Loss of Rnf43 Accelerates Kras-Mediated Neoplasia and Remodels the Tumor Immune Microenvironment in Pancreatic Adenocarcinoma

Hosein, Abdel; Dangol, Gita; Okumura, Takashi; Roszik, Jason; Rajapakshe, Kimal I.; Siemann, Megan J.; Zaid, Mohamed; Ghosh, Bidyut; Monberg, Maria E.; Guerrero, Paola A.; Singhi, Aatur D.; Haymaker, Cara L.; Abou‐Elkacem, Lotfi; Woermann, Sonja Maria; Maitra, Anirban

doi:10.1053/j.gastro.2021.12.273

Cited by 39 publications

(29 citation statements)

References 33 publications

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“…Based on the expressions of 17 immune genes, we constructed an IGRPM to assess the prognosis of patients with The results demonstrated that the risk score was negatively correlated with the OS of KIRC patients, and there was a substantial difference in survival time between the high-risk score group and low-risk score group. Moreover, most of the 17 genes used to construct IGRPM are related to the onset and progression of cancer and have the potential to become therapeutic targets for can-cer, such as OASL [39], NR3C2 [32,33], SAA1 [40], CXCL5 (C-X-C Motif Chemokine Ligand 5) [41], TLR3(toll-like receptor 3) [42], CLDN4 [43,44], THRB [45], and LGR4 [46]. However, the specific molecular mechanisms of these genes affecting the prognosis of tumor patients are not clear, so the molecular mechanisms of the effect of these genes on KIRC patients need to be further studied in the future.…”

Section: Discussionmentioning

confidence: 99%

Identification of Survival Risk and Immune-Related Characteristics of Kidney Renal Clear Cell Carcinoma

Liang

Chen

et al. 2022

Journal of Immunology Research

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Background. Immunity exerts momentous functions in the progression and treatment of kidney renal clear cell carcinoma (KIRC). A better understanding of the relationship between KIRC and immunity may make a great contribution to evaluating the prognosis and immune-related therapeutic response of KIRC. Methods. A series of information such as RNA sequence, clinical data, and tumor mutation burden (TMB) of KIRC patients were downloaded through The Cancer Genome Atlas (TCGA). Next, combining the survival information and gene expression data of TCGA and Gene Expression Omnibus (GEO), we established an immune gene-related prognosis model (IGRPM) and analyzed it. Then we constructed a nomogram which was convenient for clinicians to judge the prognosis of KIRC. Last but not the least, the expressions of some genes used to construct IGRPM in early KIRC, and adjacent normal tissues were verified through real-time fluorescence quantitative polymerase chain reaction (RT-qPCR). Perl (strawberry-perl-5.30.0.1-64bit), R software (4.0.3), and GraphPad Prism 7 were used to process the relevant data. Results. The single-sample gene set enrichment analysis (ssGSEA) showed that there were significant differences in StromalScore, ImmuneScore, ESTIMATEScore, TumorPurity, 22 kinds of human immune cells infiltration, and HLA genes expression between high immunity group (Immunity_H) and low immunity group (Immunity_L). The Immunity_H expressed more immune-related genes and enriched more immune-related functions than the Immunity_L. In addition, compared with the low-risk group, the high-risk group had worse survival outcome and higher TMB. Combining IGRPM-based risk characteristic and TMB, we found that low-TMB + low-risk was the most beneficial to the survival outcome of KIRC patients. The risk characteristic based on IGRPM could be used as an independent prognostic factor for KIRC, and the nomogram constructed for evaluating the prognosis of KIRC showed excellent predictive potential. The RT-qPCR results suggested that not all the genes used to construct IGRPM showed differential expression in early KIRC compared with adjacent normal tissues, but all these genes had significant influence on the prognosis of KIRC. Conclusion. These comprehensive immune assessments and survival predictions, integrating multiple aspects of data and clinical information, can provide additional value to the current Tumor Node Metastasis staging system for risk stratification of KIRC and may facilitate the development of KIRC immunotherapy.

