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

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. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

A transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma

“…Interestingly, in PT2 the transcriptional signature was one of inflammation and regeneration gene expression ( SOX9, IL32, and VCAM1 ) (Supplementary Fig. 4b ), which has been related to carcinogenesis and cancer progression 33 , 34 . Neighboring the proximal tubule cells was a small subpopulation of glomerular podocytes ( SEMA3G, CLDN5, and CR1 ) 35 found in the Bowman’s capsule, where they wrap around capillaries of the glomerulus (Supplementary Fig.…”

A new transcriptional metastatic signature predicts survival in clear cell renal cell carcinoma

“…Interestingly, in PT2 the transcriptional signature was one of inflammation and regeneration gene expression ( SOX9, IL32, VCAM1 ) (Extended data Fig. 4b), which has been related to carcinogenesis and cancer progression 48,49 . Neighboring the proximal tubule cells was a small subpopulation of glomerular podocytes ( SEMA3G, CLDN5, CR1 ) 50 found in the Bowman’s capsule where they wrap around capillaries of the glomerulus (Extended data Fig.…”

“…Interestingly, in PT2 the transcriptional signature was one of inflammation and regeneration gene expression (SOX9, IL32, VCAM1) (Extended data Fig. 4b), which has been related to carcinogenesis and cancer progression 48,49 .…”

SOX9 Promotes Collagen VI Secretion by Upregulating PCOLCE in Neurofibroma

“…COL2A1 expression is regulated by the strong SOX9-binding site in its intron 6 (30). The loss of SOX9 can alter the collagen IV depositions in the basement membrane, leading to enhanced squamous tumor metastasis (31).…”