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Deletion of p53 and Hyper-Activation of PIK3CA in Keratin-15(+) Stem Cells Lead to the Development of Spontaneous Squamous Cell Carcinoma

Squamous cell carcinoma (SCC) is the second commonest type of skin cancer, and SCCs make up about 90% of head and neck cancers (HNSCCs). HNSCCs harbor two frequent molecular alterations, namely, gain-of-function alterations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (P...

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Autores principales: Chen, Samantha M. Y., Bian, Li, Nicklawsky, Andrew G., Krinsky, Alexandra L., Brunetti, Tonya, Woolaver, Rachel A., Wang, Xiaoguang, Chen, Zhangguo, Young, Christian D., Gao, Dexiang, Wang, Xiao-Jing, Wang, Jing H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554792/
https://www.ncbi.nlm.nih.gov/pubmed/32916850
http://dx.doi.org/10.3390/ijms21186585
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author Chen, Samantha M. Y.
Bian, Li
Nicklawsky, Andrew G.
Krinsky, Alexandra L.
Brunetti, Tonya
Woolaver, Rachel A.
Wang, Xiaoguang
Chen, Zhangguo
Young, Christian D.
Gao, Dexiang
Wang, Xiao-Jing
Wang, Jing H.
author_facet Chen, Samantha M. Y.
Bian, Li
Nicklawsky, Andrew G.
Krinsky, Alexandra L.
Brunetti, Tonya
Woolaver, Rachel A.
Wang, Xiaoguang
Chen, Zhangguo
Young, Christian D.
Gao, Dexiang
Wang, Xiao-Jing
Wang, Jing H.
author_sort Chen, Samantha M. Y.
collection PubMed
description Squamous cell carcinoma (SCC) is the second commonest type of skin cancer, and SCCs make up about 90% of head and neck cancers (HNSCCs). HNSCCs harbor two frequent molecular alterations, namely, gain-of-function alterations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and loss-of-function mutations of tumor protein p53 (TP53). However, it remains poorly understood whether HNSCCs harboring different genetic alterations exhibit differential immune tumor microenvironments (TME). It also remains unknown whether PIK3CA hyperactivation and TP53 deletion can lead to SCC development spontaneously. Here, we analyzed the Cancer Genome Atlas (TCGA) datasets of HNSCCs and found that patients with both PIK3CA and TP53 alterations exhibited worse survival, significantly lower CD8 tumor infiltrating lymphocytes (TILs) and higher M0 macrophages than other controls. To better model human tumorigenesis, we deleted TP53 and constitutively activated PIK3CA in mouse keratin-15-expressing stem cells, which leads to the spontaneous development of multilineage tumors including SCCs, termed Keratin-15-p53-PIK3CA (KPPA) tumors. KPPA tumors were heavily infiltrated with myeloid-derived suppressor cells (MDSCs), with a drastically increased ratio of polymorphonuclear-MDSC (PMN-MDSC) versus monocytic-MDSC (M-MDSC). CD8 TILs expressed more PD-1 and reduced their polyfunctionality. Overall, we established a genetic model to mimic human HNSCC pathogenesis, manifested with an immunosuppressive TME, which may help further elucidate immune evasion mechanisms and develop more effective immunotherapies for HNSCCs.
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spelling pubmed-75547922020-10-14 Deletion of p53 and Hyper-Activation of PIK3CA in Keratin-15(+) Stem Cells Lead to the Development of Spontaneous Squamous Cell Carcinoma Chen, Samantha M. Y. Bian, Li Nicklawsky, Andrew G. Krinsky, Alexandra L. Brunetti, Tonya Woolaver, Rachel A. Wang, Xiaoguang Chen, Zhangguo Young, Christian D. Gao, Dexiang Wang, Xiao-Jing Wang, Jing H. Int J Mol Sci Article Squamous cell carcinoma (SCC) is the second commonest type of skin cancer, and SCCs make up about 90% of head and neck cancers (HNSCCs). HNSCCs harbor two frequent molecular alterations, namely, gain-of-function alterations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and loss-of-function mutations of tumor protein p53 (TP53). However, it remains poorly understood whether HNSCCs harboring different genetic alterations exhibit differential immune tumor microenvironments (TME). It also remains unknown whether PIK3CA hyperactivation and TP53 deletion can lead to SCC development spontaneously. Here, we analyzed the Cancer Genome Atlas (TCGA) datasets of HNSCCs and found that patients with both PIK3CA and TP53 alterations exhibited worse survival, significantly lower CD8 tumor infiltrating lymphocytes (TILs) and higher M0 macrophages than other controls. To better model human tumorigenesis, we deleted TP53 and constitutively activated PIK3CA in mouse keratin-15-expressing stem cells, which leads to the spontaneous development of multilineage tumors including SCCs, termed Keratin-15-p53-PIK3CA (KPPA) tumors. KPPA tumors were heavily infiltrated with myeloid-derived suppressor cells (MDSCs), with a drastically increased ratio of polymorphonuclear-MDSC (PMN-MDSC) versus monocytic-MDSC (M-MDSC). CD8 TILs expressed more PD-1 and reduced their polyfunctionality. Overall, we established a genetic model to mimic human HNSCC pathogenesis, manifested with an immunosuppressive TME, which may help further elucidate immune evasion mechanisms and develop more effective immunotherapies for HNSCCs. MDPI 2020-09-09 /pmc/articles/PMC7554792/ /pubmed/32916850 http://dx.doi.org/10.3390/ijms21186585 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Chen, Samantha M. Y.
Bian, Li
Nicklawsky, Andrew G.
Krinsky, Alexandra L.
Brunetti, Tonya
Woolaver, Rachel A.
Wang, Xiaoguang
Chen, Zhangguo
Young, Christian D.
Gao, Dexiang
Wang, Xiao-Jing
Wang, Jing H.
Deletion of p53 and Hyper-Activation of PIK3CA in Keratin-15(+) Stem Cells Lead to the Development of Spontaneous Squamous Cell Carcinoma
title Deletion of p53 and Hyper-Activation of PIK3CA in Keratin-15(+) Stem Cells Lead to the Development of Spontaneous Squamous Cell Carcinoma
title_full Deletion of p53 and Hyper-Activation of PIK3CA in Keratin-15(+) Stem Cells Lead to the Development of Spontaneous Squamous Cell Carcinoma
title_fullStr Deletion of p53 and Hyper-Activation of PIK3CA in Keratin-15(+) Stem Cells Lead to the Development of Spontaneous Squamous Cell Carcinoma
title_full_unstemmed Deletion of p53 and Hyper-Activation of PIK3CA in Keratin-15(+) Stem Cells Lead to the Development of Spontaneous Squamous Cell Carcinoma
title_short Deletion of p53 and Hyper-Activation of PIK3CA in Keratin-15(+) Stem Cells Lead to the Development of Spontaneous Squamous Cell Carcinoma
title_sort deletion of p53 and hyper-activation of pik3ca in keratin-15(+) stem cells lead to the development of spontaneous squamous cell carcinoma
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554792/
https://www.ncbi.nlm.nih.gov/pubmed/32916850
http://dx.doi.org/10.3390/ijms21186585
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