Master Regulators of Oncogenic KRAS Response in Pancreatic Cancer: An Integrative Network Biology Analysis

Background KRAS is the most frequently mutated gene in pancreatic ductal adenocarcinoma (PDAC), but the mechanisms underlying the transcriptional response to oncogenic KRAS are still not fully understood. We aimed to uncover transcription factors that regulate the transcriptional response of oncogenic KRAS in pancreatic cancer and to understand their clinical relevance. Methods and Findings We applied a well-established network biology approach (master regulator analysis) to combine a transcriptional signature for oncogenic KRAS derived from a murine isogenic cell line with a coexpression network derived by integrating 560 human pancreatic cancer cases across seven studies. The datasets included the ICGC cohort (n = 242), the TCGA cohort (n = 178), and five smaller studies (n = 17, 25, 26, 36, and 36). 55 transcription factors were coexpressed with a significant number of genes in the transcriptional signature (gene set enrichment analysis [GSEA] p < 0.01). Community detection in the coexpression network identified 27 of the 55 transcription factors contributing to three major biological processes: Notch pathway, down-regulated Hedgehog/Wnt pathway, and cell cycle. The activities of these processes define three distinct subtypes of PDAC, which demonstrate differences in survival and mutational load as well as stromal and immune cell composition. The Hedgehog subgroup showed worst survival (hazard ratio 1.73, 95% CI 1.1 to 2.72, coxPH test p = 0.018) and the Notch subgroup the best (hazard ratio 0.62, 95% CI 0.42 to 0.93, coxPH test p = 0.019). The cell cycle subtype showed highest mutational burden (ANOVA p < 0.01) and the smallest amount of stromal admixture (ANOVA p < 2.2e–16). This study is limited by the information provided in published datasets, not all of which provide mutational profiles, survival data, or the specifics of treatment history. Conclusions Our results characterize the regulatory mechanisms underlying the transcriptional response to oncogenic KRAS and provide a framework to develop strategies for specific subtypes of this disease using current therapeutics and by identifying targets for new groups.
Florian Markowetz and colleagues study transcriptional mechanisms influenced by mutated KRAS, which is common in pancreatic ductal adenocarcinomas, and possible implications for disease characteristics and prognosis.
Author Summary Why Was This Study Done? Outcomes for patients diagnosed with pancreatic cancer are very poor because surgical approaches plus other current treatments are often inadequate to treat this disease. Previous efforts have been made to subtype the disease in an effort to identify more clinically relevant groups for tailored treatment. To improve on these “landscape” studies, we focussed on transcriptional changes induced by KRAS mutations to understand perturbed pathways and their effects on patients. What Did the Researchers Do and Find? We created a transcriptional signature of oncogenic KRAS in an isogenic mouse ductal cell line. We then combined this signature with a coexpression network derived from a large collection of pancreatic cancer cases and used a well-validated algorithm to identify the transcription factors (so-called master regulators) responsible for the signature. The master regulators clustered into three distinct biological groups (Notch, cell cycle, and Hedgehog) characterised by significant differences in clinical survival and mutational load as well as immune cell and stromal infiltration. What Do These Findings Mean? Our results provide evidence that distinct modes of transcriptional reprogramming occur following KRAS-mediated transformation This improved understanding of pancreatic cancer biology may provide novel prognostic and therapeutic opportunities to counter this devastating disease.