Measuring, Modeling, And Controlling Heterogeneity (M2CH)

Our M2CH Center is one of nine U54 Research Centers of the NCI Cancer System Biology Consortium (CSBC) program. The overall goal of our M2CH Center for Cancer Systems Biology is to improve management of triple negative breast cancer (TNBC) by developing systems level strategies to prevent the emergence of cancer subpopulations that are resistant to treatment. We postulate that heterogeneity arising from epigenomic instability intrinsic to cancer cells and diverse signals from extrinsic microenvironments in which cancer cells reside are root causes of resistance.

M2CH projects figure

Introduction

The overall goal of our M2CH Center for Cancer Systems Biology is to improve management of triple negative breast cancer (TNBC) by developing systems level strategies to prevent the emergence of cancer subpopulations that are resistant to treatment. We postulate that heterogeneity arising from epigenomic instability intrinsic to cancer cells and diverse signals from extrinsic microenvironments in which cancer cells reside are root causes of resistance.
 
We learn how intrinsic and extrinsic factors influence differentiation state, proliferation and therapeutic response in TNBC through experimental manipulation and computational modeling of cancer cell lines, 3D engineered multicellular systems, xenografts and clinical specimens. We deploy single cell ‘omic and imaging technologies that allow quantitative assessment of molecular, cellular, and structural heterogeneity. We interpret these data using computational models that define control networks and structures in heterogeneous systems as well as transitions between states of therapeutic resistance and sensitivity.
 
This is accomplished in three related Projects and three Cores. Project 1 focuses on measuring and managing resistance-associated heterogeneity intrinsic to cancer cells. Project 2 focuses on identifying resistance-associated signals from the microenvironment and on mitigating effects from these signals on therapeutic response. Project 3 applies spatial systems biology approaches to TNBC specimens and multicell type models thereof to discover molecular control networks that influence how cell intrinsic plasticity and microenvironment signaling alter therapeutic responses in complex tissues. All Projects analyze core cell lines, patient derived cultures, and FDA approved, pathway-targeted drugs (afatinib, ruxolotinib, trametinib, BYL719, cabozantinib, and everolimus).
 
An Imaging Management and Analysis Core provides infrastructure and image analytics that enables efficient image data management, quantitative analysis of image features, and visualization of images and metadata generated using multiscale light and electron microscopy. An Outreach Core makes available educational materials, experimental and computational tools and data to the scientific community.

Inquiries

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