Kras and Tumor Immunity: Friend or Foe?

Cullis, Jane; Das, Shipra; Bar–Sagi, Dafna

doi:10.1101/cshperspect.a031849

Cited by 71 publications

(83 citation statements)

References 155 publications

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“…End stage tumors with genetic alterations in Kras exhibited marked modulation of the immune response, including reduced expression of inflammatory cytokines and increased markers of activated myeloid cells. These findings are consistent with the literature describing immune evasion by Kras activation by multiple mechanisms, including reduced expression of tumor antigens, and promotion of recruitment and differentiation of immune populations that inhibit anti-tumor immune activity (Cullis et al, 2017;Dias Carvalho et al, 2018) . Future studies will elucidate interactions between preneoplastic/malignant epithelial cells and the immune microenvironment through stages of PRL-induced pathogenesis.…”

Section: Discussionsupporting

confidence: 92%

Spontaneous aggressive ERα+ mammary tumor model is driven by Kras activation

Campbell¹,

O’Leary

Rugowski

et al. 2018

Preprint

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The NRL-PRL murine model, defined by mammary-selective transgenic rat prolactin ligand rPrl expression, establishes spontaneous ER+ mammary tumors, mimicking the association between elevated prolactin (PRL) and risk for development of ER+ breast cancer in postmenopausal women. Whole genome and exome sequencing in a discovery cohort (n=5) of end stage tumors revealed canonical activating mutations and copy number amplifications of Kras . The frequent mutations in this pathway were validated in an extension cohort, identifying activating Ras alterations in 79% (23/29) of tumors. Transcriptome analyses over the course of oncogenesis revealed marked alterations associated with Ras activity in established tumors, compared to preneoplastic tissues, in cell-intrinsic processes associated with mitosis, cell adhesion and invasion, as well as in the tumor microenvironment, including immune activity. These genomic analyses suggest that PRL induces a selective bottleneck for spontaneous Ras-driven tumors which may model a subset of aggressive clinical ER+ breast cancers.

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Section: Discussionsupporting

confidence: 92%

Spontaneous aggressive ERα+ mammary tumor model is driven by Kras activation

Campbell¹,

O’Leary

Rugowski

et al. 2018

Preprint

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“…Ren et al reported that TGF‐β could promote the migration of PC cells by inducing EMT during the activation of WNT signalling pathway 48 . The activation of TGF‐β signalling pathway promotes Treg cells recruitment and TAMs polarization and induces immunosuppression in the TME 49,50 . Additionally, existing studies suggests a critical positive feedback loop between the activation of EMT and the infiltration of TAMs in cancers, which, in turn, induce immune evasion and suppression in the TME 51‐53 .…”

Section: Discussionmentioning

confidence: 99%

Characterization of the prognostic and oncologic values of ITGB superfamily members in pancreatic cancer

Zhuang

Zhou

et al. 2020

J Cellular Molecular Medi

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Integrin β (ITGB) superfamily members have been reported to play important roles in multiple biological functions in various cancers. However, the prognostic and oncologic values of ITGB superfamily members have not been systematically investigated in pancreatic cancer (PC). In this study, the mRNA expression and biological functions of ITGB superfamily members in PC were evaluated by bioinformatic analysis. Our results demonstrated that ITGB1, ITGB4, ITGB5 and ITGB6 overexpressions were significantly associated with advanced AJCC stage and histologic grade, and worse prognosis in PC. A prognostic signature based on ITGB1, ITGB4, ITGB5 and ITGB6 showed a reliable predictive performance. Furthermore, one CpGs (cg20545410) in promoter region of ITGB1, four (cg18709893, cg15700850, cg20667796 and cg18326022) of ITGB4, two (cg10977398 and cg03518058) of ITGB5 and one (cg23008083) of ITGB6 were negatively associated with their corresponding mRNA expression, and positively associated with prognosis in PC. We also identified TFAP2A as the potential transcription factor for ITGB4, SP1 for ITGB1 and ITGB6, and FHL2 for ITGB5 and ITGB6. ITGB1, ITGB4, ITGB5 and ITGB6 overexpressions were all significantly involved in focal adhesion signalling pathway. ITGB1 and ITGB5 overexpressions also associated with up‐regulation of TGF‐β and WNT signalling pathway, whereas ITGB4 and ITGB6 overexpressions associated with up‐regulation of Notch signalling pathway. Besides, ITGB1, ITGB5 and ITGB6 overexpressions significantly correlated with immunosuppression in PC. In summary, our study investigated the multilevel prognostic and biological values of ITGB superfamily members in PC.

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“…Several chemokines have been implicated in inflammation-induced tumorigenesis 39 . Chemokine C-C motif ligand 5 (CCL5), also known as Regulated upon Activation, Normal T-cell Expressed and Secreted (RANTES), mediates migration and chemotaxis of cells and is expressed by several cell types such as fibroblasts, epithelial cells, tumour cells and immune cells.…”

Section: Kras-induced Inflammationmentioning

confidence: 99%

Immune modulatory effects of oncogenic KRAS in cancer

et al. 2020

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Oncogenic KRAS mutations are the most frequent mutations in human cancer, but most difficult to target. While sustained proliferation caused by oncogenic KRAS-downstream signalling is a main driver of carcinogenesis, there is increasing evidence that it also mediates autocrine effects and crosstalk with the tumour microenvironment (TME). Here, we discuss recent reports connecting KRAS mutations with tumour-promoting inflammation and immune modulation caused by KRAS that leads to immune escape in the TME. We discuss the preclinical work on KRAS-induced inflammation and immune modulation in the context of currently ongoing clinical trials targeting cancer entities that carry KRAS mutations and strategies to overcome the oncogene-induced effects on the immune system.

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Kras and Tumor Immunity: Friend or Foe?

Cited by 71 publications

References 155 publications

Spontaneous aggressive ERα+ mammary tumor model is driven by Kras activation

Spontaneous aggressive ERα+ mammary tumor model is driven by Kras activation

Characterization of the prognostic and oncologic values of ITGB superfamily members in pancreatic cancer

Immune modulatory effects of oncogenic KRAS in cancer

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