ARF6 and AMAP1 are major targets of KRAS and TP53 mutations to promote invasion, PD-L1 dynamics, and immune evasion of pancreatic cancer

Abstract

Although KRAS and TP53 mutations are major drivers of pancreatic ductal adenocarcinoma (PDAC), the incurable nature of this cancer still remains largely elusive. ARF6 and its effector AMAP1 are often overexpressed in different cancers and regulate the intracellular dynamics of integrins and E-cadherin, thus promoting tumor invasion and metastasis when ARF6 is activated. Here we show that the ARF6–AMAP1 pathway is a major target by which KRAS and TP53 cooperatively promote malignancy. KRAS was identified to promote eIF4A-dependent ARF6 mRNA translation, which contains a quadruplex structure at its 5′-untranslated region, by inducing TEAD3 and ETV4 to suppress PDCD4; and also eIF4E-dependent AMAP1 mRNA translation, which contains a 5′-terminal oligopyrimidine-like sequence, via up-regulating mTORC1. TP53 facilitated ARF6 activation by platelet-derived growth factor (PDGF), via its known function to promote the expression of PDGF receptor β (PDGFRβ) and enzymes of the mevalonate pathway (MVP). The ARF6–AMAP1 pathway was moreover essential for PDGF-driven recycling of PD-L1, in which KRAS, TP53, eIF4A/4E-dependent translation, mTOR, and MVP were all integral. We moreover demonstrated that the mouse PDAC model KPC cells, bearing KRAS/TP53 mutations, express ARF6 and AMAP1 at high levels and that the ARF6-based pathway is closely associated with immune evasion of KPC cells. Expression of ARF6 pathway components statistically correlated with poor patient outcomes. Thus, the cooperation among eIF4A/4E-dependent mRNA translation and MVP has emerged as a link by which pancreatic driver mutations may promote tumor cell motility, PD-L1 dynamics, and immune evasion, via empowering the ARF6-based pathway and its activation by external ligands.

A Driver Never Works Alone—Interplay Networks of Mutant p53, MYC, RAS, and Other Universal Oncogenic Drivers in Human Cancer

“…An upregulation of oncogenic miR-21 by mutant KRAS through activation of the RAF-MEK-ERK and PI3K-AKT pathways in the early stages of lung tumorigenesis in cell lines and mice as well as in tumors from patients, was found [87]. To promote cancer invasion, metastasis and immune evasion in pancreatic cancer, oncogenic KRAS cooperates indirectly with mutant p53 to induce overexpression of ARF6 and its effector AMAP1, involved in regulation of integrins and E-cadherin [47]. The chemoresistance observed in lung cancer patients harboring KRAS oncogenic mutations was suggested to be the consequence of KRAS mediated upregulation of NRF2 transcription factor, an oncogenic hub of oxidative stress response [88].…”

“…It was shown to interfere with DNA-repair mechanisms driven by MRE11, leading to genomic instability [43], to interfere directly or indirectly with the microRNA maturation complex to alter the landscape of micro RNA expression [38,44] or to be involved in inflammatory and unfolded protein responses due to its cytoplasmic interactions [45,46]. Known cooperation of mutant p53 with RAS family oncoproteins is more indirect-both pathways contribute to progression of neoplasia in parallel, e.g., in pancreatic cancer models [47,48]. As in the case of most tumor suppressors, the indirect interplay of p53 with CMYC, KRAS or telomerase also includes a passive LOF contribution-when mutated or otherwise inactivated WT TP53, which normally may inhibit the oncogenes, loses this function and thus allows the oncogenes to promote neoplastic phenotypes [49][50][51].…”

Development and validation of a robust immune-related prognostic signature in early-stage lung adenocarcinoma

“…We were particularly interested in studying ARF6, which was a member of small GTPases ADP-ribosylation factor family, and its downstream effector AMAP1 have been reported overexpressed in several types of cancer and could promote cancer cell proliferation, invasion and migration [68][69][70][71]. For example, KRAS and TP53 oncogenes could promote PD-L1 recycling and cell surface expression through ARF6-AMAP1 pathway, which is significantly involved in the immune evasion of pancreatic ductal adenocarcinoma cells [72]. Currently, tumor staging system has been widely used for prognosis prediction and treatment design for LUAD.…”

Prognostic value of Glypican family genes in early-stage pancreatic ductal adenocarcinoma after pancreaticoduodenectomy and possible mechanisms

“…In PDAC associated with the KRAS mutation, decitabine therapy inhibits tumor growth (57). ARF6 is reported to be in close relationship with Ras pathway and its overexpression is related to unfavorable prognosis of PDAC patients (58). PTEN plays a role in pancreatic cancer growth.…”