scholarly journals Multiplexed identification of RAS paralog imbalance as a driver of lung cancer growth

2021 ◽  
Author(s):  
Rui Tang ◽  
Emily Shuldiner ◽  
Marcus Kelly ◽  
Christopher Murray ◽  
Jess Hebert ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Genetically Engineered ◽  
Human Lung Cancer ◽  
Cancer Growth ◽  
Ras Signaling ◽  
Negative Regulators ◽  
Kras Mutations ◽  
Genetically Engineered Mouse Models ◽  
Cancer Models

Abstract Oncogenic KRAS mutations occur in approximately 30% of lung adenocarcinoma. Despite several decades of effort, oncogenic KRAS-driven lung cancer remains difficult to treat, and our understanding of the positive and negative regulators of RAS signaling is incomplete. To uncover the functional impact of diverse KRAS-interacting proteins on lung cancer growth in vivo, we used multiplexed somatic CRISPR/Cas9-based genome editing in genetically engineered mouse models with tumor barcoding and high-throughput barcode sequencing. Through a series of CRISPR/Cas9 screens in autochthonous lung tumors, we identified HRAS and NRAS as key suppressors of KRASG12D-driven tumor growth in vivo and confirmed these effects in oncogenic KRAS-driven human lung cancer cell lines. Mechanistically, RAS paralogs interact with oncogenic KRAS, suppress KRAS-KRAS interactions, and reduce downstream ERK signaling. HRAS mutations identified in KRAS-driven human tumors partially abolished this effect. Comparison of the tumor-suppressive effects of HRAS and NRAS in KRAS- and BRAF-driven lung cancer models confirmed that RAS paralogs are specific suppressors of oncogenic KRAS-driven lung cancer in vivo. Our study outlines a technological avenue to uncover positive and negative regulators of oncogenic KRAS-driven cancer in a multiplexed manner in vivo and highlights the role of RAS paralog imbalance in oncogenic KRAS-driven lung cancer.

scholarly journals Multiplexed identification of RAS paralog imbalance as a driver of lung cancer growth

2021 ◽  
Author(s):  
Rui Tang ◽  
Emily G Shuldiner ◽  
Marcus Kelly ◽  
Christopher W Murray ◽  
Jess D Hebert ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Human Lung ◽  
Lung Tumor ◽  
Genetically Engineered ◽  
Human Lung Cancer ◽  
Cancer Growth ◽  
Ras Signaling ◽  
Negative Regulators ◽  
Kras Mutations

Oncogenic KRAS mutations occur in approximately 30% of human lung adenocarcinoma. Despite tremendous effort over the past several decades, oncogenic KRAS-driven lung cancer remains difficult to treat, and our understanding of the positive and negative regulators of RAS signaling is incomplete. To uncover and corroborate the functional impact of diverse KRAS-interacting proteins on lung cancer growth in vivo, we integrate somatic CRISPR/Cas9-based genome editing in genetically engineered mouse models with tumor barcoding and high-throughput barcode sequencing (Tuba-seq). Through a series of in vivo CRISPR/Cas9 screens, we identified HRAS and NRAS as key suppressors of KRASG12D-driven lung tumor growth in vivo and confirmed these effects in oncogenic KRAS-driven human lung cancer cell lines. Mechanistically, we find that these RAS paralogs interact with oncogenic KRASG12D, suppress KRASG12D-KRASG12D interaction, and reduce downstream ERK signaling. Patient-derived mutations HRAST50M and HRASR123C partially abolished this effect. Comparison of the tumor-suppressive effects of HRAS and NRAS in KRASG12D- and BRAFV600E-driven lung cancer models confirmed that these RAS paralogs are specific suppressors of oncogenic KRAS-driven lung cancer in vivo. Our study outlines a technological avenue to specifically uncover positive and negative regulators of oncogenic KRAS-driven cancer in a multiplexed manner and highlights the role of RAS paralog imbalance in oncogenic KRAS-driven cancers.

scholarly journals EZH2 silencing with RNAi enhances irradiation-induced inhibition of human lung cancer growth in vitro and in vivo

2012 ◽  
Vol 4 (1) ◽  
pp. 135-140 ◽  
Author(s):  
HUI XIA ◽  
CHANG-HAI YU ◽  
YIMING ZHANG ◽  
JIANQI YU ◽  
JIE LI ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Human Lung ◽  
Human Lung Cancer ◽  
Cancer Growth

