Spatiotemporal modeling of cancer-niche interactions in breast cancer bone metastasis

Overview

Project Name

Spatiotemporal modeling of cancer-niche interactions in breast cancer bone metastasis

Project Center

Houston Methodist Cancer Center
Baylor College of Medicine

Project Description

About 20-40% of breast cancer patients develop metastasis to the bone, years to even decades after surgical removal of primary tumors. Little is known about the biology of the latent, microscopic bone metastases before they outgrow to overt osteolytic macrometastases. This represents a significant gap in our understanding of bone metastasis. Targeting cancer cells that have not fully adapted to the bone microenvironment might provide therapeutic benefit and prevent the occurrence of overt metastases. Bone and bone marrow comprise of several highly distinctive microenvironment niches. Dormant, single disseminated tumor cells (DTCs) reside in the perivascular niche, whereas proliferative, multi-cell bone micrometastases (BMMs) are found in the osteogenic niche that exhibits features of active osteogenesis. Mechanisms through which the transition of different niches occurs to switch fates of metastatic seeds remain elusive. The overall objectives of this project are to investigate the spatiotemporal dynamics, the molecular crosstalk, and the therapeutic targets underlying the interaction between breast cancer cells and different microenvironment niches in bone. We will pursue three specific aims. First, we will dissect the spatiotemporal dynamics of the perivascular and osteogenic niches and the cancer-niche interactions in bone micrometastasis models. We will use high-resolution, whole bone, multi photon microscopy and laser-captured microdissection (LCM) followed by transcriptome profiling (LCM-seq) to obtain relative localization and mutual impacts between cancer cells and niche cells in situ. Second, we will integrate transcriptomic and imaging data and develop computational models for discovery of new mechanisms and therapies toward blockade of cancer-niche interactions. Established and new algorithms will be used to uncover the microenvironment molecules, and autocrine and paracrine signaling pathways mediating niche-tumor interactions. Drug-repurposing analyses will be carried out to identify potential therapies that have already been used for other diseases. We will achieve a systematic understanding of early-stage bone colonization and generate testable mechanistic and therapeutic hypotheses. Third, we will validate the discovered mechanisms and predicted drug efficacies in animal models. The Zhang laboratory has adopted and established a series of genetically engineered mouse models and bone metastasis assays, which will be utilized to validate computational predictions generated by computational modeling by the Wong group. Both metastatic burden and frequency/distribution of DTCs and BMMs will be examined as endpoints. This study will unbiasedly profile the molecular process of early stage metastasis progression in the bone from DTCs to BMMs at single-to-few cell resolutions. This knowledge is unprecedented and critical for the ultimate understanding of metastasis latency, a long-standing clinical challenge. The modeling tool developed through this study will likely be applicable to other biological contexts involving highly spatiotemporally specific cancer niche interaction. The computer-aided drug repurposing will likely lead to fast clinical translation.

Investigators

Stephen T.C. Wong, PhD, PE

Dr. Wong is the Founding Chair of Systems Medicine and Bioengineering Department and Director of Advanced Cellular and Tissue Microscopy Core, Houston Methodist Research Institute; Associate Director of Shared Resources, Houston Methodist Cancer Center; John S Dunn Presidential Distinguished Chair in Biomedical Engineering and Chief Research Information Officer at Houston Methodist; Professor of Radiology, Pathology, Laboratory Medicine, and Neuroscience at Weill Cornell Medicine. The mission of the Wong Lab is to elucidate biological mechanisms and translate the findings into diagnostic, therapeutic, and prevention strategies for cancer and neurodegeneration, as well as the crosstalk between the two diseases. He was a researcher with AT&T Bell Labs and HP before starting his academic medicine career as a faculty member of Radiology at UCSF, where he was the systems architect of the pioneering UCSF picture archiving and communication systems (PACS) program that transformed the practice of radiology. Later, he directed integrated product development effort at Philips Healthcare. At Harvard, he founded two campus-wide research centers, one for bioinformatics research for neurodegeneration at Harvard Medical School, where he pioneered the integration of high content screening and systems biology to delineate disease mechanisms, and the other for functional and molecular imaging at Brigham and Women’s Hospital (BWH), including the creation of the first cyclotron and functional and molecular imaging core facilities at BWH. At Houston Methodist, Dr. Wong created the Center for Modeling Cancer Development and the Division of Shared Resources at Houston Methodist Cancer Center, as well as the T.T. & W.F. Chao Center for BRAIN, Cellular and Tissue Microscopy Core and Systems Medicine and Bioengineering Department at Houston Methodist Research Institute. Dr. Wong’s research at Houston Methodist has led to several clinical trials for breast cancer drug repositioning, digital therapeutics for cancer patients and survivors, image-guided intervention for lung cancer, and AI in precise breast cancer risk assessment. He published over 500 peer-reviewed scientific papers and granted 9 patents in informatics, imaging, and drug discovery.

Xiang “Shawn” Zhang, PhD

Dr. Zhang is Professor in the Lester and Sue Smith Breast Center and Department of Molecular and Cellular Biology at Baylor College of Medicine. Dr. Zhang has been working in the field of cancer metastasis for over 14 years and published over 60 papers in first-rate journals. The long-term goal of his laboratory at Baylor College of Medicine (BCM) is to elucidate biological mechanisms and therapeutic strategies of metastasis, the major threat to the lives of solid cancer patients. Toward this end, his group has developed a set of unique techniques and models to study the interaction between microscopic metastases and various stromal components in different organs particularly in the bone. They have discovered that in early stage of colonization disseminated breast cancer cells localize to a specific microenvironment niche comprised of osteoblasts and their precursor cells, which they named the “osteogenic niche”. The osteogenic niche interacts with cancer cells via heterotypic adherens and gap junctions, which in turn alter multiple pathways in cancer cells and confer unexpected therapeutic vulnerability and resistance.