Cancer Cell-Autonomous TRAIL-R Signaling Promotes KRAS-Driven Cancer Progression, Invasion, and Metastasis

Abstract

Many cancers harbor oncogenic mutations of KRAS. Effectors mediating cancer progression, invasion, and metastasis in KRAS-mutated cancers are only incompletely understood. Here we identify cancer cell-expressed murine TRAIL-R, whose main function ascribed so far has been the induction of apoptosis as a crucial mediator of KRAS-driven cancer progression, invasion, and metastasis and in vivo Rac-1 activation. Cancer cell-restricted genetic ablation of murine TRAIL-R in autochthonous KRAS-driven models of non-small-cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC) reduces tumor growth, blunts metastasis, and prolongs survival by inhibiting cancer cell-autonomous migration, proliferation, and invasion. Consistent with this, high TRAIL-R2 expression correlates with invasion of human PDAC into lymph vessels and with shortened metastasis-free survival of KRAS-mutated colorectal cancer patients.

A fate worse than death: apoptosis as an oncogenic process

“…Here the authors found in vivo that TRAIL-R signaling could promote a variety of effects including invasion, proliferation and migration independently of its apoptotic function but dependent upon PI3K signaling. In line with functional importance, prevention of TRAIL-R signaling (through deletion of TRAIL-R) reduces metastasis while increasing survival in a KRAS-driven mouse model of pancreatic adenocarcinoma 102 . In clinical support, high TRAIL receptor 2 expression correlates with reduced metastasis-free survival in human KRAS-driven cancers 102 .…”

“…In line with functional importance, prevention of TRAIL-R signaling (through deletion of TRAIL-R) reduces metastasis while increasing survival in a KRAS-driven mouse model of pancreatic adenocarcinoma 102 . In clinical support, high TRAIL receptor 2 expression correlates with reduced metastasis-free survival in human KRAS-driven cancers 102 . In other in vitro settings, TRAIL-R signaling has also been found to stimulate cell migration in a caspase-dependent manner 103 .…”

“…While provides therapeutic opportunities, it suggests that cancer cells must gain some advantage from expressing TRAIL receptor. Addressing this, a recent study has shown that TRAIL receptor (TRAIL-R) signaling can promote cancer independent of its role in canonical apoptosis signaling 102 . Here the authors found in vivo that TRAIL-R signaling could promote a variety of effects including invasion, proliferation and migration independently of its apoptotic function but dependent upon PI3K signaling.…”

Plumbagin enhances TRAIL-induced apoptosis of human leukemic Kasumi-1 cells through upregulation of TRAIL death receptor expression, activation of caspase-8 and inhibition of cFLIP

“…Interestingly, our study found that plumbagin could increase the expression of both DR4 and DR5 in murine xenograft tumors, which was different from the results that only the DR5 expression on the cell surface in vitro. Recently, von Karstedt et al (41) found that high TRAIL-R2 expression correlates with invasion of pancreatic ductal adenocarcinoma into lymph vessels. Upregulation of DR4 not only DR5 might imply more clinical importance and need to be further investigated.…”

Inhibition of IRE1 modifies effect of glucose deprivation on the expression of TNF?-related genes in U87 glioma cells

“…Moreover, the expression of TRAIL receptors is greatly elevated in many cancer types such as hepatocellular carcinoma, renal carcinoma and ovarian cancer, suggesting that such tumors benefit from the expression of these receptors [25,6]. It is becoming increasingly clear that death receptor engagement, especially in the context of cancer, can lead to outcomes, other than apoptosis, that become subverted by certain tumors to their benefit [23,25,30].…”