Systems Biology of Tumor-Immune-Stromal Interactions in Metastatic Progression

ABSTRACT/SUMMARY – Overall Distant metastasis is the primary cause of cancer-related death. To colonize distant tissues, cancer cells must migrate while evading elimination by the immune system. Evidence suggests that key steps in the induction process of immune tolerance occur early in the metastatic cascade, located at the regional lymph nodes proximal

to the primary tumor site. However, the nature of the interactions between malignant, immune and stromal cells remains poorly understood, including those that involve metastatic cells within the lymph nodes. Even though lymph nodes are in fact commonly assessed in cancer patients to determine disease stage and treatment plan,

they are understudied in the context of metastatic progression. To fill this scientific knowledge gap, we propose a Research Center to unravel the role of lymph nodes in metastatic progression. We have established that lymph node metastasis constitutes an essential, first step in the metastatic cascade of cancer progression. We have

found that such metastases act locally upon the adaptive immune system within the lymph nodes to begin to induce systemic tolerance of the tumor. We will further explore this new paradigm of metastases in two malignancies, head and neck cancer and lung adenocarcinoma, by focusing on the kinetics and spatiotemporal

changes at the primary tumor, lymph node and distant sites, associated with the onset and progression of metastasis. We have assembled a multidisciplinary team whose coordinated efforts will involve the application of genomic and single-cell in-situ imaging technologies on preclinical and human samples to explore the

evidence and mechanisms of the induction of immunosuppression in the lymph nodes. We propose two Research Projects that focus our scientific theme on lymph node metastasis by analyzing kinetics in a mouse model (Project 1) and spatial temporal changes in samples of lymph nodes and their concurrent primary tumor

(Project 2), inter-connected through integrative computational analyses. Both projects will utilize a shared resource core dedicated to the acquisition of patient samples and associated clinical annotation and data management (Biospecimen Core and Data Core). These efforts will yield highly multiplexed, multi-scale datasets

which will be analyzed by novel bio-computational methods to reconstruct intracellular and intercellular molecular interaction networks in order to identify, then functionally validate, critical mediators of metastasis. Our ultimate objective is to advance our understanding of the systemic consequences of lymph node metastases and identify

new biomarkers and therapeutic approaches. Our Research Center is also dedicated to promoting our early investigators as the next generation thought leaders applying principles of systems biology to the study of metastasis. Our Outreach Core activity will ensure that our Research Center’s scientific and methodological

advances in applying the principles of cancer systems biology toward the study of tumor-immune-stromal interactions are fully disseminated in the cancer research and broader communities.