Autocrine signaling by receptor tyrosine kinases in urothelial carcinoma of the bladder.

Comprehensive characterizations of bladder cancer (BCa) have established molecular phenotype classes with distinct alterations and survival trends. Extending these studies within the tyrosine kinase (TK) family to identify disease drivers could improve our use of TK inhibitors to treat specific pati...

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Autores principales:	Young H Lee, Molly M Lee, Dinuka M De Silva, Arpita Roy, Cara E Wright, Tiffany K Wong, Rene Costello, Oluwole Olaku, Robert L Grubb, Piyush K Agarwal, Andrea B Apolo, Donald P Bottaro
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/5394fb87b5264fd6b4b74d104edefe1c
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spelling	oai:doaj.org-article:5394fb87b5264fd6b4b74d104edefe1c2021-12-02T20:04:58ZAutocrine signaling by receptor tyrosine kinases in urothelial carcinoma of the bladder.1932-620310.1371/journal.pone.0241766https://doaj.org/article/5394fb87b5264fd6b4b74d104edefe1c2021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0241766https://doaj.org/toc/1932-6203Comprehensive characterizations of bladder cancer (BCa) have established molecular phenotype classes with distinct alterations and survival trends. Extending these studies within the tyrosine kinase (TK) family to identify disease drivers could improve our use of TK inhibitors to treat specific patient groups or individuals. We examined the expression distribution of TKs as a class (n = 89) in The Cancer Genome Atlas (TCGA) muscle invasive BCa data set (n >400). Patient profiles of potentially oncogenic alterations (overexpression and/or amplification) clustered TKs into 3 groups; alterations of group 1 and 3 TKs were associated with significantly worse patient survival relative to those without alterations. Many TK pathways induce epithelial-to-mesenchymal transition (EMT), which promotes tumor invasiveness and metastasis. Overexpression and/or amplification among 9 EMT transcriptional activators occurred in 43% of TCGA cases. Co-occurring alterations of TKs and EMT transcriptional activators involved most group 1 TKs; 24% of these events were associated with significantly worse patient survival. Co-occurring alterations of receptor TKs and their cognate ligands occurred in 16% of TCGA cases and several BCa-derived cell lines. Suppression of GAS6, MST1 or CSF1, or their respective receptors (AXL, MST1R and CSF1R), in BCa cell lines was associated with decreased receptor activation, cell migration, cell proliferation and anchorage independent cell growth. These studies reveal the patterns and prevalence of potentially oncogenic TK pathway-related alterations in BCa and identify specific alterations associated with reduced BCa patient survival. Detection of these features in BCa patients could better inform TK inhibitor use and improve clinical outcomes.Young H LeeMolly M LeeDinuka M De SilvaArpita RoyCara E WrightTiffany K WongRene CostelloOluwole OlakuRobert L GrubbPiyush K AgarwalAndrea B ApoloDonald P BottaroPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 7, p e0241766 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Young H Lee Molly M Lee Dinuka M De Silva Arpita Roy Cara E Wright Tiffany K Wong Rene Costello Oluwole Olaku Robert L Grubb Piyush K Agarwal Andrea B Apolo Donald P Bottaro Autocrine signaling by receptor tyrosine kinases in urothelial carcinoma of the bladder.
description	Comprehensive characterizations of bladder cancer (BCa) have established molecular phenotype classes with distinct alterations and survival trends. Extending these studies within the tyrosine kinase (TK) family to identify disease drivers could improve our use of TK inhibitors to treat specific patient groups or individuals. We examined the expression distribution of TKs as a class (n = 89) in The Cancer Genome Atlas (TCGA) muscle invasive BCa data set (n >400). Patient profiles of potentially oncogenic alterations (overexpression and/or amplification) clustered TKs into 3 groups; alterations of group 1 and 3 TKs were associated with significantly worse patient survival relative to those without alterations. Many TK pathways induce epithelial-to-mesenchymal transition (EMT), which promotes tumor invasiveness and metastasis. Overexpression and/or amplification among 9 EMT transcriptional activators occurred in 43% of TCGA cases. Co-occurring alterations of TKs and EMT transcriptional activators involved most group 1 TKs; 24% of these events were associated with significantly worse patient survival. Co-occurring alterations of receptor TKs and their cognate ligands occurred in 16% of TCGA cases and several BCa-derived cell lines. Suppression of GAS6, MST1 or CSF1, or their respective receptors (AXL, MST1R and CSF1R), in BCa cell lines was associated with decreased receptor activation, cell migration, cell proliferation and anchorage independent cell growth. These studies reveal the patterns and prevalence of potentially oncogenic TK pathway-related alterations in BCa and identify specific alterations associated with reduced BCa patient survival. Detection of these features in BCa patients could better inform TK inhibitor use and improve clinical outcomes.
format	article
author	Young H Lee Molly M Lee Dinuka M De Silva Arpita Roy Cara E Wright Tiffany K Wong Rene Costello Oluwole Olaku Robert L Grubb Piyush K Agarwal Andrea B Apolo Donald P Bottaro
author_facet	Young H Lee Molly M Lee Dinuka M De Silva Arpita Roy Cara E Wright Tiffany K Wong Rene Costello Oluwole Olaku Robert L Grubb Piyush K Agarwal Andrea B Apolo Donald P Bottaro
author_sort	Young H Lee
title	Autocrine signaling by receptor tyrosine kinases in urothelial carcinoma of the bladder.
title_short	Autocrine signaling by receptor tyrosine kinases in urothelial carcinoma of the bladder.
title_full	Autocrine signaling by receptor tyrosine kinases in urothelial carcinoma of the bladder.
title_fullStr	Autocrine signaling by receptor tyrosine kinases in urothelial carcinoma of the bladder.
title_full_unstemmed	Autocrine signaling by receptor tyrosine kinases in urothelial carcinoma of the bladder.
title_sort	autocrine signaling by receptor tyrosine kinases in urothelial carcinoma of the bladder.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/5394fb87b5264fd6b4b74d104edefe1c
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Autocrine signaling by receptor tyrosine kinases in urothelial carcinoma of the bladder.

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