RT Journal Article
SR Electronic
T1 The role of SOX9 in non-small cell lung cancer progression is histopathology-selective
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.11.23.393926
DO 10.1101/2020.11.23.393926
A1 Jie Bao
A1 Katja Närhi
A1 Ana Teodòsio
A1 Annabrita Hemmes
A1 Nora M Linnavirta
A1 Mikko I Mäyränpää
A1 Kaisa Salmenkivi
A1 John Le Quesne
A1 Emmy W Verschuren
YR 2020
UL http://biorxiv.org/content/early/2020/11/24/2020.11.23.393926.abstract
AB 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 histopathologies has however remained elusive. We show that SOX9 expression relates to poor outcome and invasive histopathology in human adenocarcinomas, and is absent in murine early minimally invasive and human in situ adenocarcinoma. Interestingly, despite wide SOX9 expression across advanced NSCLC histotypes, its genetic deletion in the murine KrasG12D;Lkb1-/- 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 a requirement for papillary adenocarcinoma progression, but opposing metastasis-suppressing function in squamous histotype tissue. This attests to a pleiotropic SOX9 function, linked to the cell of origin and microenvironmental tissue contexts.Competing Interest StatementThe authors have declared no competing interest.