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.
We seek to understand the molecular mechanisms of macromolecular assemblies that organize, express, and preserve the cell’s genetic information. We are particularly interested in developing kinetically accurate, atomic-resolution depictions of the dynamic assemblies that control DNA replication, gene regulation, and chromosome superstructure, and in exploiting this knowledge for chemotherapeutic development.
Oxidative stress, metabolic adaptation and therapeutic resistance of cancer:
We discovered that non small cell lung cancer frequently develop gain of function in Nrf2 due to KEAP1 mutations, which increases antioxidants and alters metabolism to drive tumor growth and cause therapeutic resistance. This has changed the paradigm in cancer biology and develop our understanding of dark side of antioxidants in cancer cells. Our current effort will help unravel mechanisms of oncogenic cooperation and metabolic adaptation using patient-derived xenografts in humanized immunocompetent mice and GEM models.
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.
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.
Research in our laboratory is focused on the understanding of molecular mechanisms that regulate the mitochondrial contribution to programmed cell death and inflammation signaling. Both processes are fundamental to a variety of diseases, including cancer, neurodegeneration and infectious diseases. In this context we are specifically interested in mitochondrial autophagy and interorganellar interactions, including with the endolysosomal compartment. We are applying a combination of fluorescence microscopy, molecular and cell biological, and biochemical approaches. Our studies aim at uncovering novel cell biological insights that can be exploited to combat diseases.
My laboratory aims to understand the molecular mechanisms regulating eukaryotic signaling of pathways. This knowledge provides the framework needed to interpret how alterations to a pathway, such as additional proteins, mutations to pathway components, or small molecules, modulate activity and could help guide targeted therapies. To achieve this, my lab employs a multi-prong approach that combines cell-based assays, biochemistry, enzymology, biophysics, and structural biology.
The Meeker laboratory is located at the Johns Hopkins University School of Medicine. Utilizing a combination of tissue-based, cell-based, and molecular approaches, our research goals focus on abnormal telomere biology as it relates to cancer initiation and tumor progression, with a particular interest in the Alternative Lengthening of Telomeres (ALT) phenotype. In addition, our laboratories focus on cancer biomarker discovery and validation with the ultimate aim to utilize these novel tissue-based biomarkers to improve individualized prevention, detection, and treatment strategies.
Dr. Pienta is involved in research to define the tumor microenvironment of prostate cancer metastases, as well as developing new therapies for prostate cancer. Current research projects in the lab are studying why prostate cancer preferentially disseminate to the bone and can remain dormant for many years before returning to a proliferative phenotype that results in metastatic disease. Additionally, his research team is looking at ways to isolate, identify, and characterize these disseminated tumor cells so that new therapies can be designed to target them prior to becoming “reactivated” and metastatic.
My research work focuses on various aspects of breast carcinogenesis, particularly the molecular and hormonal mechanisms underlying breast tumor growth, epithelial-mesenchymal transition, invasion, migration and breast cancer prevention. My studies have established important markers for development of acquired tamoxifen resistance. We are actively investigating novel molecular targets and pathways involved in chemopreventive role of bioactive components.
My laboratory is broadly interested in how dNTP pool levels and composition influence genetic stability, adaptive and innate immunity, inflammation, carcinogenesis, cellular senescence and aging. Current work in the lab focuses on two key aspects of dNTP metabolism. We are elucidating how the uniquely high concentration of dUTP in resting immune cells is used as a potent HIV-1 restriction factor in macrophages. We are also interested in the epigenetic effects of uracil when it is present in DNA. Our long-range goal is to design novel small molecules that predictably alter the make up of nucleotide pools in cells for antiviral, anticancer, and anti-inflammatory therapeutic uses.
Our laboratory is interested in investigating the signal transduction and gene regulation in bacterial infection- and genotoxic stress-associated colonic inflammation and tumorigenesis, using a combination of genetic, immunological, molecular, and cellular approaches. We are studying the molecular/cellular mechanisms and pathophysiological significance of the novel and critical pathogen-host interactions and DNA damage responses that can be mechanistically linked to colon cancer etiology in mouse and human.