The Shen Laboratory investigates the molecular mechanisms of mammalian development and cancer using in vivo analyses of genetically engineered mouse models. Initially, the Shen group focused on functional analyses of the signaling pathway for the TGF-beta ligand Nodal, and elucidation of the multiple mechanisms of its regulation during mouse embryogenesis. Presently, the lab research also encompasses analyses of prostate epithelial progenitor cells and their roles in organogenesis and tissue regeneration, focusing on the role of the Nkx3.1 transcriptional regulator as well as analysis of cell types of origin for prostate cancer. Ongoing projects include systems analyses of embryonic stem cell pluripotency, investigation of mechanisms of prostate epithelial lineage specification and cell-type differentiation, and generation of novel mouse models of advanced prostate cancer. Recent studies also include bladder cancer evolution and drug response through the analysis of patient-derived bladder tumor organoids.

The Acharyya laboratory is focused on understanding mechanisms of cancer progression and metastasis as well as the systemic effects of metastasis.Over 90% of cancer-related deaths in solid tumors are due to metastasis, which is the process of dissemination and growth of cancer cells in vital organs. During cancer progression, tumors systemically reprogram host physiology, metabolism, and immune responses. These systemic effects are mediated by the release of soluble factors, exosomes, and metabolites by tumors into the circulation. In metastatic disease, these systemic effects even impact tissues where cancer cells rarely metastasize, such as skeletal muscle, and leads to a debilitating muscle-wasting syndrome, known as cachexia. Cachexia is associated with a reduced tolerance to anti-neoplastic therapy, which contributes to poor prognosis and accelerated death in cancer patients. The Acharyya laboratory seeks to understand the mechanisms that drive cachexia, and to develop strategies that can treat cachexia.

Women who carry germline mutations in the BRCA1 tumor suppressor gene are prone to develop basal-like triple-negative breast tumors, an especially lethal subtype of human breast cancer. Richard Baer studies the mechanisms by which BRCA1 suppresses tumor formation and how these mechanisms are disrupted in BRCA1 mutation carriers. In vivo, BRCA1 exists in the form of a heterodimer with another structurally-related tumor suppressor, the BARD1 protein. Most of the cellular functions attributed to BRCA1, including its critical activities in genome stability and tumor suppression, are mediated by the BRCA1/BARD1 heterodimer. The Baer laboratory uses biochemical, cellular, and organismal approaches to characterize the BRCA1/BARD1 complex and its associated factors, such as the DNA repair protein CtIP. These studies seek to define the biological functions of the BRCA1/BARD1 pathway, particularly with respect to maintenance of genome stability, and how the loss of these functions promotes breast and ovarian cancer.

Katia Basso studies the process of differentiation of germinal center B cells and the mechanisms of malignant transformation leading to lymphomagenesis. Her interest is in dissecting the transcriptional networks that drive normal B cell differentiation and are hijacked in lymphomas. She integrates omics technologies, molecular and cellular biology, and in-vivo modeling to characterize normal B cells and their malignant counterparts. Her research informs on lymphoma features and dependences that impact diagnostics and therapeutics.

Christine Chio studies Pancreatic ductal adenocarcinoma (PDAC) that represents the third leading cause of cancer death in the United States. Lethality of PDA owes largely to the advanced disease stage at the time of diagnosis and to its profound resistance to existing therapies. Targeted therapy is a cornerstone of precision medicine, and is currently the focus of much anticancer drug development. However, in the context of pancreatic cancer, no chemical inhibitors exist for the most common KRAS mutations (G12D, G12V) even though it is well established that the oncogenic KRAS promotes drug resistance. Thus, a detailed understanding of the role of specific genetic lesions and their signaling surrogates in the initiation and progression of PDA is critical to improving treatment efficacy and patient outcome for this disease. Using genetically engineered mouse models and ex vivo culture systems, the Chio lab seeks to understand the basic mechanisms underlying PDAC biology such that vulnerabilities can be identified and tested for therapeutic intervention.

The research program in the Ferrando lab combines genomics, biochemical, genetic and experimental therapeutics approaches towards the identification of novel therapies for the treatment of high-risk leukemias and lymphomas. His laboratory has played major roles in the functional analysis of oncogenic NOTCH1 and the TLX1 and TLX3 oncogenes in the pathogenesis of T-ALL. In addition, he has identified and functionally characterized numerous genes somatically mutated in this disease including PTEN, WT1, PHF6, BCL11B, ETV6, EZH2 and NT5C2 as well as in peripheral T-cell lymphomas. Identifying and targeting major leukemia driver oncogenes by leveraging mouse models and forward genomics and deciphering the basic mechanisms underlying leukemic transformation and drug resistance are major areas of active research in the Ferrando lab.

