Small Leucine-Rich Proteoglycan PODNL1 Identified as a Potential Tumor Matrix-Mediated Biomarker for Prognosis and Immunotherapy in a Pan-Cancer Setting

Abstract

The podocan-like protein 1 (PODNL1), an important member of the small leucine-rich proteoglycans (SLRP) family, is a crucial component of the tumor microenvironment (TME). But its prognostic values and the role in the TME have not been systematically estimated in a pan-cancer setting. Targeting PODNL1, a systematic exploration into the TCGA datasets, reconciling with the analyses of single-cell transcriptomes and immunotherapeutic cohorts in cancers, and validation by tissue microarray-based multiplex immunofluorescence staining was performed. PODNL1 was significantly correlated with the poor prognosis and immunotherapeutic responses in various cancers. In-depth demonstration of molecular mechanisms indicated that PODNL1 expressions were notably positively correlated with cancer-associated fibroblast (CAF) infiltration levels in 33 types of cancers. It also positively correlated with the pan-fibroblast TGF-β response signature score, and the hallmarks including TGF-β, TNF-α, inflammatory response, apical junction, epithelial–mesenchymal transition and hedgehog in pan-cancer. Furthermore, high PODNL1 expressions were positively related with the regulation of tumor-promoting TGF-β signaling through downregulating SMAD2/3:4 heterotrimer regulations transcription and up-regulating the pathway restricted SMAD protein phosphorylation. Single-cell transcriptome analyses and immunofluorescence validations indicated that PODNL1 was predominantly expressed in the cancer cells and CAFs in various cancers. Additionally, the heterogeneity of cancer genotype–phenotype cross-talking was also observed associated with PODNL1. Our systematic study indicates that PODNL1 plays an important role in the complex regulation network of tumor progression, and lays a foundation for further exploration to develop PODNL1 as a valuable matrix-mediated biomarker for cancer immunotherapy and prognosis in a pan-cancer setting.

A Membrane Lipid Signature Unravels the Dynamic Landscape of Group 1 ILCs

“…Within the intersecting ILC1 core, Il7r 57 and Ckb 60 , known to be expressed in ILC progenitors (ILCPs) 58 , supports the unique origin of ILC1s from ILCPs, diverging from the NK cell lineage. Podnl1 59,60 , integral to the ILC1 core for cell adhesion and cellular matrix interactions 61 , aligns with the predominant localization of ILC1s as tissue-residents—as opposed to the circulatory nature of NK cells. St6galnac3 , a gene that encodes a sialyltransferase responsible for attaching sialic acid to glycoproteins and glycolipids 62 , contrasts sharply with the sialic acid-deficient AsGM1 glycoprotein 63 .…”

“…Within the intersecting ILC1 core, Il7r 57 and Ckb 60 , known to be expressed in ILC progenitors (ILCPs) 58 , supports the unique origin of ILC1s from ILCPs, diverging from the NK cell lineage. Podnl1 59,60 , integral to the ILC1 core for cell adhesion and cellular matrix interactions 61 , aligns with the predominant localization of ILC1s as tissue-residents-as opposed to the circulatory nature of NK cells.…”

Pan-cancer analysis reveals correlation between RAB3B expression and tumor heterogeneity, immune microenvironment, and prognosis in multiple cancers

“…Human pan-cancer TMAs (ZL-MTU122) were purchased from Shanghai Zhuoli Biotechnology Co., Ltd (Zhuoli Biotechnology Co., Shanghai, China). The TMA chip contained tumors from 20 cancers and matched adjacent normal/normal tissues 41 . Immunohistochemical (IHC) staining was performed according to the previously described method 42 .…”