The loss of internal controls that limit and regulate cell growth is a hallmark of cancer cells. Although cancer cells tolerate certain levels of changes to their DNA they must retain the blueprints for building the machinery required for cell growth and survival. Thus, they must still duplicate and transmit their genomes from one generation to the next with minimal errors in order for the tumor to continue to grow. The checkpoints that monitor these processes are rarely defective in cancer cells and are often highly active due to the loss of other control mechanisms. By inducing additional stress and/or inhibiting these remaining checkpoints we can induce death in tumors. The goal of our research is to understand how cancer cells overcome their internal stress and cope with drug-induced stress to guide the development of improved therapeutic strategies. Our work focuses on the interplay between ubiquitin ligases and cellular checkpoints, ensure the fidelity of these essential processes. We currently have two main projects. In the first project, we are examining the role of the deubiquitinating enzyme USP37 in the regulation of replication and the cell cycle. The second project focuses on the regulation of chromosome segregation in mitosis. We utilize a multi-faceted approach to achieve our goals including; proteomic, cellular, microscopy, and biochemical based analyses. Potential projects include construction of cellular models for monitoring cell growth or to enhance proteomic studies, analysis of protein-protein interactions in a purified system, and live cell analysis of cellular response to drug-induced stress, among others.
The main focus of my research is on pre-clinical development of effective strategies for metastatic cancer treatment. Currently, Vilgelm laboratory investigates ways to stimulate anti-tumor immunity by inducing “hot”, immune-cell enriched, tumor micro-environment. Specifically, modulation of molecular mechanisms controlling tumor secretome in explored. In addition my research team is developing personalized medicine approaches to induce synthetic lethality in tumor cells using rational drug combinations. They utilize a variety of pre-clinical research models including 3D organoid cultures of patient's tumor cells and humanized patient-derived models. Our ultimate goal is to develop new therapeutic approaches to stimulate anti-tumor immunity that prevents tumor relapses resulting in long lasting disease control. We are located in the Biomedical Research Tower. The summer student joining the lab will have a defined independent research project involving pre-clinical assessment of efficacy of a novel rational drug combination. She/he will have opportunity to work with patient-derived organoids, learn automated microscopy, drug screening, fluorescent imaging, and image analysis. Support and guidance will be given by senior scientists in the laboratory. We have weekly formal group meetings to guide student's research progress and regular one-on-one meetings with me will take place as well. I will work closely with student to analyse data, prepare presentations and abstracts to share the research findings from this project with the research community. Many of my prior summer students co-authored research manuscripts in well-respected journals, including Science Translational Medicine, Cancer research and EbioMedicine. I have no doubt that student joining my laboratory this summer will have exciting and productive research experience.
My main ongoing research project is focused in oncology research and looks at ESR1 and ESR2 expressions in human diffuse large B-cell lymphoma (DLBCL). Our aims for this project are to generate molecular signature profiles of ESR1 and ESR2 expressions in DLBCL, to study the drug effects of an ESR2 agonist on human DLBCL cell lines as a preclinical model, and to examine the epigenetic regulations on the expressions of ESR1, ESR2, and their isoforms in the presence of the ESR2 agonist drug.
This work is taking place in my research laboratory housed within the Division of Molecular Pathology, based in the James Cancer Hospital and The Ohio State University Wexner Medical Center, Department of Pathology. It occupies approximately 1,172 square feet of personal laboratory space which is equipped and utilized for high-throughput genomics, cell/tissue analysis, and routine laboratory work. The space holds workbench and office desk space for 6-8 technicians and postdoctoral fellows to work. There are separated benches to divide areas for sample preparation, tissue immunohistochemistry (IHC)/immunofluorescence (IF), and PCR and post-PCR analysis. There is a separate tissue culture room with automated cell extraction and culture facilities (3 BSC), extensive liquid nitrogen storage, dark room with Western-blot image developer, and adjacent small animal facilities/vivarium.
Students can also expect to gain experience in basic laboratory bench work and processes, data collection and analysis, and utilize equipment such as sequencing platforms (Illumina), quantitative PCR platforms (Bio-Rad), multiplex RNA analysis, IHC/IF platforms, and microscopes.
Summary of Project/Approach: Our long-term goal is to improve outcome of patients with GB by optimizing clinical management decisions for each patient. The objective of this application is to develop and validate new techniques in branch point decision making — specifically developing novel computer-assisted image analysis algorithms to predict pseudoprogression by analysis of features present in data available from the first resection, and to determine clear histological and molecular criteria for the histopathological designation of tumor recurrence at the patient’s second resection. This new information would inform treatment decisions of the neuro-oncology team regarding early MRI changes which are currently mired in a setting of uncertainty and to provide consistently reliable molecular pathway analysis to predict GB recurrence. Our hypothesis, based on our preliminary data and supported by the literature, is that by applying computerized image analysis of radiological and histological data with gene expression studies, improvements in diagnostic accuracy in GB can be achieved. The research project is utilizes tools from the machine learning and artificial intelligence space.
Next-generation sequencing data analysis: The student will be trained to perform next-generation sequencing analysis and get familiar with genomic visualization tools. They will apply the techniques to our own projects. For example:
Project 1: Characterizing the ambiguous mapping of reads and assessing how they influence the RNA-seq quantification.
Project 2: Identifying coding and non-coding biomarkers associated with disease propensity.
