Project Details
Projekt
Deciphering the role of LINC00261 and FOXA2 as transcriptional regulators shaping the expression landscape of pancreatic cancer
Applicant
Professorin Monika Hämmerle, Ph.D.
Subject Area
Hematology, Oncology
Pathology
Pathology
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 468534282
Pancreatic cancer has a dismal prognosis due to late diagnosis, frequent metastasis and high degree of therapy resistance. Molecularly, most PDACs are associated with somatic mutations, particularly affecting the KRAS gene. However, these known and frequent mutations did not lead to clinically valuable tumor classifications, suggesting that origins of PDAC heterogeneity may not be found at the genetic level. Importantly, integrative transcriptome analyses provided valuable insights into PDAC carcinogenesis and identified disease subtypes that have prognostic and biological relevance and are related to differences in therapy response. Moreover, detailed bioinformatic analyses identified long non-coding RNAs (lncRNAs) to be associated with certain subtypes suggesting a regulated expression and specific function of these transcripts. We recently leveraged publically available datasets and analyzed lncRNA expression in PDAC tissues as well as among different molecular subtypes. These analyses identified LINC00261 to be downregulated in pancreatic cancer, and its reduced expression was associated with significant better overall patient survival. In-depth analysis of PDAC subtypes revealed a differential expression pattern suggesting a specific regulation and function of LINC00261. In fact, an enrichment of genes related to epithelial-mesenchymal transition (EMT) has been found in LINC00261-low expressing tumors. Altogether, these results highlight LINC00261 as a tumor suppressive lncRNA and point towards a crucial role in EMT and subsequently in the metastatic cascade. Interestingly, the adjacent gene upstream of the LINC00261 locus, FOXA2, is a transcription factor crucial for endoderm differentiation. Intriguingly, preliminary experiments indicated a regulatory circuit between FOXA2 and LINC00261. Here, we will perform multi-layered interaction and expression analyses to dissect the interdependency of LINC00261 and FOXA2 as well as to unravel the molecular mechanism of action of LINC00261 in regulating epithelial cell identity. Moreover, potential synthetic lethal interactions in LINC00261-deficient cells that could be exploited clinically will be identified by applying CRISPR/Cas9-based functional genetic screens using a small library targeting genes that are inhibited by FDA-approved drugs. Aside from these LINC00261-focused translational studies, we will also investigate a novel aspect of FOXA2 as a RNA-dependent molecule using affinity capture and immunoprecipitation experiments. Taken together, our studies, supported by strong and established interactions within the research unit, will generate novel mechanistic insights into the role of LINC00261 and its genomic neighbor FOXA2 in shaping the expression landscape of PDAC. Moreover, our project will generate resources and provide a roadmap for the discovery of inherent vulnerabilities associated with tumor suppressive lncRNAs that could immediately be exploited in the clinic.
DFG Programme
Research Units
