Loss of the wild-type KRAS allele promotes pancreatic cancer progression through functional activation of YAP1

Abstract

Human pancreatic ductal adenocarcinoma (PDAC) harboring one KRAS mutant allele often displays increasing genomic loss of the remaining wild-type (WT) allele (known as LOH at KRAS ) as tumors progress to metastasis, yet the molecular ramification of this WT allelic loss is unknown. In this study, we showed that the restoration of WT KRAS expression in human PDAC cell lines with LOH at KRAS significantly attenuated the malignancy of PDAC cells both in vitro and in vivo , demonstrating a tumor suppressive role of the WT KRAS allele. Through RNA-Seq, we identified the HIPPO signaling pathway to be positively regulated by WT KRAS in PDAC cells. In accordance with this observation, PDAC cells with LOH at KRAS exhibited increased nuclear localization and activation of transcriptional coactivator YAP1. Mechanistically, we discovered that WT KRAS expression sequestered YAP1 from the nucleus, through enhanced 14-3-3zeta interaction with phosphorylated YAP1 at S127. Consistently, expression of a constitutively-active YAP1 mutant in PDAC cells bypassed the growth inhibitory effects of WT KRAS. In patient samples, we found that the YAP1-activation genes were significantly upregulated in tumors with LOH at KRAS , and YAP1 nuclear localization predicted poor survival for PDAC patients. Collectively, our results reveal that the WT allelic loss leads to functional activation of YAP1 and enhanced tumor malignancy, which explains the selection advantage of the tumor cells with LOH at KRAS during pancreatic cancer clonal evolution and progression to metastasis, and should be taken into consideration in future therapeutic strategies targeting KRAS.

DNA Topoisomerase II-α Regulated by miR-22-5p Promotes Hepatocellular Carcinoma Invasion and Migration through the Hippo Pathway

“…Hippo Signaling Pathway. Oncogenes often promote tumor progression by regulating the signaling pathways [12,13]. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis showed that TOP2A was associated to cell cycle, progesterone-mediated oocyte maturation, p53 signaling pathway, and Hippo signaling pathway (Figure 5(a)).…”

“…Dysregulation of the Hippo signaling pathway promotes cancer progression [ 12 , 13 ]. Moya et al [ 14 ] found that the activity of yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) in tumors was linked to the progression of liver tumors.…”

LSR Targets YAP to Modulate Intestinal Paneth Cell Differentiation

“…We focused on two 14-3-3 proteins, 14-3-3 zeta and 14-3-3 gamma, and two protein phosphatases, protein phosphatase 1 catalytic subunit alpha (PPP1CA) and PP2Ac (Fig. 5E), because they have been reported to participate in the regulation of YAP in multiple tissues (Hu et al, 2017; Meng et al, 2016; Qi et al, 2015; Schlegelmilch et al, 2011; Sun et al, 2021; Yan et al, 2021). It is known that the turnover of YAP is regulated through its phosphorylation and ubiquitination in a 14-3-3 dependent manner.…”

Non-genetic adaptive resistance to KRASG12C inhibition: EMT is not the only culprit

“…The relationship between YAP and the RAF/MEK/ERK cascade was discovered by genetic screens, which showed that the inhibitory combination of RAF or MEK with YAP has increased efficacy not only in BRAF-mutant cancers but also in KRAS-mutant cancers (67). In a KRAS G12C mutant PDAC model, inhibition of YAP1 improves the efficacy of KRAS blockade (68). c-MYC is another oncogenic transcription factor being involved in crucial processes such as metabolic reprograming, extracellular matrix remodeling, inflammation, and regulation of a variety of malignant features in cancer (69).…”

“…The relationship between YAP and the RAF/MEK/ERK cascade was discovered by genetic screens, which showed that the inhibitory combination of RAF or MEK with YAP has increased efficacy not only in BRAF-mutant cancers but also in KRAS-mutant cancers ( 67 ). In a KRAS G12C mutant PDAC model, inhibition of YAP1 improves the efficacy of KRAS blockade ( 68 ).…”