Downregulation of PTPRT elevates the expression of survivin and promotes the proliferation, migration, and invasion of lung adenocarcinoma.

BACKGROUND: Receptor-type tyrosine-protein phosphatase T (PTPRT) is a transmembrane protein that is involved in cell adhesion. We previously found that PTPRT was downregulated in multiple cancer types and the mutation of PTPRT was associated with cancer early metastasis. However, the impacts of PTPRT downregulation on tumour proliferation, invasion, and clinical interventions such as immune checkpoint inhibitor (ICI) therapies remained largely unknown. METHODS: Gene expression data of non-small cell lung cancer (NSCLC) samples from The Cancer Genome Atlas database were downloaded and used to detect the differential expressed genes between PTPRT-high and PTPRT-low subgroups. Knockdown and overexpress of PTPRT in lung cancer cell lines were performed to explore the function of PTPRT in vitro. Western blot and qRT-PCR were used to evaluate the expression of cell cycle-related genes. CCK-8 assays, wound-healing migration assay, transwell assay, and colony formation assay were performed to determine the functional impacts of PTPRT on cell proliferation, migration, and invasion. KM-plotter was used to explore the significance of selected genes on patient prognosis. RESULTS: PTPRT was found to be downregulated in tumours and lung cancer cell lines compared to normal samples. Cell cycle-related genes (BIRC5, OIP5, and CDCA3, etc.) were specifically upregulated in PTPRT-low lung adenocarcinoma (LUAD). Modulation of PTPRT expression in LUAD cell lines affected the expression of BIRC5 (survivin) significantly, as well as the proliferation, migration, and invasion of tumour cells. In addition, low PTPRT expression level was correlated with worse prognosis of lung cancer and several other cancer types. Furthermore, PTPRT downregulation was associated with elevated tumour mutation burden and tumour neoantigen burden in lung cancer, indicating the potential influence on tumour immunogenicity. CONCLUSION: Our findings uncovered the essential roles of PTPRT in the regulation of proliferation, migration, and invasion of LUAD, and highlighted the clinical significance of PTPRT downregulation in lung cancer.

Single-cell and spatial transcriptomics reveal POSTN+ cancer-associated fibroblasts correlated with immune suppression and tumour progression in non-small cell lung cancer.

BACKGROUND: Cancer-associated fibroblasts (CAFs) are potential targets for cancer therapy. Due to the heterogeneity of CAFs, the influence of CAF subpopulations on the progression of lung cancer is still unclear, which impedes the translational advances in targeting CAFs. METHODS: We performed single-cell RNA sequencing (scRNA-seq) on tumour, paired tumour-adjacent, and normal samples from 16 non-small cell lung cancer (NSCLC) patients. CAF subpopulations were analyzed after integration with published NSCLC scRNA-seq data. SpaTial enhanced resolution omics-sequencing (Stereo-seq) was applied in tumour and tumour-adjacent samples from seven NSCLC patients to map the architecture of major cell populations in tumour microenvironment (TME). Immunohistochemistry (IHC) and multiplexed IHC (mIHC) were used to validate marker gene expression and the association of CAFs with immune infiltration in TME. RESULTS: A subcluster of myofibroblastic CAFs, POSTN+ CAFs, were significantly enriched in advanced tumours and presented gene expression signatures related to extracellular matrix remodeling, tumour invasion pathways and immune suppression. Stereo-seq and mIHC demonstrated that POSTN+ CAFs were in close localization with SPP1+ macrophages and were associated with the exhausted phenotype and lower infiltration of T cells. POSTN expression or the abundance of POSTN+ CAFs were associated with poor prognosis of NSCLC. CONCLUSIONS: Our study identified a myofibroblastic CAF subpopulation, POSTN+ CAFs, which might associate with SPP1+ macrophages to promote the formation of desmoplastic architecture and participate in immune suppression. Furthermore, we showed that POSTN+ CAFs associated with cancer progression and poor clinical outcomes and may provide new insights on the treatment of NSCLC.

Spatial transcriptome unveils a discontinuous inflammatory pattern in proficient mismatch repair colorectal adenocarcinoma.

The preexistence of immune cells in the tumor microenvironment substantiates the efficacy of immunotherapy in cancer patients. Although the complex intratumoral immune heterogeneity has been extensively studied in single cell resolution, hi-res spatial investigations are limited. In this study, we performed a spatial transcriptome analysis of 4 colorectal adenocarcinoma specimens and 2 paired distant normal specimens to identify the molecular pattern involved in a discontinuous inflammatory response in pathologically annotated cancer regions. Based on the location of spatially varied gene expression, we unmasked the spatially-varied immune ecosystem and identified the locoregional "warmed-up" immune response in predefined "cold" tumor with substantial infiltration of immune components. This "warmed-up" immune profile was found to be associated with the in-situ copy number variance and the tissue remodeling process. Further, "warmed-up" signature genes indicated improved overall survival in CRC patients obtained from TCGA database.