Jean Gautier studies the mechanisms responsible for the maintenance of genome stability. The laboratory employs diverse experimental approaches to elucidate the causes and the role of genome instability in cancer. Cell-free extracts derived from the egg of the frog Xenopus laevis are used as a simple model system to study processes that govern genome stability, including DNA replication control, DNA repair, and the cellular response to DNA damage. In addition, cultured normal and tumor cells and mouse models are exploited to analyze biological responses to DNA damage. The Gautier laboratory use a range of techniques including biochemistry, proteomics, live-cell imaging, super-resolution microscopy, Hi-C and genome-wide translocation sequencing.

Over the past 20 years, the integrative approach of the Gu Laboratory, combining biochemical analyses and advanced genetically manipulated mouse models has been instrumental to dissect the precise roles of protein modifications in regulating p53-mediated tumor suppression. The Gu lab has made significant contributions to establishing the roles of acetylation-mediated regulation of non-histone proteins. They established that site-specific acetylation plays a critical role in promoter-specific regulation of p53 targets. They discovered that the acidic domain containing proteins act as a new “reader” for acetylated substrates critically involved in acetylation-mediated actions. These studies have laid the foundation for the view that reversible acetylation is a general mechanism for regulation of non-histone proteins. Through in-depth investigation, the Gu lab has revealed that “dynamic ubiquitination” (polyubiquitination, monoubiquitination and deubiquitination) is the major mechanism by which the stability and subcellular localization of p53 protein are determined. They found that the deubiquitinase USP7 (also called HAUSP) interacts with both p53 and Mdm2; and is an important therapeutic target for human cancers through activating p53 and downregulating oncoproteins such as N-Myc. By using p53 acetylation-deficient mutant mice, the Gu lab has demonstrated that acetylation is required for p53-mediated cell-cycle arrest, senescence and apoptosis in vivo. Subsequently, they found that p53 is able to induce its tumor suppression through its metabolic targets including promoting ferroptosis.

The research program pursued by Antonio Iavarone seeks to unravel the biologic and genetic alterations driving subgroups of malignant brain tumors and exploit this information for rational therapeutic stratification. The Iavarone group identified master regulators of cancer initiation and progression in distinct sub-groups of brain tumors. They discovered the first example of oncogenic and tumor addicting gene fusions in glioblastoma (FGFR3-TACC3) and reported that FGFR3-TACC3 fusions trigger tumorigenesis through activation of oxidative phosphorylation. These fusions are among the most frequent chromosomal translocations across all types of human cancer and the FDA approved the targeting of these chromosomal translocations with FGFR inhibitors. Antonio Iavarone chaired the Pan-Glioma ATLAS-TCGA Working Group and the Neurofibromatosis 1 synodos that united international researchers to formulate guidelines for accurate diagnosis and prognosis of glioma patients. By using all the computational and experimental tools at disposal, they combine innovations in both areas to continue making transformative mechanistic discoveries and provide personalized therapeutics to increasing number of patients with deadly tumor types.

Programs in Anna Lasorella’s lab combine the use of protein biochemistry, mouse models, and integrative systems biology to pursuit normal and pathological cellular functions of glioma-related genes. The common thread running through her research activities is her interest in identifying and characterizing drivers of malignancy in the brain that are linked to developmental processes and can inspire novel therapeutic strategies for malignant glioma. Her work generated transformative knowledge on the role of cell fate determination factors, such as ID proteins, in brain tumor development and maintenance and characterized, using molecular definition, the normal and oncogenic functions of these factors. Furthermore, she successfully pioneered the use of high throughput genomic technologies in the search for actionable lesions in glioblastoma. More recent research interest focuses on trans-disciplinary approaches combining data science and computational pharmacology to develop experimentally validated pipelines for personalized cancer therapeutics.

Teresa Palomero studies the genetics and mechanisms of transformation in Peripheral T-cell Lymphoma (PTCL), a heterogenous group of mature T-cell malignancies. Her group developed a cutting-edge research program implementing the integrative use of whole exome sequencing, gene expression profiling and single cell sequencing to identify novel drivers of transformation and tumor evolution in PTCL. They identified RHOA G17V and FYN mutations as major drivers of Angioinmunoblastic T cell lymphoma (AITL); dissected the mutational landscape of cutaneous T cell lymphoma (CTCL) and Sezary Syndrome; and identified new activating alterations in VAV1 in PTCL. Moreover, they pioneered the development of some of the first genetically engineered mouse models of AITL. Using those models in combination with in-depth understanding of the mechanisms of transformations in PTCL, the Palomero laboratory has the expertise to evaluate the impact of targeted therapies in T-cell lymphoma.

