Identifizierung der Rolle von HMGA2 während der tRNA Synthese in Bauchspeicheldrüsenkrebs
Zusammenfassung der Projektergebnisse
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal of all human malignancies, responsible for 466,003 deaths worldwide in 2020 and is projected to be the second leading cause of cancer deaths by 2030. For decades, pancreatic cancer researchers have focused on understanding the genetic mutations that drive pancreatic cancer through whole exome sequencing, with the goal of identifying therapeutic targets. All this work led to the same conclusion: that PDAs are genetically very similar—both between patients and between primary and metastatic tumors within the same patient. However, clinical experience suggests that pancreatic cancer is much more diverse given the heterogeneity of responses to chemotherapy observed in patients. To understand these differences, researchers have turned to the PDA transcriptome, looking for common transcriptional signatures across human PDAs, patient-derived xenografts (PDXs), organoids, and cell lines. Molecular characterization studies have described two major transcriptional subsets, referred to as 'classical’ and ‘basal’. Basal PDAs (~25% of PDAs) have the worst overall survival and are the only class to act as an independent poor prognostic factor. Thus, there is an urgent need to improve our understanding of basal PDA pathogenesis and to leverage this understanding towards new therapeutics. I have discovered that the expression of the oncofetal RNA-binding protein LIN28B and the chromatin protein high-mobility group (HMG) protein AT-hook 2 (HMGA2) drives the basal subtype of PDA. Surprisingly, I find that HMGA2 orchestrates the pathogenesis of basal PDAs by hijacking a precise node of the translation machinery, representing a promising new subtype-specific molecular vulnerability.
Projektbezogene Publikationen (Auswahl)
-
Abstract A094: LIN28B/HMGA2 axis accelerates PDA by promoting oncogenic protein synthesis. Cancer Research, 84(2_Supplement), A094-A094.
Dobersch, Stephanie; Cavendar, Sarah; Yamamoto, Naomi; Boila, Liberales Debraj; Wladyka, Cindy; Roudier, Martine; Notta, Faiyaz; Eisenman, Robert; Hsieh, Andrew & Kugel, Sita
