A senescence-based prognostic gene signature for colorectal cancer and identification of the role of SPP1-positive macrophages in tumor senescence

Abstract

BackgroundSenescence is significantly associated with cancer prognosis. This study aimed to construct a senescence-related prognostic model for colorectal cancer (CRC) and to investigate the influence of senescence on the tumor microenvironment.MethodsTranscriptome and clinical data of CRC cases were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Senescence-related prognostic genes detected by univariate Cox regression were included in Least Absolute Shrinkage and Selection Operator (LASSO) analysis to construct a model. The efficacy of the model was validated using the receiver operating characteristic (ROC) curve and survival analysis. Differentially expressed genes (DEGs) were identified and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed. CIBERSORT and Immuno-Oncology Biological Research (IOBR) were used to investigate the features of the tumor microenvironment. Single-cell RNA-seq data were used to investigate the expression levels of model genes in various cell types. Immunofluorescence staining for p21, SPP1, and CD68 was performed with human colon tissues.ResultsA seven-gene (PTGER2, FGF2, IGFBP3, ANGPTL4, DKK1, WNT16 and SPP1) model was finally constructed. Patients were classified as high- or low-risk using the median score as the threshold. The area under the ROC curve (AUC) for the 1-, 2-, and 3-year disease-specific survival (DSS) were 0.731, 0.651, and 0.643, respectively. Survival analysis showed a better 5-year DSS in low-risk patients in the construction and validation cohorts. GO and KEGG analyses revealed that DEGs were enriched in extracellular matrix (ECM)-receptor interactions, focal adhesion, and protein digestion and absorption. CIBERSORT and IOBR analyses revealed an abundance of macrophages and an immunosuppressive environment in the high-risk subgroup. Low-risk patients had higher response rates to immunotherapy than high-risk patients. ScRNA-seq data revealed high expression of SPP1 in a subset of macrophages with strong senescence-associated secretory phenotype (SASP) features. Using CRC tumor tissues, we discovered that SPP1+ macrophages were surrounded by a large number of senescent tumor cells in high-grade tumors.ConclusionOur study presents a novel model based on senescence-related genes that can identify CRC patients with a poor prognosis and an immunosuppressive tumor microenvironment. SPP1+ macrophages may correlate with cell senescence leading to poor prognosis.

The rational modulation of autophagy sensitizes colorectal cancer cells to 5‐fluouracil and oxaliplatin

“…Furthermore, senescent cells may also favor cancer stemness, 86 as observed here and by others in response to 5FU 87 and, to a greater extent, to OXA 51,88–90 . As a final consequence of the enrichment of senescent cells in the tumor microenvironment, the protumor effects exerted by senescence have a dominant effect on the nonproliferative phenotype of these cells since high levels of senescence are associated with a worse prognosis in CRC 91–93 . Thus, CRC patients with a molecular background susceptible to senescence, such as the HCT116 lineage, could benefit from the use of senolytic therapies after chemotherapy, a strategy that has already been tested in other tumor types 94…”

Identification and Verification of KEAP1-related genes and targets regulated by potential ingredients in KRAS mutant colorectal cancer

“…This interaction might be regulated by chemerin, TGF-β, and interleukin-1, which would stimulate the formation of immune-excluded desmoplasic structure and limit the T cell in ltration. Furthermore, we nd patients with high FAP or SPP1 expression achieved less therapeutic bene t from an anti-PD-L1 therapy cohortv [15]. These results provide a potential therapeutic strategy by disrupting FAP + broblasts and SPP1 + macrophages interaction to improve immunotherapy.…”

Fibroblasts from HPV-negative oropharynx squamous cell carcinomas stimulate the release of osteopontin from cancer cells via the release of IL-6

“…CAFs may interact with SPP1-expressing macrophages in the TME, and this feature has been associated with the EMT-like CAF phenotype ( 41 ). In colorectal carcinoma, a combination of FAP-expressing fibroblasts and OPN-expressing TAMs corelate with poor responses to immune checkpoint ( 42 ), and indeed, in poorly differentiated tumours, OPN in TAMs has been shown to induce senescence in tumour cells in high grade tumours, with the development of a profound SASP which may drive tumour progression ( 43 ).…”