A defining hallmark of primary and metastatic cancers is the invasion of malignant cells through surrounding tissues. Our lab is interested in the mechanical transgression of neoplastic transformation and the underlying physics of cancer cell metastasis. Toward this end, we are applying a constellation of enabling engineering platforms, in combination with multiple (epi)genome, chemical and mechanical manipulations, to trace the evolution of biophysical events that are hardwired to local cellular motions to metastatic-invasion of cancers - at nanoscale resolution.
Our research laboratory studies roles mobile DNAs play in human disease. Our group was one of the first to develop a targeted method for amplifying mobile DNA insertion sites in the human genome, and we showed that these are a significant source of structural variation. Since that time, we have continued to develop methods and reagents to characterize these understudied sequences in genomes and to understand mechanisms underlying the expression and genetic stability of interspersed repeats in normal and malignant tissues. We developed a monoclonal antibody to one of the proteins encoded for by Long INterspersed Element-1 (LINE-1) and showed its aberrant expression in a wide breadth of human cancers. We also have major projects focused on identifying functional consequences of inherited sequence variants, and exciting evidence that these predispose to cancer risk and other disease phenotypes. We use a combination of genome wide association study (GWAS) analyses, custom RNA-seq analyses, semi-high throughput gene expression reporter assays, and murine models to pursue this hypothesis.
The Casero laboratory is interested in inflammation/infection-associated carcinogenesis and identifying molecular targets to be exploited in chemoprevention strategies. Spermine oxidase (SMOX) is one such target that is highly induced in several inflammatory conditions. SMOX produces DNA-damaging H2O2 and is linked to carcinogenesis. Studies are ongoing to target SMOX for chemoprevention.
My research focuses on the keratin filament cytoskeleton in epithelial cells with an emphasis on skin tissue. He is working to gain a better understanding of keratin genes at a mechanistic and molecular level. His laboratory discovered several novel functions for keratin proteins, including a role in regulating protein synthesis and epithelial cell growth during epithelial remodeling events. Dr. Coulombe’s research has led him to devise a therapeutic strategy for the treatment of epidermolysis bullosa simplex (EBS) and related disorders.
The Drummond-Barbosa lab investigates how whole-body physiology influences the activity of tissue-resident stem cells using the Drosophila ovary system. They are currently identifying adipocyte and brain factors that contribute to the control of germline stem cells and their differentiating progeny in response to changes in diet or other stimuli.
Dr. Ewald has spent the past decade developing imaging, genetic, and 3D organotypic culture techniques to enable real-time analysis of cell behavior and molecular function in breast cancer. As a graduate student in Scott Fraser’s Lab at Caltech he utilized his physics training to develop and apply novel light microscopy approaches to reveal cellular interactions within intact tissues in real-time. During Dr. Ewald’s postdoctoral studies in Zena Werb’s Lab at UCSF, he developed novel 3D organotypic culture and imaging techniques to reveal the cellular mechanisms and molecular regulation of morphogenesis in primary normal and neoplastic mammary epithelia. His laboratory seeks to understand how epithelial cancer cells escape their normal developmental constraints and acquire the ability to invade and disseminate into normal tissues.
Laboratory of Gene Regulation
Gene regulation: Using multi-disciplinary and quantitative imaging, genomics and proteomics approaches, my lab uncovers novel roles of non-coding RNAs, non-membranous granules, and post-translational modifications.
Technology development: My lab develops proteomics and informatics tools to dissect the roles of a post-translational modification called ADP-ribosylation.
Disease focus: My lab seeks to translate our basic scientific findings to therapy, e.g., PARP inhibitor in cancers and Chikungunya viral infection.
My laboratory is interested in the molecular mechanisms by which cells interpret signals from their environment that instruct them to proliferate, differentiate, or die by apoptosis. A particular focus of the lab is the regulation of NF-κB, a pleiotropic transcription factor that is required for normal innate and adaptive immunity and which is inappropriately activated in several types of human cancer.
My group currently focuses on identifying genetic alterations in cancer affecting sensitivity and resistance to targeted therapies, and connecting such changes to key clinical characteristics and novel therapeutic approaches. We have recently developed methods that allow non-invasive characterization of cancer, including the PARE method that provided the first whole genome analysis of tumor DNA in the circulation of cancer patients. These analyses provide a window into real-time genomic analyses of cancer patients and provide new avenues for personalized diagnostic and therapeutic intervention.
Neurodegeneration is a poorly understood biomedical phenomenon and a major public health challenge in our increasingly aging society. Our goal is to describe at the molecular and cellular levels how specific neurons degenerate, how protein folding and misfolding operate in the cell, and how protective systems fail at disease stages.
My research activities focus on defining the environmental and genetic determinants of allergic airway diseases such as asthma. My lab members and I have specifically explored the role of CD4+ Th2 cells and cytokines (IL-13), and innate immune pathways (complement activation pathways, TLRs, CLRs), in the pathogenesis of asthma. I have made substantial contributions to our understanding of the molecular mechanisms underlying allergenicity of common allergens-specifically how allergens and airborne pollutants activate innate immune pathways through molecular mimicry (Nature). More recently, I have turned my attention to how the gut microbiome alters susceptibility to allergen and PM-induced asthma.