RT Journal Article
SR Electronic
T1 Subpopulations of cancer-associated fibroblasts expressing fibroblast activation protein and podoplanin in non-small cell lung cancer are a predictor of poor clinical outcome
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.09.28.509919
DO 10.1101/2022.09.28.509919
A1 Mathieson, Layla
A1 Koppensteiner, Lilian
A1 Pattle, Samuel
A1 Dorward, David A
A1 O’Connor, Richard
A1 Akram, Ahsan
YR 2022
UL http://biorxiv.org/content/early/2022/09/30/2022.09.28.509919.abstract
AB Cancer-associated fibroblasts (CAFs) are the dominant cell type in the stroma of solid organ cancers, including non-small cell lung cancer (NSCLC). Fibroblast heterogeneity is widely recognised in many cancers, with subpopulations of CAFs being identified and potentially being indicative of prognosis and treatment efficacy. Here, the subtypes displayed by CAFs isolated from human NSCLC resections are initially identified by flow cytometry, using the markers FAP, CD29, αSMA, PDPN, CD90, FSP-1 and PDGFRβ, showing five distinct subpopulations, CAF-S1-S5. Our findings show that when comparing fibroblasts from tumour tissue with that from adjacent lung tissue, CAF-S2 and CAF-S3 are found in the normal tissue and marker expression suggests a less activated phenotype whereas CAF-S1, CAF-S4 and CAF-S5 are predominantly found in the tumour tissue and are positive for a combination of markers of fibroblast activation. We focus on these subtypes most associated with fibroblast activation, primarily focussing on a previously unreported CAF-S5 subtype, and comparing to the previously identified CAF-S1. Both these subsets express FAP and PDPN as markers of fibroblast activation, but CAF-S5 lacks expression of the common activation marker αSMA. The spatial relevance of these subtypes in a cohort of 163 NSCLC patients was then investigated by multiplex immunofluorescence on a tumour micro-array of patient samples, revealing CAF-S5 are found further from tumour regions than CAF-S1. To understand the functional role of CAF-S5, scRNA sequencing data was used to compare the subset to the previously identified CAF-S1, finding that CAF-S5 displays an inflammatory phenotype, whereas CAF-S1 displays a contractile phenotype. We demonstrate that presence of either the CAF-S1 or CAF-S5 subtype is correlated to worse survival outcome in NSCLC, highlighting the importance of the identification of CAF subtypes in NSCLC.Competing Interest StatementThe authors have declared no competing interest.