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Large-scale and high-resolutionmass spectrometry-based proteomics profiling defines molecular subtypes of esophageal cancer for therapeutic targeting

ABSTRACT: Esophageal cancer (EC) is anaggressive cancer type without clinically relevant molecular subtypes defined, which hinders the development of effective strategies forEC treatment. Here, we reporteda large-scale, high-resolution massspectrometry-based proteomicand phosphoproteomics profiling of EC tumor and the corresponding adjacent non-tumor tissues, revealing a catalog of proteins, phosphositesas well as pathways that are dysregulated in ECs. The EC cohort was stratified into two molecular subtypes, S1 and S2, based on proteomic analysis, withthe S2 subtype characterized by the up-regulation of spliceosome and ribosomal proteins, and being more aggressive.Moreover, we identified a subtype signature composed of ELOA and SCAF4 and constructed a subtype diagnostic model, the accuracy of which was independently validated in a large cohort of EC patients (n=295). Potential drugs were predicted for treating patients in S2 subtype, and threecandidate drugs, GW8510, Menadione and Sulconazole,were validated to significantly inhibit the proliferation and migration of EC cell lines . On the basis of nude mice with xenograft tumors, we found that treatment with the three drugs markedly reduced the size of tumors. Finally, the three drugs were shown to reverse the expression patterns of most proteins that are dysregulated in S2 subtype in KYSE150 cells.Taken together, our proteomic analysis defined subtypesand subtype signature of EC, and providedmolecular basis for finding potential treatmentsfor EC.

ORGANISM(S): Trichuris Sp. Ex Homo Sapiens Jp-2011

SUBMITTER: Liyan Xu

PROVIDER: PXD021701 | iProX | Mon Jul 05 00:00:00 BST 2021

REPOSITORIES: iProX

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Large-scale and high-resolution mass spectrometry-based proteomics profiling defines molecular subtypes of esophageal cancer for therapeutic targeting.

Liu Wei W Xie Lei L He Yao-Hui YH Wu Zhi-Yong ZY Liu Lu-Xin LX Bai Xue-Feng XF Deng Dan-Xia DX Xu Xiu-E XE Liao Lian-Di LD Lin Wan W Heng Jing-Hua JH Xu Xin X Peng Liu L Huang Qing-Feng QF Li Cheng-Yu CY Zhang Zhi-Da ZD Wang Wei W Zhang Guo-Rui GR Gao Xiang X Wang Shao-Hong SH Li Chun-Quan CQ Xu Li-Yan LY Liu Wen W Li En-Min EM

Nature communications 20210816 1

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, w ...[more]

PMID: 34400640

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Project description:Background: Endothelial cells (EC) sit at the forefront of dramatic physiologic changes occurring in the pulmonary circulation during late embryonic and early postnatal life. First, as the lung moves from the hypoxic fetal environment to oxygen-rich postnatal environment, marked changes in pulmonary EC structure and function facilitate a marked increase in blood flow from the placenta to the lungs. Subsequently, pulmonary angiogenesis expands the microvasculature to drive exponential distal lung growth during early postnatal life. Yet, how these marked physiologic changes alter distinct EC subtypes to facilitate the transition of the pulmonary circulation and regulate vascular growth and remodeling remains incompletely understood. Methods: In this report, we employed single cell RNA-transcriptomics and in situ RNA imaging to profile pulmonary EC in the developing mouse lung from just before birth through this period of rapid postnatal growth. Results: Multiple, transcriptionally distinct macro- and microvascular EC were identified in the late embryonic and early postnatal lung, with gene expression profiles distinct from their adult EC counterparts. A novel arterial subtype, unique to the developing lung localized to the distal parenchyma and expressed genes that regulate vascular growth and patterning. Birth particularly heightened microvascular diversity, inducing dramatic shifts in the transcriptome of distinct microvascular subtypes in pathways related to proliferation, migration and antigen presentation. Two distinct waves of EC proliferation were identified, including one just prior to birth, and a second during early alveolarization, a time of exponential pulmonary angiogenesis. Chronic hyperoxia, an injury that impairs parenchymal and vascular growth, induced a common gene signature among all pulmonary EC, unique alterations to distinct microvascular EC subtypes, and disrupted EC-EC and EC-immune cell cross talk. Conclusions: Taken together, these data reveal tremendous diversity of pulmonary EC during a critical window of postnatal vascular growth, and provide a detailed molecular map that can be used to inform both normal vascular development and alterations in EC diversity upon injury. These data have important implications for lung diseases marked by dysregulated angiogenesis and pathologic pulmonary vascular remodeling.

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Large-scale and high-resolutionmass spectrometry-based proteomics profiling defines molecular subtypes of esophageal cancer for therapeutic targeting

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Large-scale and high-resolution mass spectrometry-based proteomics profiling defines molecular subtypes of esophageal cancer for therapeutic targeting.

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