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Introduction: High-grade neuroendocrine tumors of the lung such as SCLC are recalcitrant cancers for which more effective systemic therapies are needed. Despite their histopathologic and molecular heterogeneity, they are generally treated as a single disease entity with similar chemotherapy regimens. Whereas marked clinical responses can be observed, they are short-lived. Inter- and intratumoral heterogeneity is considered a confounding factor in these unsatisfactory clinical outcomes, yet the origin of this heterogeneity and its impact on therapeutic responses is not well understood.

Methods: New genetically engineered mouse models are used to test the effects of PTEN loss on the development of lung tumors initiated by Rb1 and Trp53 tumor suppressor gene deletion.

Results: Complete PTEN loss drives more rapid tumor development with a greater diversity of tumor histopathology ranging from adenocarcinoma to SCLC. PTEN loss also drives transcriptional heterogeneity as marked lineage plasticity is observed within histopathologic subtypes. Spatial profiling indicates transcriptional heterogeneity exists both within and among tumor foci with transcriptional patterns correlating with spatial position, implying that the growth environment influences gene expression.

Conclusions: These results identify PTEN loss as a clinically relevant genetic alteration driving the molecular and histopathologic heterogeneity of neuroendocrine lung tumors initiated by Rb1/Trp53 mutations.

Titel:	PTEN Loss Expands the Histopathologic Diversity and Lineage Plasticity of Lung Cancers Initiated by Rb1/Trp53 Deletion.
Autor/in / Beteiligte Person:	Zhang, L ; Liu, C ; Zhang, B ; Zheng, J ; Singh, PK ; Bshara, W ; Wang, J ; Gomez, EC ; Zhang, X ; Wang, Y ; Zhu, X ; Goodrich, DW
Link:	Full Text Finder (Volltext)
Zeitschrift:	Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, Jg. 18 (2023-03-01), Heft 3, S. 324-338
Veröffentlichung:	2016- : New York, NY : Elsevier ; <i>Original Publication</i>: Hagerstown, MD : Lippincott Williams & Wilkins, c2006-, 2023
Medientyp:	academicJournal
ISSN:	1556-1380 (electronic)
DOI:	10.1016/j.jtho.2022.11.019
Schlagwort:	Animals Humans Mice PTEN Phosphohydrolase genetics Retinoblastoma Binding Proteins genetics Tumor Suppressor Protein p53 genetics Ubiquitin-Protein Ligases Adenocarcinoma Lung Neoplasms pathology Small Cell Lung Carcinoma pathology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural Language: English [J Thorac Oncol] 2023 Mar; Vol. 18 (3), pp. 324-338. <i>Date of Electronic Publication: </i>2022 Dec 05. MeSH Terms: Adenocarcinoma* ; Lung Neoplasms* / pathology ; Small Cell Lung Carcinoma* / pathology ; Animals ; Humans ; Mice ; PTEN Phosphohydrolase / genetics ; Retinoblastoma Binding Proteins / genetics ; Tumor Suppressor Protein p53 / genetics ; Ubiquitin-Protein Ligases Comments: Comment in: J Thorac Oncol. 2023 Mar;18(3):260-261. (PMID: 36842808) References: Surg Oncol Clin N Am. 2016 Jul;25(3):447-68. (PMID: 27261908) ; Cancer Discov. 2018 Oct;8(10):1316-1331. (PMID: 30228179) ; Nat Genet. 2012 Oct;44(10):1111-6. (PMID: 22941189) ; Cancers (Basel). 2021 Feb 16;13(4):. (PMID: 33669241) ; Nat Rev Cancer. 2019 May;19(5):289-297. (PMID: 30926931) ; Cancer Cell. 2003 Sep;4(3):181-9. (PMID: 14522252) ; Nat Methods. 2012 Mar 04;9(4):357-9. (PMID: 22388286) ; Cancer Cell. 2017 Feb 13;31(2):286-299. (PMID: 28196596) ; Nature. 