We may also have other high-throughput genomics projects open for participation.
Cancer is a life-changing experience that affects a patient’s physical, emotional, and social well-being. Spiritual care provides some patients with resources and support to cope with a difficult illness. The goal of this proposed study is to use a mixed-method approach to complete a phase 1a/b intervention study that would result in a beta version of the Interactive Spirituality Program for Oncology Patients or, MyInSPO, to improve spiritual and religious well-being in cancer care. Results from this study will be leveraged to secure external funding for continued piloting and efficacy testing of MyInSPO.
The student in my lab will be involved in identifying binding partners of two proteins that we are studying in the lab called RANBP9 and RANBP10. In particular the student will perform tissue culture, extract proteins and perform co-immunoprecipitation from mouse cells. This cells were derived from mice engineered with CRISPR/Cas9. Therefore, the student will learn/be exposed to this technology too.
The Kirschner lab studies the genetics of endocrine tumors, with a focus on genes that cause inherited human tumor syndromes. Our current studies involve studying the function of three genes, known as PRKAR1A, PTEN, and SDHD. Despite the fact that each of these genes is expressed in all tissues throughout the body, mutation of any one of them causes a distinct set of tumors in patients. These tumor syndromes are passed in families as autosomal dominant traits, meaning each child from an affected parent has a 50% chance of inheriting the mutation and the tumor predisposition. We use mouse models engineered to have mutations in each of these genes to understand the mechanism by which these mutations cause unregulated cellular growth. Working both in mouse models and in tissue culture cells (some from tumor cultures and some from cell lines) we study how these mutations affect cellular signaling and cellular metabolism. We are also interested in the question in how these genes affect the chance that a tumor will undergo metastatic spread from the original site to distant tissues in the body. By understanding these pathway both in inherited and non-inherited tumors, we hope one day to be able to suppress tumor growth and tumor spread in order to provide better treatment to patients with these and other tumors.
The Cruz-Monserrate laboratory research program is focused on studying pancreatic diseases in particular pancreatic ductal adenocarcinoma (PDAC) which is one of the most deadly human malignancies, with dismal long-term survival and limited advances in treatment. The long-term goals of my research laboratory are to develop novel strategies for the detection, prevention and treatment of PDAC and pancreatitis via uncovering unique mechanisms related to the initiation of these diseases. Towards this goal we have shown that the molecule integrin alpha6beta4, the enzyme Cathepsin E (CTSE), and pH-sensitive imaging probes are all early biomarkers of PDAC development. We have been engaged in the development of novel imaging probes that have the potential to detect and treat pancreas containing early lesions of PDAC using the enzymatic activity of CTSE using pre-clinical mouse models. This technology applies to any other diseases that express CTSE at high levels which is the case of pancreatic cancer.
We are also interested in the prevention of obesity-associated tumor development. Obesity has been associated with an increased risk of cancer development, in particular PDAC. Obesity rates in adults and children have also skyrocketed during the past 2 decades. Therefore, it is critical that we begin to understand the molecular mechanisms of how obesity promotes cancer development. In an effort to discover alternative methods of studying obesity and its relationship to PDAC development, we work with a mouse model of obesity-associated PDAC which we use to study some of the mechanisms that link obesity and PDAC.
There are multiple projects available related to the topics described above which can be further refine based the students interests and future career goals.
Waterpipe Warning Label Study: The Food and Drug Administration has the authority to regulate tobacco products, including waterpipe (hookah) tobacco and its components, such as the pipe that people use to smoke tobacco. Currently, the FDA mandates that waterpipe tobacco packages include the message WARNING: This product contains nicotine. Nicotine is an addictive chemical. In our preliminary work, we found that this message does not resonate well with young adults. Using qualitative and quantitative research methods, we developed another message that was found to be more effective and we also developed graphic images to pair with the new message. Our current project is focused on examining the impact of a text vs. graphic vs. no warning label on waterpipe (hookah) smoking behavior and toxicant uptake. We are conducting a laboratory smoking study whereby dyads come into the lab and smoke waterpipe. We are measuring smoking topography and exhaled carbon monoxide and videotaping the smoking sessions. The student working on this project will gain experience conducting a clinical research study, coding qualitative data (audio and video), and analyzing a portion of the data for an independent research project.
Project: Rural Intervention for Screening Effectiveness (RISE)
Women living in rural areas are more likely to get cancer and less likely to have received recommended cancer screening tests that prevent or find cancer early. Additionally, the number of women who die from breast, colon, and cervical cancer are higher in Ohio and Indiana than the rest of the US. Researchers at The Ohio State University and Indiana University-Purdue University Indianapolis are working to reduce the cancer burden in rural areas and have developed a program to help rural women understand the need for cancer screening.
Purpose: To compare two different ways to increase cancer screening participation for breast, cervical, and colorectal cancer, and determine which method is more effective.
Method: Researchers will contact women in 32 rural counties across Northwest Ohio and Northeast Indiana by mail and then by telephone to invite them to join the study and to complete a baseline survey.
A potential research/analytic project for a student involves analyzing baseline assessment surveys.
In addition, the selected student will have opportunities to participate in program activities within The Center for Cancer Health Equity (CCHE) at the OSUCCC – James. CCHE is dedicated to increasing cancer awareness in the community, with an emphasis on increasing participation in cancer clinical trials, especially by minority participants. Dr. Paskett serves as the director of the CCHE.