Research Project

An integrated systems approach for incompletely penetrant onco-phenotypes


Project Title

An integrated systems approach for incompletely penetrant onco-phenotypes

List of Collaborating Institutions

University of Virginia
Institute of Computational Biology, Helmholtz Center, Munich, Germany

Project Websites

Project Description

Perturbation of cancer cells often leads to heterogeneous outcomes, in that most cells exhibit a dominant phenotype, but the rest appear resistant or hypersensitive to the perturbation. If the penetrance of such a phenotype is heritably incomplete, then it becomes extremely difficult to decipher the upstream molecular events that heterogenize the population and cause response variability. By combining quantitative measurements with dynamical models, systems approaches should be useful if provided with a core network of important biomolecules. The daunting hurdle lies in identifying phenotype-relevant regulatory heterogeneities that define the network for penetrance at the single-cell level. Our proposal seeks to exploit a new approach, called stochastic frequency matching (SFM), for elaborating the molecular networks upstream of incompletely penetrant phenotypes. SFM identifies and parameterizes single-cell heterogeneities—which emerge after a uniform perturbation but before the appearance of a variable phenotype—to hone in on regulatory states corresponding to future penetrance. For an onco-phenotype incompletely triggered by ErbB receptor tyrosine kinase signaling in 3D cultured breast epithelia, we implemented SFM using microarrays to uncover a network of critical nucleocytoplasmic regulators. The goals of this proposal are to apply systems approaches to the ErbB nucleocytoplasmic network and adapt SFM more broadly to RNA sequencing of breast cancer patients with ErbB amplification. Based on our provisional SFM results, we hypothesize that ErbB signaling heterogeneously reconfigures the nucleocytoplasmic shuttling state of cells to determine incomplete penetrance of the onco-phenotype. The aims are to: 1) Identify network-level mechanisms for the incompletely penetrant ErbB1:ErbB2 phenotype. 2) Determine whether drivers of incomplete penetrance in 3D define shuttling states in human cancers and promote ErbB2-driven mammary tumors in mice. 3) Sequence and parameterize regulatory-state heterogeneity in HER2+ breast cancers to assemble patient-specific network models of shuttling variability and sensitivity. Drivers of incomplete penetrance are important for understanding transitions during tumor initiation-progression and for developing therapeutic interventions with more reliable patient outcomes. SFM gives the Cancer Systems Biology Consortium a means to identify driver networks in a comprehensive and hypothesis-driven way.


Kevin Janes, Ph.D.

Kevin Janes received his B.S. and B.A. degrees in Biomedical Engineering and Spanish at Johns Hopkins University in 1999. He was a Fulbright Scholar at La Universidad de Santiago de Compostela in Spain before attaining his Ph.D. in Bioengineering at M.I.T. in 2005 under the joint supervision of Douglas Lauffenburger and Michael Yaffe. Dr. Janes completed a postdoctoral fellowship at Harvard Medical School in the Department of Cell Biology with Joan Brugge and began his faculty position at the University of Virginia in 2008. During that time, Dr. Janes was recognized as a Pew Scholar, a Packard Fellow, a Kavli Fellow, and a recipient of the NIH Director’s New Innovator Award. He is currently an Associate Professor in the Department of Biomedical Engineering at the University of Virginia, the Vice-Chair of the Tumor Biochemistry and Endocrinology study section at the American Cancer Society, and a member of the Board of Reviewing Editors for Science Signaling.

Fabian Theis, Ph.D.

Fabian Theis obtained MSc degrees in Mathematics and Physics at the University of Regensburg in 2000. He also received a PhD degree in Physics from the same university in 2002 and a PhD in Computer Science from the University of Granada in 2003. In the summer of 2007, Dr. Theis became working group head of CMB at the Institute of Bioinformatics at the Helmholtz Center Munich. He earned multiple awards including Almirall Forderpreis and Oscar-Gans award and M4 award. He is currently a full professor and director of the institute of Computational Biology at the Helmholtz Research Center for Environmental Health, Munich, Germany. He serves as organizer and Chair for multiple European and international programs and conferences, and a member of editorial boards for Biology Direct, Simula Springer Briefs on Computing. He is associate editor for Computational Intelligence and Neuroscience, editor for Current Opinion in Biotechnology.

Christiane Fuchs, Ph.D.

Christiane Fuchs received her M. Sc. both in Computational Mathematics with Modelling at Brunel University West London, UK in 2003 and in Mathematics at University of Hanover, Germany in 2005. She then received her Ph.D. in Statistics at Ludwig Maximilians University Munich, Germany in 2010. Dr. Fuchs completed a postdoctoral fellowship in Biostatistics at Helmholtz Zentrum Munchen, Germany in 2013. She is currently a full professor in the Department of Statistics at Ludwig Maximilians University in Munich, Germany, a Board Member of Collaborative Research Centre and a review editor for Frontiers in Mathematics of Computation and Data Science. Dr. Fuchs is recognized as a winner of Prostate Cancer DREAM Challenge and won the Gustav Adolf Lienert Prize for young scientists by the German Region of the International Biometric Society.

Kristen Atkins, M.D.

Kristen Atkins received her BAS degree in Biology at University of Delaware in 1990, Doctorate of Medicine degree at the University of Vermont in 1996, and completion of Pathology Residency at Stanford University in 1999 and Cytopathology Fellowship at Virginia Commonwealth University in 2001. She began her clinical pathologist position in 2001. She earned Best Doctors in America® List, UVA Master Educator Award for Graduate Medical Education, and Mullholland Award for Teaching Excellence in Foundations of Medicine at University of Virginia. She is currently an Associate Professor in the Department of Pathology at UVA and serves as Gynecologic Pathology Fellowship co-director and Pathology Residency Director. She is a member of Editorial Boards for International Society of Gynecologic Pathologists, American Journal of Surgical Pathology, American Society of Cytopathology and US and Canadian Academy of Pathologists.

Jennifer Harvey, M.D.

Jennifer Harvey received her BS degree in zoology and chemistry at Northern Arizona University in 1983 and her Doctorate of Medicine degree at the University of Arizona in 1988. She completed her residency training in diagnostic radiology at the University of Arizona in 1993. Dr. Harvey is a full professor and director of the Division of Breast Imaging and breast program in the Department of Radiology at UVA. She earned multiple awards such as Best Doctors in America® List, Sharon L. Hostler Women in Medicine Leadership Award School of Medicine, University of Virginia and Lifetime Service Award, American Board of Radiology. She is a member of Radiological Society of North America, American Roentgen Ray Society, Society of Breast Imaging, American Society of Breast Disease, and American College of Radiology. Dr. Harvey is Chair of Breast Core Exam Committee, American Board of Radiology, and an Associate Editor for Radiographics.