The scientific goals of the CMCD are to investigate mechanisms of tumorigenesis, cancer heterogeneity, progression and metastasis using a combination of computational biology, experimental biology and high-throughput technologies. Additional objectives are to develop bioinformatics tools and mathematical models for understanding the molecular mechanisms of tumor-niche communications, simulating the tumor behavior at cellular and tissue levels, and predicting treatment responses of cancer under different perturbations and drug treatments.
The CMCD encompasses many research projects of integrative data analysis and computational modeling at multiple scales of cancer biology. An example of the research projects is modeling breast cancer development based on the concept of tumor-initiating cells (TIC) (also referred to as cancer stem cells [CSC]). Our recent clinical data, as well as experimental evidence in both murine mammary tumors and human xenograft models, support the existence of a subpopulation of cancer cells from the original tumor that are greatly enriched in the residual cancers that survive conventional systemic therapies. These residual cancer cells are characterized by their intrinsic resistance to chemotherapy and relative growth quiescence. However, a discreet subset of these residual cells possesses enhanced self-renewal capacity, as well as the ability to form tumors upon transplantation. These residual tumor-initiating cells, which may be located in a certain tumor microenvironment, may therefore be responsible for tumor growth, maintenance, resistance to treatment and disease relapse. Our discoveries indicate that the failure of traditional systemic therapies, such as radiation and chemotherapy, to cure breast cancer may be due to the fact that they incorrectly target only the highly proliferative cells, while allowing the survival of the tumor-initiating CSC that are intrinsically resistant to these treatments. These findings fundamentally modify our conceptual approach to oncogenesis and have dramatic implications for breast cancer prevention, treatment and drug development.
In the CMCD, we seek to build upon, and significantly extend, ongoing laboratory and clinical studies and use newly developed experimental and imaging methods to identify, localize, purify and characterize TIC to a degree not possible before. This will then allow us to identify and image TIC in vivo and to mathematically model TIC behaviors and communications with multiple niche factors, e.g., stromal, fibroblast cells, growth, angiogenesis factors and nutrients during tumor development with respect not only to spatial localization and movement, but also to proliferation, apoptosis and specific changes in gene expression and cellular signaling. Combined functional genomics and data-mining strategies will allow us to characterize novel growth regulators. Furthermore, our combined experimental and systems biology approach will allow us to evaluate responses to experimental therapeutics that may inhibit or kill TIC specifically in a manner not possible before. Aside from a wealth of basic biological insight, extensions of this work may allow drug repositioning as well as development of directed, mechanism-based and “stem cell”-centric drug screening and evaluation methods.
Other ongoing projects in the center include:
- Computational modeling of the initiation of breast cancer and cell-cell interaction in different microenvironments
- Mathematical modeling of triple-negative breast cancer and breast cancer brain metastasis and their treatment responses
- Identification of key proteins and modeling subsequent pathways affecting genome stability in breast cancer formation and metastasis
- Modeling of next-generation sequencing data to identify tumor-stroma crosstalk in lung cancer
- Modeling of microenvironmental regulation of epithelial-mesenchymal transitions in cancer
- Modeling stroma-tumor interactions in ovarian cancer progression
The CMCD welcomes scientific collaborations in advancing the understanding, modeling and predicting of tumor formation and development. For details, please contact the Center's principal investigator, Stephen Wong, PhD, email@example.com.