Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in
            <i>KRAS</i>
            mutant lung adenocarcinoma

Metz, Heather; Kargl, Julia; Busch, Stephanie; Kim, Kyoung-Hee; Kurland, Brenda F.; Abberbock, Shira; Randolph‐Habecker, Julie; Knoblaugh, Sue E.; Kolls, Jay K.; White, Morris F.; Houghton, A. McGarry

doi:10.1073/pnas.1601989113

Cited by 15 publications

(18 citation statements)

References 43 publications

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“…2A). These results provide evidence of a functional redundancy in Irs1 and Irs2 signal transduction in Kras-driven lung tumor cells, and are consistent with a recent report demonstrating increased rather than decreased tumor formation in a Kras-driven mouse model of lung cancer with loss of Irs1 alone (18). Intriguingly, however, Erk1/2 activation (pT202/Y204) levels varied significantly among the different cell lines upon ligand treatment, and did not correlate with the loss of Irs1/Irs2, reflecting heterogeneity in the tumor cell populations ( Fig.…”

Section: Loss Of Irs1 and Irs2 Suppresses Akt Signaling And Leads To supporting

confidence: 91%

“…It is noteworthy that genetic loss of Irs1 alone in a similar Krasdriven mouse model of lung cancer, which however expresses wild-type p53, resulted in increased rather than decreased tumor burden and reduced survival (18). This seemingly contradictory result is however not surprising, given that the tumor cells had retained wild-type Irs2 expression.…”

Section: Discussionmentioning

confidence: 99%

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Ablation of insulin receptor substrates 1 and 2 suppresses Kras -driven lung tumorigenesis

Lee

Tsai

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Non-small-cell lung cancer (NSCLC) is a leading cause of cancer death worldwide, with 25% of cases harboring oncogenic Kirsten rat sarcoma (). Although KRAS direct binding to and activation of PI3K is required for -driven lung tumorigenesis, the contribution of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) in the context of mutant remains controversial. Here, we provide genetic evidence that lung-specific dual ablation of insulin receptor substrates 1/2 (/), which mediate insulin and IGF1 signaling, strongly suppresses tumor initiation and dramatically extends the survival of a mouse model of lung cancer with activation and loss. Mice with / loss eventually succumb to tumor burden, with tumor cells displaying suppressed Akt activation and strikingly diminished intracellular levels of essential amino acids. Acute loss of / or inhibition of IR/IGF1R in -mutant human NSCLC cells decreases the uptake and lowers the intracellular levels of amino acids, while enhancing basal autophagy and sensitivity to autophagy and proteasome inhibitors. These findings demonstrate that insulin/IGF1 signaling is required for-mutant lung cancer initiation, and identify decreased amino acid levels as a metabolic vulnerability in tumor cells with IR/IGF1R inhibition. Consequently, combinatorial targeting of IR/IGF1R with autophagy or proteasome inhibitors may represent an effective therapeutic strategy in -mutant NSCLC.

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Section: Loss Of Irs1 and Irs2 Suppresses Akt Signaling And Leads To supporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Ablation of insulin receptor substrates 1 and 2 suppresses Kras -driven lung tumorigenesis

Lee

Tsai

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…The significant association between low IRS-1 expression and overall survival of SCC patients observed in our current study may reflect the inclusion of later stage tumors in our dataset. Low IRS-1 expression has also been reported to predict poor outcomes specifically for K-RAS mutant ADC [24]. Our analysis, which was neutral for mutational status, showed an opposite survival trend, but not significant association, for IRS-1 expression in ADC.…”