2015 Aug 6;524(7563):47-53. (PMID: 26168399) ; Cancer Cell. 2003 Sep;4(3):209-21. (PMID: 14522255) ; Mod Pathol. 2012 Jan;25 Suppl 1:S18-30. (PMID: 22214967) ; Nat Rev Cancer. 2017 Nov 10;17(12):765. (PMID: 29123245) ; Bioinformatics. 2012 Aug 15;28(16):2184-5. (PMID: 22743226) ; Mol Cancer Res. 2014 May;12(5):654-9. (PMID: 24482365) ; Nat Commun. 2021 Dec 6;12(1):7081. (PMID: 34873156) ; Bioinformatics. 2014 Apr 1;30(7):923-30. (PMID: 24227677) ; J Thorac Oncol. 2019 Oct;14(10):1784-1793. (PMID: 31228622) ; Science. 2017 Jan 6;355(6320):78-83. (PMID: 28059767) ; Cell Rep. 2016 Jul 19;16(3):631-43. (PMID: 27373156) ; Am J Surg Pathol. 2002 Sep;26(9):1184-97. (PMID: 12218575) ; Cold Spring Harb Perspect Med. 2021 Apr 1;11(4):. (PMID: 32513672) ; Genome Biol. 2014;15(12):550. (PMID: 25516281) ; Bioinformatics. 2011 Jun 15;27(12):1739-40. (PMID: 21546393) ; Cancer Cell. 2011 Jun 14;19(6):754-64. (PMID: 21665149) ; Proc Natl Acad Sci U S A. 2011 Jan 11;108(2):704-9. (PMID: 21187395) ; Cancer Res. 2008 Feb 15;68(4):1119-27. (PMID: 18281487) ; Oncologist. 2007 Sep;12(9):1096-104. (PMID: 17914079) ; Cell Rep. 2019 Jun 11;27(11):3345-3358.e4. (PMID: 31189116) ; Lancet. 2011 Nov 12;378(9804):1741-55. (PMID: 21565397) ; Mol Ther Oncolytics. 2021 Feb 06;20:470-483. (PMID: 33718595) ; Nat Protoc. 2009;4(7):1064-72. (PMID: 19561589) ; Genes Dev. 2020 Aug 1;34(15-16):1017-1032. (PMID: 32747478) ; Nat Rev Dis Primers. 2021 Jan 14;7(1):3. (PMID: 33446664) ; Cell Cycle. 2011 Aug 15;10(16):2806-15. (PMID: 21822053) ; Nat Genet. 2012 Oct;44(10):1104-10. (PMID: 22941188) ; Science. 2017 Jan 6;355(6320):84-88. (PMID: 28059768) ; J Thorac Oncol. 2015 Apr;10(4):553-64. (PMID: 25675280) ; J Thorac Oncol. 2019 Feb;14(2):245-254. (PMID: 30336325) ; Genome Res. 2002 Jun;12(6):996-1006. (PMID: 12045153) ; Mod Pathol. 2007 Jun;20(6):638-47. (PMID: 17431413) ; Cell. 2019 Oct 3;179(2):403-416.e23. (PMID: 31585080) ; Sci Transl Med. 2011 Mar 23;3(75):75ra26. (PMID: 21430269) ; Genome Biol. 2013 Apr 25;14(4):R36. (PMID: 23618408) ; Am J Respir Crit Care Med. 2018 Dec 1;198(11):1355-1356. (PMID: 29877729) ; Nat Commun. 2015 Mar 11;6:6377. (PMID: 25758528) ; Transl Lung Cancer Res. 2018 Feb;7(1):21-31. (PMID: 29535910) ; Proc Natl Acad Sci U S A. 2014 Apr 1;111(13):4745-6. (PMID: 24707043) ; Lancet Oncol. 2015 Apr;16(4):e165-72. (PMID: 25846096) ; J Thorac Oncol. 2020 Apr;15(4):520-540. (PMID: 32018053) ; J Thorac Oncol. 2015 Sep;10(9):1243-1260. (PMID: 26291008) ; Cell. 2014 Mar 13;156(6):1298-1311. (PMID: 24630729) Grant Information: P30 CA016056 United States CA NCI NIH HHS; R01 CA207757 United States CA NCI NIH HHS; R01 CA234162 United States CA NCI NIH HHS Contributed Indexing: Keywords: Genetically engineered mouse models; Small cell lung cancer; Tumor heterogeneity; Tumor suppressor genes Substance Nomenclature: EC 3.1.3.67 (PTEN Phosphohydrolase) ; EC 3.1.3.67 (PTEN protein, human) ; 0 (RB1 protein, human) ; 0 (Retinoblastoma Binding Proteins) ; 0 (Tumor Suppressor Protein p53) ; EC 2.3.2.27 (Ubiquitin-Protein Ligases) Entry Date(s): Date Created: 20221206 Date Completed: 20230303 Latest Revision: 20240302 Update Code: 20240302 PubMed Central ID: PMC9974779

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PTEN Loss Expands the Histopathologic Diversity and Lineage Plasticity of Lung Cancers Initiated by Rb1/Trp53 Deletion.