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 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 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 The Oncogenic Potential of a Mutant TP53 Gene Explored in Two Spontaneous Lung Cancer Mice Models

2020 ◽  
Author(s):  
Julian Ramelow ◽  
Christopher Brooks ◽  
Li GaO ◽  
Abeer A Almiman ◽  
Terence M Williams ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Mouse Models ◽  
Human Lung ◽  
Lung Tumor ◽  
Mutant Gene ◽  
Genetic Mutation ◽  
Tumor Formation ◽  
Human Lung Cancer ◽  
Oncogenic Potential ◽  
Age Related

Abstract BackgroundLung cancer is the number one cancer killer worldwide. A major impediment to progress in the lung cancer treatment field is the lack of realistic mouse models that replicate the complexity of human malignancy and immune contexture within the tumor microenvironment. Such models are urgently needed. Mutations of the tumor suppressor gene TP53 are among the most common alterations in human lung cancers.MethodsPreviously, we developed a line of lung cancer mouse model where mutant human TP53-273H is expressed in a lung specific manner in FVB/N background. To investigate whether the human TP53 mutant has a similar oncogenic potential when it is expressed in another strain of mouse, we crossed the FVB/N-SPC-TP53-273H mice to A/J strain and created A/J-SPC-TP53-273H transgenic mice. We then compared lung tumor formation between A/J-SPC-TP53-273H and FVB/N-SPC-TP53-273H.ResultsWe found the TP53-273H mutant gene has a similar oncogenic potential in lung tumor formation in both mice strains, although A/J strain mice have been found to be a highly susceptible strain in terms of carcinogen-induced lung cancer. Both transgenic lines survived more than 18 months and developed age related lung adenocarcinomas. With micro CT imaging, we found the FVB-SPC-TP53-273H mice survived more than 8 weeks after initial detection of lung cancer, providing a sufficient window for evaluating new anti-cancer agents.ConclusionsOncogenic potential of the most common genetic mutation, TP53-273H, in human lung cancer is unique when it is expressed in different strains of mice. Our mouse models are useful tools for testing novel immune check point inhibitors or other therapeutic strategies in treatment of lung cancer.

Bicistronic transfer of CDKN2A and p53 culminates in collaborative killing of human lung cancer cells in vitro and in vivo

Gene Therapy ◽  
2019 ◽  
Vol 27 (1-2) ◽  
pp. 51-61
Author(s):  
Juliana G. Xande ◽  
Ana P. Dias ◽  
Rodrigo E. Tamura ◽  
Mario C. Cruz ◽  
Bárbara Brito ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Cells ◽  
Human Lung ◽  
Lung Cancer Cells ◽  
Human Lung Cancer ◽  
Human Lung Cancer Cells
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