582 Novel cytotoxic bradykinin antagonist dimers inhibit human lung cancer growth in vitro and in vivo

Lung Cancer ◽  
1997 ◽  
Vol 18 ◽  
pp. 150 ◽  
Author(s):  
D. Chan ◽  
L. Gera ◽  
B. Helfrich ◽  
K. Helm ◽  
E. Whalley ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Human Lung ◽  
Human Lung Cancer ◽  
Cancer Growth ◽  
Bradykinin Antagonist

Inhibition of human lung cancer growth following adenovirus-mediated mda-7 gene expression in vivo

Oncogene ◽  
2002 ◽  
Vol 21 (29) ◽  
pp. 4558-4566 ◽  
Author(s):  
Tomoyuki Saeki ◽  
Abner Mhashilkar ◽  
Xin Swanson ◽  
X Helena Zou-Yang ◽  
Kerry Sieger ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lung Cancer ◽  
Human Lung ◽  
Human Lung Cancer ◽  
Cancer Growth

The natural human monoclonal IgM antibody LM-1 inhibits human lung cancer growth in vitro and in vivo

2005 ◽  
Vol 23 (16_suppl) ◽  
pp. 7347-7347
Author(s):  
S. Brändlein ◽  
F. Hensel ◽  
E. Wozniak ◽  
H.-K. Müller-Hermelink ◽  
H. P. Vollmers
Keyword(s):  
Lung Cancer ◽  
Human Lung ◽  
Human Lung Cancer ◽  
Cancer Growth ◽  
Igm Antibody

scholarly journals POU2F2 promotes the proliferation and motility of lung cancer cells by activating AGO1

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Ronggang Luo ◽  
Yi Zhuo ◽  
Quan Du ◽  
Rendong Xiao
Keyword(s):  
Lung Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Human Lung ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Cancer Tissues

Abstract Background To detect and investigate the expression of POU domain class 2 transcription factor 2 (POU2F2) in human lung cancer tissues, its role in lung cancer progression, and the potential mechanisms. Methods Immunohistochemical (IHC) assays were conducted to assess the expression of POU2F2 in human lung cancer tissues. Immunoblot assays were performed to assess the expression levels of POU2F2 in human lung cancer tissues and cell lines. CCK-8, colony formation, and transwell-migration/invasion assays were conducted to detect the effects of POU2F2 and AGO1 on the proliferaion and motility of A549 and H1299 cells in vitro. CHIP and luciferase assays were performed for the mechanism study. A tumor xenotransplantation model was used to detect the effects of POU2F2 on tumor growth in vivo. Results We found POU2F2 was highly expressed in human lung cancer tissues and cell lines, and associated with the lung cancer patients’ prognosis and clinical features. POU2F2 promoted the proliferation, and motility of lung cancer cells via targeting AGO1 in vitro. Additionally, POU2F2 promoted tumor growth of lung cancer cells via AGO1 in vivo. Conclusion We found POU2F2 was highly expressed in lung cancer cells and confirmed the involvement of POU2F2 in lung cancer progression, and thought POU2F2 could act as a potential therapeutic target for lung cancer.

scholarly journals APOBEC3B expression generates an immunogenic model of Kras mutant lung cancer

2020 ◽  
Author(s):  
Sophie de Carné Trécesson ◽  
Jesse Boumelha ◽  
Emily K. Law ◽  
Pablo Romero-Clavijo ◽  
Edurne Mugarza ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Immune System ◽  
Mouse Models ◽  
Cytosine Deaminase ◽  
Adaptive Immune System ◽  
Genetically Engineered ◽  
Human Lung Cancer ◽  
Tumour Regression ◽  
Host Immune System ◽  
Mutational Burden

ABSTRACTMutations in oncogenes such as KRAS and EGFR cause a high proportion of lung cancers. Drugs targeting these proteins cause tumour regression but ultimately fail to cure these cancers, leading to intense interest in how best to combine them with other treatments, such as immunotherapies. However, preclinical systems for studying the interaction of lung tumours with the host immune system are inadequate, in part due to the low tumour mutational burden in genetically engineered mouse models. Here we set out to develop mouse models of mutant Kras-driven lung cancer with an elevated tumour mutational burden by expressing the human DNA cytosine deaminase, APOBEC3B, to mimic the mutational signature seen in human lung cancer. This causes an increase in mutational burden in Kras mutant and p53 deleted (KP) tumours and in carcinogen-induced tumours, but these mutations are sub-clonal and do not lead to sensitivity of the autochthonous tumours to immune interventions. However, when clonal cell lines are derived from these tumours they provide an immunogenic syngeneic transplantation lung cancer model that is sensitive to immunotherapy. The ability of a KRAS-G12C inhibitor to cause regression of these tumours is markedly potentiated by the adaptive immune system, providing an opportunity for the study of combinations of targeted and immunotherapies in immune-hot lung cancer.

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