Abstract
Esophageal cancer (EC) is a type of aggressive cancer without clinically relevant molecular subtypes, hindering the development of effective strategies for treatment. To define molecular subtypes of EC, we perform mass spectrometry-based proteomic and phosphoproteomics profiling of EC tumors and adjacent non-tumor tissues, revealing a catalog of proteins and phosphosites that are dysregulated in ECs. The EC cohort is stratified into two molecular subtypes—S1 and S2—based on proteomic analysis, with the S2 subtype characterized by the upregulation of spliceosomal and ribosomal proteins, and being more aggressive. Moreover, we identify a subtype signature composed of ELOA and SCAF4, and construct a subtype diagnostic and prognostic model. Potential drugs are predicted for treating patients of S2 subtype, and three candidate drugs are validated to inhibit EC. Taken together, our proteomic analysis define molecular subtypes of EC, thus providing a potential therapeutic outlook for improving disease outcomes in patients with EC.
Highlights
Esophageal cancer (EC) is a type of aggressive cancer without clinically relevant molecular subtypes, hindering the development of effective strategies for treatment
A case-by-case inspection revealed that the number of phosphosites identified in each patient did not differ much, like the phosphoproteins, tumor samples in general had a higher number of phosphosites than non-tumor samples (Supplementary Fig. 2j, k)
We analyzed the subcellular distribution of the quantified proteins and phosphoproteins, revealing that most of them were mainly distributed in the nucleus, plasma membrane, cytosol, mitochondria, and extracellular space, which was consistent with previous reports (Fig. 1g and Supplementary Data 1d)[15]
Summary
Esophageal cancer (EC) is a type of aggressive cancer without clinically relevant molecular subtypes, hindering the development of effective strategies for treatment. To define molecular subtypes of EC, we perform mass spectrometry-based proteomic and phosphoproteomics profiling of EC tumors and adjacent non-tumor tissues, revealing a catalog of proteins and phosphosites that are dysregulated in ECs. The EC cohort is stratified into two molecular subtypes—S1 and S2—based on proteomic analysis, with the S2 subtype characterized by the upregulation of spliceosomal and ribosomal proteins, and being more aggressive. Our proteomic analysis define molecular subtypes of EC, providing a potential therapeutic outlook for improving disease outcomes in patients with EC. Large-scale, mass spectrometry (MS)-based proteomics have identified novel cancer subtypes and therapeutic targets for patients with colon, ovarian, breast, gastric, and liver cancers[9,10,11,12,13,14,15,16,17,18,19,20], and provided valuable resources that have expanded our understanding of these cancers. Several potential drugs that specific for malignant subtype S2 are predicted and verified by functional experiments, which might provide new therapeutic opportunities to improve treatment outcome of EC
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