SOX9 has distinct roles in the formation and progression of different non-small cell lung cancer histotypes

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Bao , J , Närhi , K , Teodosio , A , Hemmes , A , Linnavirta , N M , Mäyränpää , M , Salmenkivi , K , Le Quesne , J & Verschuren , E W 2021 , ' SOX9 has distinct roles in the formation and progression of different non-small cell lung cancer histotypes ' , Journal of Pathology , vol. 255 , no. 1 , 105276 , pp. 16-29 . https://doi.org/10.1002/path.5733

Title: SOX9 has distinct roles in the formation and progression of different non-small cell lung cancer histotypes
Author: Bao, Jie; Närhi, Katja; Teodosio, Ana; Hemmes, Annabrita; Linnavirta, Nora M.; Mäyränpää, Mikko; Salmenkivi, Kaisa; Le Quesne, John; Verschuren, Emmy W.
Contributor organization: Research Program in Systems Oncology
Lung Cancer Model Systems
Institute for Molecular Medicine Finland
Helsinki Institute of Life Science HiLIFE
University of Helsinki
Research Group Verschuren Emmy
HUSLAB
Department of Pathology
Helsinki University Hospital Area
Date: 2021-09
Language: eng
Number of pages: 14
Belongs to series: Journal of Pathology
ISSN: 0022-3417
DOI: https://doi.org/10.1002/path.5733
URI: http://hdl.handle.net/10138/340480
Abstract: The transcription factor SOX9 is a key regulator of multiple developmental processes and is frequently re-expressed in non-small cell lung cancer (NSCLC). Its precise role in the progression of NSCLC histotypes has, however, remained elusive. We show that SOX9 expression relates to poor overall survival and invasive histopathology in human non-mucinous adenocarcinoma and is absent in murine early minimally invasive and low in human in situ adenocarcinoma. Interestingly, despite wide SOX9 expression across advanced NSCLC histotypes, its genetic deletion in the murine Kras(G12D);Lkb1(fl/fl) model selectively disrupted only the growth of papillary NSCLC, without affecting the initiation of precursor lesions or growth of mucinous or squamous tissue. Spatial tissue phenotyping indicated a requirement of SOX9 expression for the progression of surfactant protein C-expressing progenitor cells, which gave rise to papillary tumours. Intriguingly, while SOX9 expression was dispensable for squamous tissue formation, its loss in fact led to enhanced squamous tumour metastasis, which was associated with altered collagen IV deposition in the basement membrane. Our work therefore demonstrates histopathology-selective roles for SOX9 in NSCLC progression, namely as a promoter for papillary adenocarcinoma progression, but an opposing metastasis-suppressing role in squamous histotype tissue. This attests to a pleiotropic SOX9 function, linked to the cell of origin and microenvironmental tissue contexts. (c) 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
Subject: SOX9
non-small cell lung cancer
histopathology
cell of origin
metastasis
extracellular matrix
collagen IV
in vivo models
UP-REGULATION
KRAS
ADENOCARCINOMA
EXPRESSION
CLASSIFICATION
MUTATIONS
PATTERNS
ACTIVATION
RESISTANCE
CARCINOMA
3122 Cancers
Peer reviewed: Yes
Rights: cc_by_nc
Usage restriction: openAccess
Self-archived version: publishedVersion


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