Single-cell characterization of tumor and microenvironment coevolution in Peripheral T-cell Lymphomas
Overview
Project Name
Single-cell characterization of tumor and microenvironment coevolution in Peripheral T-cell Lymphomas
Center Summary
Tumor, stromal cells and frequently pathogens coexist in a complex ecosystem whose interactions can determine clinical outcomes. A paradigmatic example of tumor-stromal coevolution in the presence of latent viral infection is given by peripheral T-cell lymphomas (PTCLs), a highly diverse aggressive group of non-Hodgkin lymphomas with less than 30% 5-year survival. Using large scale genomic approaches, our team has recently identified key driver genetic alterations for several PTCL subtypes. Despite these recent genomic efforts, the molecular determinants in many of these tumors and their contribution to lymphomagenesis, proliferation and prognosis remain unknown. Furthermore, with a few exceptions, the genomic heterogeneity in PTCL fails to delineate between clinical outcomes, underlying the necessity for new molecular markers.
One of the key characteristics of PTCLs is their highly complex stromal milieu where clonal lymphoid malignant cells commonly represent only a minority of the tumor. Our preliminary analyses have identified clinically relevant microenvironmental immune cell signatures in PTCL, including the association of naïve B-cells with good prognosis and M2 macrophage infiltration with poor survival. In addition, we have characterized the viral ecology of PTCL and found a significant association between the Epstein-Barr virus (EBV) replication stage and survival in EBV-associated subtypes. Taken together, these recent findings highlight the importance of the tumor microenvironment in the origin, development and prognosis of PTCL. But how do the tumor and microenvironment coevolve and inform prognosis?
High throughput single cell experiments provide the opportunity to dissect the complex stromal environment and its role in oncogenesis and progression. Our team has recently developed single-cell analytic approaches to address key challenges of particular relevance in the study of dynamic complex cell populations as the ones found in PTCLs, including denoising and reconstruction of progression. In this proposal, we will further develop and apply these technologies in the setting of PTCL to analyze the coevolution of malignant lymphoid cells and the microenvironment in mouse models and human samples.
Investigators
Investigators
Raul Rabadan
Raul Rabadan is a Professor in the Department of Systems Biology and Biomedical Informatics at Columbia University. He is the director of the Program for Mathematical Genomics at Columbia University and the NCI Center for Topology of Cancer Evolution and Heterogeneity. From 2001 to 2003, Dr. Rabadan was a fellow at the Theoretical Physics Division at CERN, the European Organization for Nuclear Research, in Geneva, Switzerland. In 2003 he joined the Physics Group of the School of Natural Sciences at the Institute for Advanced Study. Previously, Dr. Rabadan was the Martin A. and Helen Chooljian Member at The Simons Center for Systems Biology at the Institute for Advanced Study in Princeton, New Jersey.
Teresa Palomero
Teresa Palomero is an Associate Professor in the Institute for Cancer Genetics and the Department of Pathology and Cell Biology at Columbia University Medical Center. Dr. Palomero obtained her PhD at the University of Oviedo (Spain) and completed her postdoctoral work in the Dana Farber Cancer Institute in Boston, working on the regulation of transcription factor oncogenes in T-ALL. She joined the faculty at Columbia University in 2005 where she has been working on the identification of novel mutations associated with T cell malignancies, functional analyses of the mechanisms used by driver alterations in T-cell lymphoma and generation of preclinical models for dissecting lymphoma development, the interaction of the tumor and microenvironment components and identifying novel targeted therapies.
Ioan Filip
Ioan Filip is a postdoctoral research scientist in Systems Biology working on new multi-omics methods for cancer immunology. He received his Ph.D. in Mathematics from Columbia University in 2016 and, as a member of the Rabadan Lab, Ioan is also pursuing algebraic and topological evolutionary models of viruses and tumors.
Jose R. Cortes
Jose R. Cortes is Research Scientist in the Institute for Cancer Genetics at Columbia University Medical Center. Dr. Cortes has a background in T-cell immunology and ample expertise the analysis of T-cell development and transformation in preclinical models for peripheral T-cell lymphoma. His work has determined that the highly prevalent RHOA G17V mutation identified in angioimmunoblastic T-cell lymphoma (AITL) is lineage specification driver that induces differentiation towards Follicular T helper cells, a T cell subset involved in B cell activation in the germinal center and the cell of origin of AITL.
Robert Albero
Robert Albero is a postdoctoral fellow working on the epigenetic mechanisms driving hematological malignancies. During his PhD in IDIBAPS (Barcelona) he described the role of cyclin D1 in transcription dysregulation in mantle cell lymphoma. He joined the Institute of Cancer Genetics at Columbia University in 2018 and his scientific interests are focused on the integration of genomic and epigenomic data in preclinical models of T-cell malignancies and develop new therapeutical approaches.