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SOX9 has distinct roles in the formation and progression of different non‐small cell lung cancer histotypes
Author(s) -
Bao Jie,
Närhi Katja,
Teodòsio Ana,
Hemmes Annabrita,
Linnavirta Nora M,
Mäyränpää Mikko I,
Salmenkivi Kaisa,
Le Quesne John,
Verschuren Emmy W
Publication year - 2021
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5733
Subject(s) - adenocarcinoma , biology , cancer research , metastasis , pathology , sox9 , tumor progression , lung cancer , cancer , transcription factor , medicine , gene , genetics
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. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.