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

Bao, J., Närhi, K., Teodòsio, A., Hemmes, A., Linnavirta, N. M., Mäyränpää, M. I., Salmenkivi, K., Le Quesne, J. and Verschuren, E. W. (2021) SOX9 has distinct roles in the formation and progression of different non‐small cell lung cancer histotypes. Journal of Pathology, 255(1), pp. 16-29. (doi: 10.1002/path.5733) (PMID:34021911)

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 KrasG12D;Lkb1fl/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.

• Item Type: Articles
• Additional Information: This research was supported by the University of Helsinki Doctoral Programme in Biomedicine (JB); The Finnish Medical Foundation (MIM); MRC Toxicology Unit core funding (JLQ); Innovative Medicines Initiative Joint Undertaking grant agreement No 115188, the resources of which are composed of a financial contribution from the European Union's Seventh Framework Programme (FP7/2007-2013) and EFPIA companies' in-kind contribution (EWV); and the Academy of Finland grant 307111 (EWV).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Le Quesne, Professor John
• Authors: Bao, J., Närhi, K., Teodòsio, A., Hemmes, A., Linnavirta, N. M., Mäyränpää, M. I., Salmenkivi, K., Le Quesne, J., and Verschuren, E. W.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Journal of Pathology
• Publisher: John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland
• ISSN: 0022-3417
• ISSN (Online): 1096-9896
• Published Online: 22 May 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Journal of Pathology 255(1):16-29
• Publisher Policy: Reproduced under a Creative Commons licence