Co-expression network analysis identifies Spleen Tyrosine Kinase (SYK) as a candidate oncogenic driver in a subset of small-cell lung cancer

Abstract

BackgroundOncogenic mechanisms in small-cell lung cancer remain poorly understood leaving this tumor with the worst prognosis among all lung cancers. Unlike other cancer types, sequencing genomic approaches have been of limited success in small-cell lung cancer, i.e., no mutated oncogenes with potential driver characteristics have emerged, as it is the case for activating mutations of epidermal growth factor receptor in non-small-cell lung cancer. Differential gene expression analysis has also produced SCLC signatures with limited application, since they are generally not robust across datasets. Nonetheless, additional genomic approaches are warranted, due to the increasing availability of suitable small-cell lung cancer datasets. Gene co-expression network approaches are a recent and promising avenue, since they have been successful in identifying gene modules that drive phenotypic traits in several biological systems, including other cancer types.ResultsWe derived an SCLC-specific classifier from weighted gene co-expression network analysis (WGCNA) of a lung cancer dataset. The classifier, termed SCLC-specific hub network (SSHN), robustly separates SCLC from other lung cancer types across multiple datasets and multiple platforms, including RNA-seq and shotgun proteomics. The classifier was also conserved in SCLC cell lines. SSHN is enriched for co-expressed signaling network hubs strongly associated with the SCLC phenotype. Twenty of these hubs are actionable kinases with oncogenic potential, among which spleen tyrosine kinase (SYK) exhibits one of the highest overall statistical associations to SCLC. In patient tissue microarrays and cell lines, SCLC can be separated into SYK-positive and -negative. SYK siRNA decreases proliferation rate and increases cell death of SYK-positive SCLC cell lines, suggesting a role for SYK as an oncogenic driver in a subset of SCLC.ConclusionsSCLC treatment has thus far been limited to chemotherapy and radiation. Our WGCNA analysis identifies SYK both as a candidate biomarker to stratify SCLC patients and as a potential therapeutic target. In summary, WGCNA represents an alternative strategy to large scale sequencing for the identification of potential oncogenic drivers, based on a systems view of signaling networks. This strategy is especially useful in cancer types where no actionable mutations have emerged.

Syk Is Recruited to Stress Granules and Promotes Their Clearance through Autophagy

“…The identification of additional roles for Syk in tumorigenesis has increased interest in the use of Syk inhibitors as chemotherapeutic agents for the treatment of disorders in which the expression of Syk serves as a pro-survival factor (4). The inhibition of or knockdown in expression of Syk promotes apoptosis in multiple cancer cell types, including many hematopoietic malignancies as well as K-Ras-dependent lung and pancreatic cancer (5), small cell lung cancer (6), ovarian cancer (7), and retinoblastoma (8). For many cancer cells, the expression of Syk can protect them from cell death due to genotoxic or oxidative stress (9).…”

The innate immune signaling in cancer and cardiometabolic diseases: Friends or foes?

“…Emerging evidence suggests that Syk inhibition induces apoptosis and blocks tumor growth in lymphoma or leukemia through the B cell receptor (BCR) signaling pathways [138,139]. Beyond hematologic neoplasms, the tumor-promoting function of Syk has also been observed in solid tumors, including nasopharyngeal carcinoma, lung cancer and ovarian cancer, but its mechanisms are unknown [140][141][142]. Syk is also a tumor suppressor in some solid tumors.…”

Calling in SYK: SYK's dual role as a tumor promoter and tumor suppressor in cancer

“…The silencing of SYK expression markedly inhibits anchorage-independent growth and induces apoptosis in SYK-expressing ovarian cancer cells. An analysis of genes co-expressed in small cell lung cancer (SCLC) reveals SYK as a potential oncogenic driver [74]. An examination of primary tumor samples found SYK present in 11 of 33 SCLC tissues at levels much higher than those in normal alveolar epithelium.…”