IMPAD1 and KDELR2 drive invasion and metastasis by enhancing Golgi-mediated secretion

Abstract

Summary Non-small cell lung cancer (NSCLC) is the deadliest form of cancer worldwide, due in part to its proclivity to metastasize. Identifying novel drivers of invasion and metastasis holds therapeutic potential for the disease. We conducted a gain-of-function invasion screen, which identified two separate hits, IMPAD1 and KDELR2, as robust, independent drivers of lung cancer invasion and metastasis. Given that IMPAD1 and KDELR2 are known to be localized to the ER-Golgi pathway, we studied their common mechanism of driving in vitro invasion and in vivo metastasis and demonstrated that they enhance Golgi-mediated function and secretion. Therapeutically inhibiting matrix metalloproteases (MMPs) suppressed both IMPAD1- and KDELR2-mediated invasion. The hits from this unbiased screen and the mechanistic validation highlight Golgi function as one of the key cellular features altered during invasion and metastasis.

MBIP (MAP3K12 binding inhibitory protein) drives NSCLC metastasis by JNK-dependent activation of MMPs

“…Based on our prior screen results [ 6 , 7 ] and the in silico findings, we hypothesized that MBIP amplification may participate in controlling cellular migration and invasion to drive metastasis. To test this hypothesis, we generated murine 393P, 344SQ, 531LN3 and human H157 lung cancer cell lines with doxycycline inducible MBIP expression.…”

“…There is an urgent unfulfilled need to find novel therapeutically targetable drivers for lung cancer metastasis since the clinical options for treatment of metastatic NSCLC are still largely limited. As a follow-up study to our recent in vitro and in vivo gain-of-function screens that identified potential genes promoting invasion and metastasis, here we investigated the mechanistic and clinical relevance of MBIP in the context of NSCLC metastasis [ 6 , 7 ]. MBIP has been reported to be clinically associated with papillary thyroid cancer T staging and its genomic amplification has been found in significant proportions of lung adenocarcinomas in combination with other drivers like NKX2–1 [ 15 , 16 , 28 ].…”

“…To identify and study novel metastasis drivers we have used both in vitro and in vivo gain-of-function and loss-of-function screens [ 6 – 10 ]. Using in vitro and in vivo positive selection screens, we recently identified a number of putative driver genes of lung cancer progression and metastasis, including the Mitogen Associated Protein 3 Kinase 12 Binding Inhibitory Protein (MBIP) [ 6 , 7 ]. MBIP is a member of the mitogen-activated protein kinase kinase kinase (MAP3K) family [ 11 ].…”

Amplifying Tumor–Stroma Communication: An Emerging Oncogenic Function of Mutant p53

“…During progression, tumor cells frequently display increased secretory activity, which associates with structural adaptations of the secretory apparatus, such as expansion of the Golgi network and optimization of vesicular trafficking ( 53 – 56 ), correlating with poor prognosis ( 57 – 60 ). However, the mechanisms responsible for reprogramming the secretory machinery in cancer cells have remained elusive.…”

KDELR2 knockdown synergizes with temozolomide to induce glioma cell apoptosis through the CHOP and JNK/p38 pathways

“…The functions of KDELRs are associated with cancer biology (19,(27)(28)(29)(30), especially in glioma: KDELR1 can significantly reduce the expression of the ER transcription factor CREB3 (27) and block hypoxia-induced autophagy in glioblastoma (28); KDELR2 has been associated with the median survival rate of non-small cell lung cancer (29), and it promotes glioblastoma tumorigenesis, which is regulated by hypoxia-inducible factor 1 (HIF-1) (30). Knockdown of KDELR2 has been shown to reduce cell viability, promote cell cycle arrest, and induce apoptotic cell death by targeting cell cycle proteins (31) In addition, KDELR3 promotes high melanoma metastasis (19).…”