Using open-source parts and 3D-printed components, the Lee lab develops a robotic system for mammalian cell cultures that accurately reproduces user-defined concentration profiles for one or more stimuli, such as cytokines or drugs. The team applies the dynamic stimulation system to investigate NF-kB signaling in single cells exposed to time-varying concentrations of TNF, a molecular network that is often deregulated in autoimmunity and cancer. Cellular responses to dynamic stimuli reveals context-dependent sensitivities and new classes of single cell responses that are distinct from the canonical NF-kB response during persistent stimulation. Guided by computational modeling, the team show that new response classes can be modulated with chemicals that target rates for basal cellular processes, including transcription and translation.
Taken together, the work shows that dynamic stimuli can be used to more accurately recapitulate biological complexity, to reveal hidden capabilities of biological systems, and to provide new opportunities to rationally manipulate disease-associated signaling mechanisms.
Mokashi CS, Schipper DL, Qasaimeh MA, Lee REC. A System for Analog Control of Cell Culture Dynamics to Reveal Capabilities of Signaling Networks. (2019) iScience [Epub ahead of print]
George Oster (1940-2018), professor of Cell and Developmental Biology at the University of California, Berkeley, is a pioneer and world leader in biophysics, mathematical biology, and applied mathematics. He is also a great mentor who guided numerous young researchers along their career paths.
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Photo: Informal group meetings almost every morning in a local cafe (taken in year 2005).
Dr. Joeseph Ayoob was named as the National Research Mentoring Network Mentor of the Month for July 2019, where he is also one of only four NRMN’s Master Mentors. Dr. Ayoob is an Associate Professor in the Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh. Additionally, he is the Founding Program Director of our NSF-funded Training and Experimentation in Computational Biology (TECBio) Research Experience for Undergraduates (REU) Program and the UPMC Hillman Cancer Center and University of Pittsburgh’s Computational Biology Research Academy (CoBRA) for outstanding high-school scholars. Dr. Ayoob is also the Co-Founding Program Director for our CPCB MetaSchool Graduate Student Professional Development Series and the Course Director for Laboratory Methods for Computational Biologists, part of our Joint Carnegie Mellon/Pitt, Ph.D. Program in Computational Biology (CPCB), as well as the Co-Founding Director for the Computational Biomedicine & Biotechnology Masters Program (COBB). Click here to read more about his story as a scientist and mentor.
About the program:
Despite several decades of efforts to increase diversity in the U.S. biomedical workforce, the issue of the under-representation of many populations remains. Scholars from non-majority backgrounds–whether by race, ethnicity, socioeconomic status, sexual orientation, or disability–have overcome many barriers yet still carry the burdens of disadvantaged and discrimination. NRMN is funded by NIH and is a part of the NIH Diversity Program Consortium (DPC), which is a national collaborative that develops, implements, and determines the effectiveness of innovative approaches to strengthen institutional capacity to sustain mentor-mentee relationships. The NRMN is a nationwide consortium of biomedical professionals and institutions collaborating to provide enhanced networking and mentorship experiences in support of the training and career development of individuals from under represented backgrounds who are pursuing biomedical, behavioral, clinical, and social science research careers (collectively termed biomedical research careers). The NRMN is intended to enable mentees across career stages to find effective mentors who will engage in productive, supportive, and culturally responsive mentoring relationships. The NRMN monthly newsletter serves over 15,000 researchers around the country across all career stages in the biomedical sciences.
Drs. Branden Van Oss and Anne-Ruxandra Carvunis review the field of de novo gene birth in their new PLOS Genetics Topic Page article. As part of the Topic Page initiative, the journal article also seeds a new Wikipedia page on the topic.
Abstract: De novo gene birth is the process by which new genes evolve from DNA sequences that were ancestrally non-genic. De novo genes represent a subset of novel genes, and may be protein-coding or instead act as RNA genes. The processes that govern de novo gene birth are not well understood, though several models exist that describe possible mechanisms by which de novo gene birth may occur. Although de novo gene birth may have occurred at any point in an organism’s evolutionary history, ancient de novo gene birth events are difficult to detect. Most studies of de novo genes to date have thus focused on young genes, typically taxonomically-restricted genes (TRGs) that are present in a single species or lineage, including so-called orphan genes, defined as genes that lack any identifiable homolog. It is important to note, however, that not all orphan genes arise de novo, and instead may emerge through fairly well-characterized mechanisms such as gene duplication (including retroposition) or horizontal gene transfer followed by sequence divergence, or by gene fission/fusion. Though de novo gene birth was once viewed as a highly unlikely occurrence , there are now several unequivocal examples of the phenomenon that have been described. It furthermore has been advanced that de novo gene birth plays a major role in the generation of evolutionary innovation.
|Branden Van Oss, PhD
||Anne-Ruxandra Carvunis, PhD
To view the full article, please click here.
Targeting the temporal dynamics of hypoxia-induced tumor-secreted factors halts tumor migration
Targeting microenvironmental factors that foster migratory cell phenotypes is a promising strategy for halting tumor migration. However, lack of mechanistic understanding of the emergence of migratory phenotypes impedes pharmaceutical drug development. Using our 3D microtumor model with tight control over tumor size, we recapitulated the tumor size-induced hypoxic microenvironment and emergence of migratory phenotypes in microtumors from epithelial breast cells and patient-derived primary metastatic breast cancer cells, mesothelioma cells, and lung cancer xenograft cells (PDX). The microtumor models from various patient-derived tumor cells and PDX cells revealed upregulation of tumor-secreted factors including matrix metalloproteinase-9 (MMP9), fibronectin (FN), and soluble E-cadherin (sE-CAD), consistent with clinically reported elevated levels of FN and MMP9 in patient breast tumors compared to healthy mammary glands. Secreted factors in the conditioned media of large microtumors induced a migratory phenotype in non-hypoxic, non-migratory small microtumors. Subsequent mathematical analyses identified a two-stage microtumor progression and migration mechanism whereby hypoxia induces a migratory phenotype in the initialization stage which then becomes self-sustained through a positive feedback loop established among the tumor-secreted factors. Computational and experimental studies showed that inhibition of tumor-secreted factors effectively halts microtumor migration despite tumor-to-tumor variation in migration kinetics, while inhibition of hypoxia is effective only within a time window and is compromised by tumor-to-tumor variation, supporting our notion that hypoxia initiates migratory phenotypes but does not sustain it. In summary, we show that targeting temporal dynamics of evolving microenvironments, especially tumor-secreted factors during tumor progression, can halt tumor migration.
Singh M, Tian XJ, Donnenberg VS, Watson AM, Zhang JY, Stabile LP, Watkins SC, Xing J, Sant S. (2019) Targeting the temporal dynamics of hypoxia-induced tumor-secreted factors halts tumor migration. Cancer Res. DOI: 10.1158/0008-5472.CAN-18-3151
|Shilpa Sant, PhD
||Jianhua Xing, PhD