During embryogenesis, multiple developmental signaling pathways control the biological processes that form and shape cells, tissues, and organs. These pathways tightly regulate behaviors and elicit responses that determine cell fate, such as migration, proliferation, and differentiation. In many cancer types, these pathways are dysregulated or hyperactive, which has been postulated to fuel cancer progression. However, unlike mutations in other cancer-driving genes, mutations in the genes that encode for components of developmental pathways are rare. To determine if changes in expression instead correlated with poor clinical outcomes, researchers Andrew G. Xue and Dr. Marina Chan in the Gujral Lab (Human Biology Division) investigated the association between developmental pathway activation and clinical outcomes in over 8,000 patients spanning 17 cancer types. The group recently published the results of this study in the journal Translational Research.
The investigators first determined if the activation of developmental signaling pathways correlated with patient survival using a pan-cancer dataset with well-annotated clinical outcomes from The Cancer Genome Atlas (TCGA) project. They performed a differential expression analysis and identified gene sets that were enriched in cohorts with good (>5 years) and poor (<5 years) survival. In the poor outcomes cohort, the investigators found enrichment in genes that encode components of the noncanonical Wnt and the TGF-β developmental signaling pathways, along with genes involved in the epithelial-mesenchymal transition (EMT) program, across multiple cancer cell types. “We discovered a highly significant overlap between developmental processes and promotion of epithelial-mesenchymal transition, a process linked to cancer progression and poor prognosis in patients, suggesting a potential link between co-opting of developmental pathways in cancer and cancer proliferation and spread.”, explains Andrew Xue, an undergraduate student in computational biology at MIT.
Next, the investigators sought to determine if the relationship between developmental signaling pathways and the EMT program is present during normal embryonic development. To this end, they examined single-cell gene expression data from several organs and tissues in developing mouse embryos. Using hierarchical clustering of the enrichment in the expression of the gene components of the EMT program and developmental pathways, the authors showed that expression patterns of the EMT program cluster with the noncanonical Wnt and the TGF-β pathways in most organs. These data suggested that the noncanonical Wnt and the TGF-β pathways regulate the EMT program both during organ development and tumor formation.
In developmental signaling pathways, ligand-receptor interactions “carry” the signal through the pathway. Thus, the enrichment of a receptor-ligand pair expression could serve as a proxy for the enrichment of the entire pathway. To explore if receptor-ligand pair expression levels could characterize the developmental signal correlation with clinical outcomes (e.g., whether high expression of receptor-ligand pair correlates with poor survival), the researchers examined expression of receptor-ligand pairs in each developmental pathway across cancer types. They found that enrichment of specific receptor-ligand pairs also correlated with poor clinical outcomes. Importantly, expression of the Wnt pathway receptor encoding gene, FZD2, strongly correlated with EMT program activation across cancer types and with poor clinical outcomes. Dr. Chan, a senior scientist in the lab, expands on the implications of this finding: “We also identified FZD2, a Frizzled family receptor involved in both canonical and noncanonical Wnt developmental pathway signaling, as strongly correlated with EMT and EMT-related processes, and also linked to patient survival. Therefore, we suggest that FZD2 is a driver of a mesenchymal-like cell state that contributes to cancer progression and metastasis and is, thus, a potential therapeutic target”.
In summary, the study provides an in-depth analysis of how components of developmental signaling pathways correlate with clinical outcomes across major cancer types. Going forward, the Gujral lab will further investigate the role of FZD2 in tumor growth and metastasis in a variety of cancer types using a combination of mouse and patient-derived models.
This research was supported by grants from the National Institutes of Health/National Cancer Institute, a Kimmel Scholar Award from the Sidney Kimmel Foundation, and the American Cancer Society.
Dr. Taran Gujral is a member of the Fred Hutch/UW cancer consortium.
Xue, A. G., Chan, M., & Gujral, T. S. (2020). Pan-cancer analysis of the developmental pathways reveals noncanonical wnt signaling as a driver of mesenchymal-type tumors. Translational research
doi: 10.1016/j.trsl.2020.06.003