An Approach for the Identification of Targets Specific to Bone Metastasis Using Cancer Genes Interactome and Gene Ontology Analysis

Abstract

Metastasis is one of the most enigmatic aspects of cancer pathogenesis and is a major cause of cancer-associated mortality. Secondary bone cancer (SBC) is a complex disease caused by metastasis of tumor cells from their primary site and is characterized by intricate interplay of molecular interactions. Identification of targets for multifactorial diseases such as SBC, the most frequent complication of breast and prostate cancers, is a challenge. Towards achieving our aim of identification of targets specific to SBC, we constructed a ‘Cancer Genes Network’, a representative protein interactome of cancer genes. Using graph theoretical methods, we obtained a set of key genes that are relevant for generic mechanisms of cancers and have a role in biological essentiality. We also compiled a curated dataset of 391 SBC genes from published literature which serves as a basis of ontological correlates of secondary bone cancer. Building on these results, we implement a strategy based on generic cancer genes, SBC genes and gene ontology enrichment method, to obtain a set of targets that are specific to bone metastasis. Through this study, we present an approach for probing one of the major complications in cancers, namely, metastasis. The results on genes that play generic roles in cancer phenotype, obtained by network analysis of ‘Cancer Genes Network’, have broader implications in understanding the role of molecular regulators in mechanisms of cancers. Specifically, our study provides a set of potential targets that are of ontological and regulatory relevance to secondary bone cancer.

ABL kinases promote breast cancer osteolytic metastasis by modulating tumor-bone interactions through TAZ and STAT5 signaling

“…We found that a gene signature consisting of 273 genes important for breast cancer bone metastasis showed decreased expression in ABL1/ABL2 knockdown cells (Fig. 6B) (38). Further, inactivation of the ABL kinases resulted in decreased expression of the genes in the Hippo, JAK/STAT, and Cytokine/Cytokine Receptor pathway signatures (Fig.…”

A Data and Informatics Driven Drug Discovery Framework to Bridge Traditional and Modern Medicine

“…Findings from such studies have added to the information as well as to the noise. Lately, the focus has been towards creating systems biological molecular interactome models of complex diseases using these data [2][3][4][5][6][7]. This endeavour has been supported by methodologies such as data mining, Natural Language Processing (NLP), crowd sourcing and graph theory [2,3,16].…”

“…However, contrary to expectations, reductionist investigations of complex diseases have led to increase in noise making it difficult to ascertain specific causative molecular mechanisms that could be used to control the disease [1]. Hence prompted by increasing need of integrating disparate molecular elements, systems biological strategies have been developed to create a holistic picture of molecular mechanisms underlying complex diseases [2][3][4][5][6][7]. These integrative models allow one to wade through the noise and to pin down specific targets and regulatory mechanisms, thus providing a rational strategy towards disease control.…”

“…How could we possibly bridge traditional knowledge and modern medicine to facilitate accelerated drug discovery? In this article, informed with our research explorations, we provide a data and informatics driven framework that juxtaposes systems biological models of complex diseases, reported efficacy of medicinal plant extracts, and compilations of structured libraries of small molecules, aimed at an effective and rational drug discovery process ( Figure 1) [5][6][7][8][9][10][11][12][13][14][15].…”

Genome-Wide Identification of Bone Metastasis-Related MicroRNAs in Lung Adenocarcinoma by High-Throughput Sequencing

“…Bone metastasis is a complex process that involves a series of molecular events involving multiple steps, factors and genes [5]. First, tumor cells separate from the primary tumor origin and then intrude into the circulatory system through newly formed tumor vessels.…”