Section: Discussioncontrasting

confidence: 53%

Insulin Receptor Substrate-1 (IRS-1) and IRS-2 expression levels are associated with prognosis in non-small cell lung cancer (NSCLC)

et al. 2019

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The insulin-like growth factor-1 (IGF-1) signaling pathway has been implicated in non-small cell lung cancer (NSCLC) outcomes and resistance to targeted therapies. However, little is known regarding the molecular mechanisms by which this pathway contributes to the biology of NSCLC. The insulin receptor substrate (IRS) proteins are cytoplasmic adaptor proteins that signal downstream of the IGF-1R and determine the functional outcomes of this signaling pathway. In this study, we assessed the expression patterns of IRS-1 and IRS-2 in NSCLC to identify associations between IRS-1 and IRS-2 expression levels and survival outcomes in the two major histological subtypes of NSCLC, adenocarcinoma (ADC) and squamous cell carcinoma (SCC). High IRS-2 expression was significantly associated with decreased overall survival in adenocarcinoma (ADC) patients, whereas low IRS-1 cytoplasmic expression showed a trend toward association with decreased overall survival in squamous cell carcinoma (SCC) patients. Tumors with low IRS-1 and high IRS-2 expression were found to be associated with poor outcomes in ADC and SCC, indicating a potential role for IRS-2 in the aggressive behavior of NSCLC. Our results suggest distinct contributions of IRS-1 and IRS-2 to the biology of ADC and SCC that impact disease progression.

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“…Although IL22-producing ILC3s are reported in stage I/II NSCLC, where they are suggested to have antitumor activity and are associated with favorable prognosis (36), we did not see any contribution by these cells in producing IL22 in the lungs of mice with Kras mutant tumors. Metz et al showed that IL22 induces the production of chemokines, including CCL2, by Kras mutant lung cancer cell lines (37). This could explain the observed reduction in the number of macrophages and expression of cytokines in our Kras mutant/IL22KO mouse.…”

Section: Discussionmentioning

confidence: 99%

IL22 Promotes Kras-Mutant Lung Cancer by Induction of a Protumor Immune Response and Protection of Stemness Properties

Khosravi

Caetano

Cumpian

et al. 2018

Cancer Immunology Research

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Somatic mutations are the most common oncogenic variants in lung cancer and are associated with poor prognosis. Using a-induced lung cancer mouse model, CC-LR, we previously showed a role for inflammation in lung tumorigenesis through activation of the NF-κB pathway, along with induction of interleukin 6 (IL6) and an IL17-producing CD4 T-helper cell response. IL22 is an effector molecule secreted by CD4 and γδ T cells that we previously found to be expressed in CC-LR mice. IL22 mostly signals through the STAT3 pathway and is thought to act exclusively on nonhematopoietic cells with basal IL22 receptor (IL22R) expression on epithelial cells. Here, we found that higher expression of in patients with-mutant lung adenocarcinoma was an independent indicator of poor recurrence-free survival. We then showed that genetic ablation of in CC-LR mice (CC-LR/IL22KO mice) caused a significant reduction in tumor number and size. This was accompanied by significantly lower tumor cell proliferation, angiogenesis, and STAT3 activation. ablation was also associated with significant reduction in lung-infiltrating inflammatory cells and expression of protumor inflammatory cytokines. Conversely, this was accompanied with increased antitumor Th1 and cytotoxic CD8 T-cell responses, while suppressing the protumor immunosuppressive T regulatory cell response. In CC-LR/IL22KO mice, we found significantly reduced expression of core stemness genes and the number of prototypical SPCCCSP stem cells. Thus, we conclude that IL22 promotes -mutant lung tumorigenesis by driving a protumor inflammatory microenvironment with proliferative, angiogenic, and stemness contextual cues in epithelial/tumor cells..

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Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma

Cited by 15 publications

References 43 publications

Ablation of insulin receptor substrates 1 and 2 suppresses Kras -driven lung tumorigenesis

Ablation of insulin receptor substrates 1 and 2 suppresses Kras -driven lung tumorigenesis

Insulin Receptor Substrate-1 (IRS-1) and IRS-2 expression levels are associated with prognosis in non-small cell lung cancer (NSCLC)

IL22 Promotes Kras-Mutant Lung Cancer by Induction of a Protumor Immune Response and Protection of Stemness Properties

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