Characterization of Distinct Populations of Carcinoma-Associated Fibroblasts from Non–Small Cell Lung Carcinoma Reveals a Role for ST8SIA2 in Cancer Cell Invasion

Abstract

Carcinoma-associated fibroblasts (CAFs) are abundant stromal cells in tumor microenvironment that are critically involved in cancer progression. Contrasting reports have shown that CAFs can have either pro- or antitumorigenic roles, indicating that CAFs are functionally heterogeneous. Therefore, to precisely target the cancer-promoting CAF subsets, it is necessary to identify specific markers to define these subpopulations and understand their functions. We characterized two CAFs subsets from 28 non–small cell lung cancer (NSCLC) patient tumors that were scored and classified based on desmoplasia [mainly characterized by proliferating CAFs; high desmoplastic CAFs (HD-CAF; n = 15) and low desmoplastic CAFs (LD-CAF; n = 13)], which is an independent prognostic factor. Here, for the first time, we demonstrate that HD-CAFs and LD-CAFs show different tumor-promoting abilities. HD-CAFs showed higher rate of collagen matrix remodeling, invasion, and tumor growth compared to LD-CAFs. Transcriptomic analysis identified 13 genes that were differentially significant (fold ≥1.5; adjusted P value < .1) between HD-CAFs and LD-CAFs. The top upregulated differentially expressed gene, ST8SIA2 (11.3 fold; adjusted P value = .02), enhanced NSCLC tumor cell invasion in 3D culture compared to control when it was overexpressed in CAFs, suggesting an important role of ST8SIA2 in cancer cell invasion. We confirmed the protumorigenic role of ST8SIA2, showing that ST8SIA2 was significantly associated with the risk of relapse in three independent NSCLC clinical datasets. In summary, our studies show that functional heterogeneity in CAF plays key role in promoting cancer cell invasion in NSCLC.

LOXL1 Is Regulated by Integrin α11 and Promotes Non-Small Cell Lung Cancer Tumorigenicity

“…A list of 30 NSCLC cell lines used in Figure 1b is provided in Supplementary Table S7. Primary human carcinoma-associated fibroblasts were isolated from NSCLC resection specimens, as described in [1,2]. Patient demographics, tumor stage, and pathological diagnosis for 20 tumors from which these CAFs have been isolated [2] are provided in Supplementary Table S8.…”

“…Cancer-associated fibroblast (CAF) is a major TME cellular component, playing key roles in NSCLC tumorigenicity [1]. CAFs contribute to extracellular matrix remodeling and desmoplasia, a prognostic marker for relapse in NSCLC patients [2]. Collagen matrix remodeling and cross-linking are critical factors in tumor progression and metastasis that involve integrins, matrix-metalloproteinases (MMPs), and lysyl oxidases (LOX) [3].…”

Biological Functions and Analytical Strategies of Sialic Acids in Tumor

“…Altered expression of sialylglycans is associated with epithelial-mesenchymal transition (EMT), an essential step for tumor progression and metastasis [53]. Transforming growth factor-β (TGF-β) induced EMT process caused upregulation of various sialyltransferases such as ST3GAL1, ST3GAL2, ST6GAL1, ST6GAL2, ST8SIA1, ST8SIA2, and ST8SIA4 [54][55][56][57][58][59][60][61]. The upregulation of those sialyltransferases resulted in accumulation of sialylglycans on the cell surface, assisting tumor cells in surviving and metastasis.…”

Identification of glycogene-type and validation of ST3GAL6 as a biomarker predicts clinical outcome and cancer cell invasion in urinary bladder cancer

“…For instance, CA19-9 is a sLe A -type glycan epitope, serves as a routine serum biomarker for pancreatic and gastric cancers 21 . Dysregulated glycosyltransferases, such as sialyltransferase 22 , at the level of transcription and/or post-transcription were associated with cancer cell invasion 23 , migration and chemoresistance 24 . It is thus intriguing and important to identify the glycogene-type and/or glycosyltransferases as the biomarkers for molecular stratification in UBCs.…”