KRAS mutations as essential promoters of lymphangiogenesis via extracellular vesicles in pancreatic cancer

Abstract

Kirsten rat sarcoma virus ( KRAS ) gene mutations are present in more than 90% of pancreatic ductal adenocarcinomas (PDACs). KRAS G12D is the most frequent alteration, promoting preneoplastic lesions and associating with a more aggressive phenotype. These tumors possess increased intratumoral lymphatic networks and frequent lymph node (LN) metastases. In this issue of the JCI , Luo, Li, et al. explored the relationship between the presence of the KRAS G12D mutation and lymphangiogenesis in PDAC. The authors used in vitro and in vivo models and an elegant mechanistic approach to describe an alternative pathway for lymphangiogenesis promotion. KRAS G12D induced SUMOylation of heterogenous nuclear ribonucleoprotein A1 (hnRNPA1) via SAE1 and SUMO2 activation. SUMOylated hnRNPA1 was loaded into extracellular vesicles (EVs) and internalized by human endothelial lymphatic cells (HLEC). Further, SUMOylated hnRNPA1 promoted lymphangiogenesis and LN metastasis by stabilizing prospero homeodomain protein 1 ( PROX1 ) mRNA. These data provide mechanistic insight into cancer lymphangiogenesis with the potential for developing biomarkers and RAS pathway therapeutics.

The microprotein encoded by exosomal lncAKR1C2 promotes gastric cancer lymph node metastasis by regulating fatty acid metabolism

“…Lymphangiogenesis is directly related to LNM in various types of cancer, and exosomes and non-coding RNA have been proven to be involved in the process [ 30 – 33 ]. The IHC analysis using anti-podoplanin antibody indicated that the density of lymph vessels was much higher in patients with LNM (Fig.…”

The Oxidative Drug Combination for Suppressing KRAS G12D Inducible Tumour Growth

“…KRAS has been identified as the most frequently mutated gene in human cancers that is responsible for 30% of all human carcinomas [1][2][3][4]. Studies found that the mutant version of KRAS was presented in 90% of pancreatic cancers [5][6][7], and up to 40% of colorectal cancers [3]. RAS interacts with proteins involved in many cellular processes, including cell growth, differentiation, mitosis, and metabolism.…”