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Section: Discussionmentioning

confidence: 99%

Identification of Survival Risk and Immune-Related Characteristics of Kidney Renal Clear Cell Carcinoma

Liang

Chen

et al. 2022

Journal of Immunology Research

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“…Kras G12D/+ Trp53 R172H/+ Pdx-1 -Cre (KPC) mice are well characterized as a genetically engineered PDAC model system with autonomously growing tumors to mimic KRAS G12D mutation–induced PDAC progression ( 35 ). Therefore, we evaluated the effect of SUMOylation of EV-packaged hnRNPA1 on the regulation of PROX1 expression to induce LN metastasis of KRAS G12D PDAC in the KPC mouse model.…”

Section: Resultsmentioning

confidence: 99%

KRAS mutant–driven SUMOylation controls extracellular vesicle transmission to trigger lymphangiogenesis in pancreatic cancer

Luo¹,

Li²,

Wang³

et al. 2022

Journal of Clinical Investigation

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Lymph node (LN) metastasis occurs frequently in pancreatic ductal adenocarcinoma (PDAC) and predicts poor prognosis for patients. The KRAS G12D mutation confers an aggressive PDAC phenotype that is susceptible to lymphatic dissemination. However, the regulatory mechanism underlying KRAS G12D mutation–driven LN metastasis in PDAC remains unclear. Herein, we found that PDAC with the KRAS G12D mutation ( KRAS G12D PDAC) sustained extracellular vesicle–mediated (EV-mediated) transmission of heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) in a SUMOylation-dependent manner and promoted lymphangiogenesis and LN metastasis in vitro and in vivo. Mechanistically, hnRNPA1 bound with SUMO2 at the lysine 113 residue via KRAS G12D -induced hyperactivation of SUMOylation, which enabled its interaction with TSG101 to enhance hnRNPA1 packaging and transmission via EVs. Subsequently, SUMOylation induced EV-packaged-hnRNPA1 anchoring to the adenylate- and uridylate-rich elements of PROX1 in lymphatic endothelial cells, thus stabilizing PROX1 mRNA. Importantly, impeding SUMOylation of EV-packaged hnRNPA1 dramatically inhibited LN metastasis of KRAS G12D PDAC in a genetically engineered Kras G12D/+ Trp53 R172H/+ Pdx-1 -Cre (KPC) mouse model. Our findings highlight the mechanism by which KRAS mutant–driven SUMOylation triggers EV-packaged hnRNPA1 transmission to promote lymphangiogenesis and LN metastasis, shedding light on the potential application of hnRNPA1 as a therapeutic target in patients with KRAS G12D PDAC.

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“…1e, Supplementary Table 2 ). These candidates included well-known PDAC tumor suppressor genes, such as Cdkn2a 24 , Rnf43 25 , Fbxw7 26 or NF2 27 , as well as genes with poorly understood function, such as Usp15 and Scaf1 .…”

Section: Resultsmentioning

confidence: 99%

In vivo CRISPR screens reveal SCAF1 and USP15 as novel drivers of pancreatic cancer

Martinez

Weber

Woo

et al. 2022

Preprint

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Functionally characterizing the genetic alterations that drive pancreatic cancer progression is a prerequisite for Precision Medicine. Here, we developed a somatic CRISPR/Cas9 mutagenesis screen to assess the transforming potential of 125 recurrently mutated long-tail pancreatic cancer genes, which revealed USP15 and SCAF1 as novel and potent Pancreatic ductal adenocarcinoma PDAC tumor suppressors, with USP15 functioning in a haplo-insufficient manner. Mechanistically, we found that loss of USP15 leads to reduced inflammatory responses associated with TNFa, TGF-b and IL6 signaling and sensitizes pancreatic cancer cells to PARP inhibition and gemcitabine. Similarly, genetic ablation of SCAF1 reduced inflammatory responses linked to TNFa,TGF-b and mTOR signaling and increased sensitivity to PARP inhibition. Furthermore, we identified that loss of SCAF1 resulted in the formation of a truncated inactive USP15 isoform at the expense of full length USP15, functionally coupling SACF1 and USP15. Notably, USP15 and SCAF1 mutations or copy number losses are observed in 31% of PDAC patients. Together, our results demonstrate the utility of in vivo CRISPR to integrate human cancer genomics with mouse modeling to delineate novel cancer driver genes USP15 and SCAF1 such as with potential prognostic and therapeutic implications.

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Loss of Rnf43 Accelerates Kras-Mediated Neoplasia and Remodels the Tumor Immune Microenvironment in Pancreatic Adenocarcinoma

Cited by 39 publications

References 33 publications

Identification of Survival Risk and Immune-Related Characteristics of Kidney Renal Clear Cell Carcinoma

Identification of Survival Risk and Immune-Related Characteristics of Kidney Renal Clear Cell Carcinoma

KRAS mutant–driven SUMOylation controls extracellular vesicle transmission to trigger lymphangiogenesis in pancreatic cancer

In vivo CRISPR screens reveal SCAF1 and USP15 as novel drivers of pancreatic cancer

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