Laura Pasqualucci’s research interests are to elucidate the genetic basis of mature B cell malignancies, with emphasis on diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL). She takes advantage of integrated multi-omics approaches, biochemical assays and genetically-engineered mouse models to identify and functionally characterize human lymphoma-associated genetic alterations, understand the role of the affected genes in the physiologic germinal center (GC) reaction, a specialized microenvironment from which most B cell lymphomas come from, and dissect the mechanisms by which their dysregulation promotes lymphoma initiation and maintenance, the ultimate goal being to exploit this information for the development of novel biomarkers and rational therapeutic approaches. A major area of investigation focuses on the methyltransferase KMT2D and the acetyltransferase CREBBP, two histone/chromatin modifiers that we discovered as highly recurrent mutational targets and early events in the evolutionary history of FL/DLBCL, the loss of which contributes to the pathogenesis of these diseases by remodeling the epigenome of the GC.

The Zha lab has developed novel mouse models to investigate lymphocyte development, oncogenesis and therapeutic responses under physiological conditions. The lab has extensive experience in the molecular mechanism of DNA double-strand break (DSB) repair and the DNA damage responses in the context of lymphocyte development, hematopoiesis, lymphomagenesis, and therapeutic responses. Specifically, they have developed strong expertise in analyzing the non-homologous end-joining (NHEJ) DNA repair pathway and DNA damage responses during the somatic assembly (for example, V(D)J recombination) and subsequent modifications (for example, immunoglobulin class switch recombination) of the antigen receptor genes in developing lymphocytes.

Zhiguo Zhang’s laboratory studies epigenetic inheritance and cancer epigenetics. How epigenetic states are transmitted into daughter cells is a challenging, but yet poorly understood, question in the chromatin and epigenetic fields. Recently, it became clear that epigenetic alterations contribute to tumorigenesis and development of drug. However, how alterations in epigenetic landscape contribute to tumorigenesis and drug resistance is largely unexplored. The laboratory focuses on three major directions to study epigenetic inheritance and cancer epigenetics. First, how parental histones, the primary carrier of epigenetic information, are reassembled into nucleosomes following DNA replication in yeast and mammalian cells. Second, how onco-histone mutations found in gliomas reprogram cancer epigenomes. Third, how epigenetic changes drive drug resistance in brain tumors. The overall goal is to elucidate the molecular mechanisms of epigenetic inheritance and drug resistance and discover novel therapeutics for cancer treatment in the future.

Cory Abate-Shen seeks to understand how normal mechanisms of transcriptional regulation and cellular differentiation are co-opted in cancer. Research in the Abate-Shen laboratory is focused on prostate and bladder cancer and encompasses mechanism-based studies, analyses of genetically-engineered mouse models (GEMMs), and state-of-the-art systems biology approaches. They have developed an extensive series of GEMMs that represent the full spectrum of prostate cancer phenotypes, ranging from pre-invasive to invasive cancer, including castration-resistance, neuroendocrine differentiation, and metastasis. Capitalizing on these GEMMs, they have generated genome-wide transcriptional regulatory networks to pursue cross-species computational analyses of mouse and human prostate cancer, which have led to the identification of master regulators of cancer progression, biomarkers of disease outcome, and regulators of drug response and resistance. The lab has also developed novel approaches to target gene recombination specifically to bladder urothelium, which led to the generation of a novel series of mouse models of muscle invasive bladder cancer. These have enabled co-clinical trials that are impacting the treatment of patients with high-risk bladder cancer.

The amount of high throughput data in biological and clinical systems, from next-generation sequencing experiments to electronic health records, is increasing dramatically, allowing for the development of a quantitative understanding of these complex systems. Raul Rabadan has assembled an interdisciplinary team interested in developing mathematical and computational tools to extract useful biological information from large data sets.

The Shen Laboratory investigates the molecular mechanisms of mammalian development and cancer using in vivo analyses of genetically engineered mouse models. Initially, the Shen group focused on functional analyses of the signaling pathway for the TGF-beta ligand Nodal, and elucidation of the multiple mechanisms of its regulation during mouse embryogenesis. Presently, the lab research also encompasses analyses of prostate epithelial progenitor cells and their roles in organogenesis and tissue regeneration, focusing on the role of the Nkx3.1 transcriptional regulator as well as analysis of cell types of origin for prostate cancer. Ongoing projects include systems analyses of embryonic stem cell pluripotency, investigation of mechanisms of prostate epithelial lineage specification and cell-type differentiation, and generation of novel mouse models of advanced prostate cancer. Recent studies also include bladder cancer evolution and drug response through the analysis of patient-derived bladder tumor organoids.