A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS–Driven Lung Cancer

Cai, Hongchen; Chew, Su Kit; Li, Chuan; Tsai, Min K.; Andrejka, Laura; Murray, Christopher W.; Hughes, Nicholas W.; Shuldiner, Emily G.; Ashkin, Emily L.; Tang, Rui; Hung, King L.; Chen, Leo C.; Lee, Claudia; Yousefi, Maryam; Lin, Wen‐Yang; Kunder, Christian A.; Cong, Le; McFarland, Christopher D.; Petrov, Dmitri A.; Swanton, Charles; Winslow, Monte M.

doi:10.1158/2159-8290.cd-20-1325

Cited by 45 publications

(71 citation statements)

References 81 publications

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“…However, we found that there were more important mechanisms of ISM1 in CRC that have not been reported. In the GSEA results, enriched pathways, such as the EMT, hypoxia, KRAS signaling, angiogenesis, Notch and Hedgehog signaling pathways, were significantly positively associated with ISM1, and most of these pathways are vital to cell proliferation, migration and resistance in cancer ( Wang et al, 2020 ; Andrysik et al, 2021 ; Cai et al, 2021 ), including CRC. We exclusively focused on the EMT signaling pathway because 71% of genes in the pathway exhibited a significantly positive correlation with ISM1.…”

Section: Discussionmentioning

confidence: 99%

Effect of ISM1 on the Immune Microenvironment and Epithelial-Mesenchymal Transition in Colorectal Cancer

Liang

et al. 2021

Front. Cell Dev. Biol.

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Background: An increasing number of studies have shown that Isthmin 1 (ISM1), a secreted protein, is important in tumorigenesis and invasion, including in colorectal cancer (CRC). However, the mechanisms are still unclear. This study aims to explore the function and prognosis capacity of ISM1 in CRC.Methods: We investigated the expression of ISM1 in 18 CRC tissues vs. adjacent normal tissues from GSE50760, 473 CRC tissues vs. 41 normal tissues from The Cancer Genome Atlas (TCGA), and across gastrointestinal cancer types. Differences were further confirmed in CRC tissues via quantitative real-time polymerase chain reaction (qRT-PCR). Then, we analyzed correlations between clinicopathologic features and ISM1 expression, including prognostic prediction value, using the Kaplan–Meier method and multivariate Cox regression. Gene set enrichment analysis (GSEA) was performed to identify ISM1-related pathways. In vitro experiments were performed to verify the role of ISM1 in epithelial-mesenchymal transition (EMT) and CRC progression.Results: Multiple datasets showed that ISM1 is upregulated in CRC tissues, which was validated. Patients with higher ISM1 expression had shorter overall survival (OS), and ISM1 expression served as an independent prognostic factor. Enrichment analysis showed that ISM1 upregulation was positively correlated with cancer-related pathways, such as EMT, hypoxia, and the Notch and KRAS signaling pathways. We were exclusively interested in the connection between ISM1 and EMT because 71% of genes in this pathway were significantly positively co-expressed with ISM1, which may account for why patients with higher ISM1 expression are prone to regional lymph node involvement and progression to advanced stages. In addition, we found that ISM1 was positively correlated with multiple immunosuppressive pathways such as IL2/STAT5, TNF-α/NF-κB, and TGF-β, and immune checkpoints, including PD-L1, PD-1, CTLA-4, and LAG3, which may account for upregulation of ISM1 in immunotherapy-resistant patients. Notably, through in vitro experiments, we found that ISM1 promoted EMT and colon cancer cell migration and proliferation.Conclusion: ISM1 is critical for CRC development and progression, which enhances our understanding of the low response rate of CRC to immunotherapy via immunosuppressive signaling pathways.

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Section: Discussionmentioning

confidence: 99%

Effect of ISM1 on the Immune Microenvironment and Epithelial-Mesenchymal Transition in Colorectal Cancer

Liang

et al. 2021

Front. Cell Dev. Biol.

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“…The previous study did not explore the causes of poor survival and prognosis in the high-risk group. In our study, the relationship with immune infiltration was found in the high-risk group to be mainly enriched in genes upregulated in response to hypoxia [ 50 – 52 ], TNF [ 53 , 54 ], EMT [ 55 , 56 ], wound healing, fibrosis, metastasis, and KRAS activation [ 57 , 58 ]. These pathways are closely related to tumorigenesis, invasion, and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of Autophagy-Related Gene Nomograms to Predict the Prognostic Value of Patients with Cervical Cancer

