Cancers are driven by inheritable genetic/epigenetic changes, including somatic mutations and copy number variations (CNV). Genetic changes perturb cellular signaling pathways through the following mechanisms: 1) by changing the structures (and therefore the functions) of signaling proteins, through somatic mutations; and 2) by changing the quantity of proteins involved in signaling pathways (e.g., increasing expression of an enzyme producing a certain signaling molecule), through CNV and DNA methylation. Each signaling pathway regulates the expression of a set of genes that usually perform certain functions together, such as handling cell proliferation or death. We call this set of genes a response-module. If a pathway is perturbed, then expressions of genes regulated by the pathway will change accordingly, further altering the behavior of cells and turning normal cells into cancerous ones. One important objective of cancer disease mechanism research is to understand which genetic change is responsible for the perturbation of which signaling pathway. Currently, large-scale studies, such as the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), have detected genetic changes (e.g., somatic mutation and CNA) and expression changes (e.g., RNA expression and protein expression) in tens of thousands of tumors. These data provide an unprecedented opportunity to study cancer disease mechanisms and to investigate the heterogeneity of common cancers. However, the scale of the data also poses significant challenges in computational methodology development, particularly because many bioinformatics problems belong to a class of problems referred to as NP-hard problems. The PI of this transitional K99/R00 proposal has extensive experience in developing algorithms addressing this type of computational problem. The major goal of this proposal is to provide sufficient training for the PI to gain biological insight so that he can develop efficient algoriths to enhance computational cancer research. In addition to the PI receiving formal didactic and out-of-class training in cancer biology, this project will also develop specific computational algorithms and tools to study cancer disease mechanisms using the TCGA data. More specifically, the project proposes two aims.
AIM 1 is to develop graph models and design efficient algorithms that are capable of revealing perturbed signaling pathways by combining multiple types of omics data.
AIM 2 is to study the impact of pathway perturbations on cancer development and clinical outcome The specific aims proposed will address the following major issues or challenges: 1) Given a set of genes that have been differently expressed as the result of perturbations of multiple signaling pathways in tumors, how do we group them into units in such a way that the genes in each unit are likely to have been regulated by one common signal?; and 2) Given the dozens or hundreds of somatic mutations or CNAs in a tumor, how do we recognize the small portion that is likely to perturb cancer pathways, as well as trace perturbation sources, i.e., somatic mutations or CNAs in the tumor, to those cancer pathways? By applying the tools developed in this project to different types of cancer data from TCGA or other resources, we will have a better understanding of disease mechanisms for different cancers.

Public Health Relevance

In this project, we will develop and implement a tool that uses a novel graph-based model to study cancer disease mechanisms through reconstructing signaling transduction pathways. We will combine data-mining and knowledge- mining techniques, as well as design exact algorithms for NP-hard problems introduced in the project, in pursuit of a greater understanding of the processes that lead to the development of this deadly disease.

Agency
National Institute of Health (NIH)
Institute
National Library of Medicine (NLM)
Type
Research Transition Award (R00)
Project #
5R00LM011673-05
Application #
9325563
Study Section
Special Emphasis Panel (ZLM1)
Program Officer
Ye, Jane
Project Start
2014-02-15
Project End
2018-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Miscellaneous
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Lu, Songjian; Fan, Xiaonan; Chen, Lujia et al. (2018) A novel method of using Deep Belief Networks and genetic perturbation data to search for yeast signaling pathways. PLoS One 13:e0203871
Pangeni, Rajendra P; Zhang, Zhou; Alvarez, Angel A et al. (2018) Genome-wide methylomic and transcriptomic analyses identify subtype-specific epigenetic signatures commonly dysregulated in glioma stem cells and glioblastoma. Epigenetics 13:432-448
Sadahiro, Hirokazu; Kang, Kyung-Don; Gibson, Justin T et al. (2018) Activation of the Receptor Tyrosine Kinase AXL Regulates the Immune Microenvironment in Glioblastoma. Cancer Res 78:3002-3013
Yan, Gaibo; Chen, Vicky; Lu, Xinghua et al. (2017) A signal-based method for finding driver modules of breast cancer metastasis to the lung. Sci Rep 7:10023
Huang, Tianzhi; Kim, Chung Kwon; Alvarez, Angel A et al. (2017) MST4 Phosphorylation of ATG4B Regulates Autophagic Activity, Tumorigenicity, and Radioresistance in Glioblastoma. Cancer Cell 32:840-855.e8
Huang, Tianzhi; Alvarez, Angel A; Pangeni, Rajendra P et al. (2016) A regulatory circuit of miR-125b/miR-20b and Wnt signalling controls glioblastoma phenotypes through FZD6-modulated pathways. Nat Commun 7:12885
Hill, Steven M; Heiser, Laura M; Cokelaer, Thomas et al. (2016) Inferring causal molecular networks: empirical assessment through a community-based effort. Nat Methods 13:310-8
Lu, Songjian; Cai, Chunhui; Yan, Gonghong et al. (2016) Signal-Oriented Pathway Analyses Reveal a Signaling Complex as a Synthetic Lethal Target for p53 Mutations. Cancer Res 76:6785-6794
Lu, Songjian; Mandava, Gunasheil; Yan, Gaibo et al. (2016) An exact algorithm for finding cancer driver somatic genome alterations: the weighted mutually exclusive maximum set cover problem. Algorithms Mol Biol 11:11
Lu, Songjian; Lu, Kevin N; Cheng, Shi-Yuan et al. (2015) Identifying Driver Genomic Alterations in Cancers by Searching Minimum-Weight, Mutually Exclusive Sets. PLoS Comput Biol 11:e1004257