Single-cell transcriptomic analysis in a mouse model deciphers cell transition states in the multistep development of esophageal cancer

Abstract

Esophageal squamous cell carcinoma (ESCC) is prevalent in some geographical regions of the world. ESCC development presents a multistep pathogenic process from inflammation to invasive cancer; however, what is critical in these processes and how they evolve is largely unknown, obstructing early diagnosis and effective treatment. Here, we create a mouse model mimicking human ESCC development and construct a single-cell ESCC developmental atlas. We identify a set of key transitional signatures associated with oncogenic evolution of epithelial cells and depict the landmark dynamic tumorigenic trajectories. An early downregulation of CD8 + response against the initial tissue damage accompanied by the transition of immune response from type 1 to type 3 results in accumulation and activation of macrophages and neutrophils, which may create a chronic inflammatory environment that promotes carcinogen-transformed epithelial cell survival and proliferation. These findings shed light on how ESCC is initiated and developed.

Arachidonic Acid Metabolism Controls Macrophage Alternative Activation Through Regulating Oxidative Phosphorylation in PPARγ Dependent Manner

“…Previous studies have demonstrated that PGE2 promotes TAMs formation in glioblastoma ( 33 ), colorectal cancer ( 35 ), ovarian cancer ( 37 ), neuroblastoma ( 38 ) and prostate cancer ( 39 ). Based on the accumulation of macrophages ( 40 ) and differential expression of COX-2 in ESCC ( 41 ), it could be inferred that above correlation may also exist in the TME of ESCC. Our data supported this opinion and also suggested that besides tumor cell-derived PGE2, macrophage-derived PGE2 may also make contribution to M2-TAMs polarization through PPARγ-OXPHOS pathway.…”

Hypothalamic Rax+ tanycytes contribute to tissue repair and tumorigenesis upon oncogene activation in mice

“…The cDNA libraries were then prepared using TruePrep DNA Library Prep Kit V2 (Vazyme, TD503-02) and sequenced on an Illumina NovaSeq6000 platform. To compare the transcriptomic profiles of tanycyte-and esophageal squamous cell-derived tumors, we used the recently published bulk RNAseq data collected from normal esophageal epithelial cells and esophageal epithelial cell carcinoma 56 , and performed principal component analysis (PCA) and Spearman's correlation analysis.…”

Fibrotic enzymes modulate wound‐induced skin tumorigenesis

“…In their study, the authors stated that they profiled fibroblasts from dysplastic skin regions that are early neoplastic lesions, which could represent a more "inflammatory" and earlier stage in the process of carcinogenesis progression than the CAFs in our InvEE model. Indeed, single-cell sequencing data of oesophageal cancer at different stages of tumour development showed that distinct fibroblast clusters are dominating different stages of cancer development, with a surge of fibroblasts expressing a strong inflammatory gene signature at the early inflammatory stage, which is then replaced by a fibroblast cluster with a predominant TGF-b signalling signature during dysplasia and carcinoma in situ stages (Yao et al, 2020). Another possible explanation is the fact that a different subpopulation of activated fibroblasts could be involved in the two different animal models.…”