Jiang

Wang

et al. 2021

Journal of Oncology

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Autophagy is a process of engulfing one’s own cytoplasmic proteins or organelles and coating them into vesicles, fusing with lysosomes to form autophagic lysosomes, and degrading the contents it encapsulates. Increasing studies have shown that autophagy disorders are closely related to the occurrence of tumors. However, the prognostic role of autophagy genes in cervical cancer is still unclear. In this study, we constructed risk signatures of autophagy-related genes (ARGs) to predict the prognosis of cervical cancer. The expression profiles and clinical information of autophagy gene sets were downloaded from TCGA and GSE52903 queues as training and validation sets. The normal cervical tissue expression profile data from the UCSC XENA website (obtained from GTEx) were used as a supplement to the TCGA normal cervical tissue. Univariate COX regression analysis of 17 different autophagy genes was performed with the consensus approach. Tumor samples from TCGA were divided into six subtypes, and the clinical traits of the six subtypes had different distributions. Further absolute shrinkage and selection operator (LASSO) and multivariable COX regression yielded an autophagy genetic risk model consisting of eight genes. In the training set, the survival rate of the high-risk group was lower than that of the low-risk group ( p < 0.0001). In the validation set, the AUC area of the receiver operating characteristic (ROC) curve was 0.772 for the training set and 0.889 for the verification set. We found that high and low risk scores were closely related to TNM stage ( p < 0.05). The nomogram shows that the risk score combined with other indicators, such as G, T, M, and N, better predicts 1-, 3-, and 5-year survival rates. Decline curve analysis (DCA) shows that the risk model combined with other indicators produces better clinical efficacy. Immune cells with an enrichment score of 28 showed statistically significant differences related to high and low risk. GSEA enrichment analysis showed the main enrichment being in KRAS activation, genes defining epithelial and mesenchymal transition (EMT), raised in response to the low oxygen level (hypoxia) gene and NF-kB in response to TNF. These pathways are closely related to the occurrence of tumors. Our constructed autophagy risk signature may be a prognostic tool for cervical cancer.

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“…Given the widespread genetic and epigenetic alterations in human tumors, genomic analyses have limited ability to delineate causal relationships between genomic alterations and tumor development [1]. To determine whether combinatorial tumor suppressor gene inactivation can drive lung tumor initiation in the absence of oncogene activation, we coupled Cre/loxP-based genetically engineered mouse models and somatic CRISPR/Cas9-based genome editing with tumor barcoding and high-throughput barcode sequencing (Tuba-seq) [31][32][33][34][35]. We used Cre/loxP to inactivate each of five "core" tumor suppressor genes (Trp53, Lkb1/Stk11, Keap1, Nf1, and Pten).…”

Section: Combinatorial Tumor Suppressor Gene Inactivation Enables Lung Tumor Developmentmentioning

confidence: 99%

“…We used Cre/loxP to inactivate each of five "core" tumor suppressor genes (Trp53, Lkb1/Stk11, Keap1, Nf1, and Pten). These genes operate within diverse pathways and are frequently inactivated in human lung cancers, including oncogene-negative lung adenocarcinomas (Figure S2a-b) [35][36][37][38]. We used CRISPR/Cas9 to coincidentally inactivate panels of additional tumor suppressor genes in lung epithelial cells in mice with floxed alleles of each of the "core" tumor suppressors, a Cre-reporter allele (R26 LSL-Tom (T) [36]), and a Cre-regulated Cas9 allele (H11 LSL-Cas9 (C) [37]).…”

Section: Combinatorial Tumor Suppressor Gene Inactivation Enables Lung Tumor Developmentmentioning

confidence: 99%

Combinatorial tumor suppressor inactivation efficiently initiates lung adenocarcinoma with therapeutic vulnerabilities

Yousefi

Boross

Weiss

et al. 2021

Preprint

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Lung cancer is the leading cause of cancer death worldwide, with lung adenocarcinoma being the most common subtype. Many oncogenes and tumor suppressor genes are altered in this cancer type and the discovery of oncogene mutations has led to the development of targeted therapies and better clinical outcomes. However, a large fraction of lung adenocarcinomas lacks mutations in known oncogenes, and the genesis and treatment of these oncogene-negative tumors remain enigmatic. Here, we perform iterative in vivo functional screens with quantitative autochthonous mouse model systems to uncover the genetic and biochemical changes that enable efficient lung tumor initiation in the absence of oncogene alterations. Through the generation of hundreds of diverse combinations of tumor suppressor alterations, we demonstrate that inactivation of suppressors of the RAS and PI3K pathways drive the development of oncogene-negative lung adenocarcinoma. Pathway-level human genomic data analysis and histology identified RAS/MAPK and PI3K pathway activation as a common event in oncogene-negative human lung adenocarcinomas. We demonstrate that oncogene-negative tumors and cell lines with activated RAS/MAPK and PI3K pathways are vulnerable to pharmacological inhibition of these signaling axes. Collectively, these results transform our understanding of this prevalent yet understudied subtype of lung adenocarcinoma.

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A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS–Driven Lung Cancer

Cited by 45 publications

References 81 publications

Effect of ISM1 on the Immune Microenvironment and Epithelial-Mesenchymal Transition in Colorectal Cancer

Effect of ISM1 on the Immune Microenvironment and Epithelial-Mesenchymal Transition in Colorectal Cancer

Identification and Validation of Autophagy-Related Gene Nomograms to Predict the Prognostic Value of Patients with Cervical Cancer

Combinatorial tumor suppressor inactivation efficiently initiates lung adenocarcinoma with therapeutic vulnerabilities

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