Proteogenomic landscape of human pancreatic ductal adenocarcinoma in an Asian population reveals tumor cell-enriched and immune-rich subtypes

Do Young Hyeon; Dowoon Nam; Youngmin Han; Duk Ki Kim; Gibeom Kim; Daeun Kim; Jingi Bae; Seunghoon Back; Dong Gi Mun; Inamul Hasan Madar; Hangyeore Lee; Su Jin Kim; Hokeun Kim; Sangyeop Hyun; Chang Rok Kim; Seon Ah Choi; Yong Ryoul Kim; Juhee Jeong; Suwan Jeon; Yeon Woong Choo; Kyung Bun Lee; Wooil Kwon; Seunghyuk Choi; Taewan Goo; Taesung Park; Young Ah Suh; Hongbeom Kim; Ja Lok Ku; Min Sik Kim; Eunok Paek; Daechan Park; Keehoon Jung; Sung Hee Baek; Jin Young Jang; Daehee Hwang; Sang Won Lee

doi:10.1038/s43018-022-00479-7

Proteogenomic landscape of human pancreatic ductal adenocarcinoma in an Asian population reveals tumor cell-enriched and immune-rich subtypes

Do Young Hyeon, Dowoon Nam, Youngmin Han, Duk Ki Kim, Gibeom Kim, Daeun Kim, Jingi Bae, Seunghoon Back, Dong Gi Mun, Inamul Hasan Madar, Hangyeore Lee, Su Jin Kim, Hokeun Kim, Sangyeop Hyun, Chang Rok Kim, Seon Ah Choi, Yong Ryoul Kim, Juhee Jeong, Suwan Jeon, Yeon Woong ChooKyung Bun Lee, Wooil Kwon, Seunghyuk Choi, Taewan Goo, Taesung Park, Young Ah Suh, Hongbeom Kim, Ja Lok Ku, Min Sik Kim, Eunok Paek, Daechan Park, Keehoon Jung, Sung Hee Baek, Jin Young Jang, Daehee Hwang, Sang Won Lee

Department of Chemistry

Research output: Contribution to journal › Article › peer-review

30 Citations (Scopus)

Abstract

We report a proteogenomic analysis of pancreatic ductal adenocarcinoma (PDAC). Mutation–phosphorylation correlations identified signaling pathways associated with somatic mutations in significantly mutated genes. Messenger RNA–protein abundance correlations revealed potential prognostic biomarkers correlated with patient survival. Integrated clustering of mRNA, protein and phosphorylation data identified six PDAC subtypes. Cellular pathways represented by mRNA and protein signatures, defining the subtypes and compositions of cell types in the subtypes, characterized them as classical progenitor (TS1), squamous (TS2–4), immunogenic progenitor (IS1) and exocrine-like (IS2) subtypes. Compared with the mRNA data, protein and phosphorylation data further classified the squamous subtypes into activated stroma-enriched (TS2), invasive (TS3) and invasive-proliferative (TS4) squamous subtypes. Orthotopic mouse PDAC models revealed a higher number of pro-tumorigenic immune cells in TS4, inhibiting T cell proliferation. Our proteogenomic analysis provides significantly mutated genes/biomarkers, cellular pathways and cell types as potential therapeutic targets to improve stratification of patients with PDAC.

Original language	English
Pages (from-to)	290-307
Number of pages	18
Journal	Nature Cancer
Volume	4
Issue number	2
DOIs	https://doi.org/10.1038/s43018-022-00479-7
Publication status	Published - 2023 Feb

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

ASJC Scopus subject areas

Oncology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s43018-022-00479-7

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Hyeon, D. Y., Nam, D., Han, Y., Kim, D. K., Kim, G., Kim, D., Bae, J., Back, S., Mun, D. G., Madar, I. H., Lee, H., Kim, S. J., Kim, H., Hyun, S., Kim, C. R., Choi, S. A., Kim, Y. R., Jeong, J., Jeon, S., ... Lee, S. W. (2023). Proteogenomic landscape of human pancreatic ductal adenocarcinoma in an Asian population reveals tumor cell-enriched and immune-rich subtypes. Nature Cancer, 4(2), 290-307. https://doi.org/10.1038/s43018-022-00479-7

Hyeon, DY, Nam, D, Han, Y, Kim, DK, Kim, G, Kim, D, Bae, J, Back, S, Mun, DG, Madar, IH, Lee, H, Kim, SJ, Kim, H, Hyun, S, Kim, CR, Choi, SA, Kim, YR, Jeong, J, Jeon, S, Choo, YW, Lee, KB, Kwon, W, Choi, S, Goo, T, Park, T, Suh, YA, Kim, H, Ku, JL, Kim, MS, Paek, E, Park, D, Jung, K, Baek, SH, Jang, JY, Hwang, D & Lee, SW 2023, 'Proteogenomic landscape of human pancreatic ductal adenocarcinoma in an Asian population reveals tumor cell-enriched and immune-rich subtypes', Nature Cancer, vol. 4, no. 2, pp. 290-307. https://doi.org/10.1038/s43018-022-00479-7

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title = "Proteogenomic landscape of human pancreatic ductal adenocarcinoma in an Asian population reveals tumor cell-enriched and immune-rich subtypes",

abstract = "We report a proteogenomic analysis of pancreatic ductal adenocarcinoma (PDAC). Mutation–phosphorylation correlations identified signaling pathways associated with somatic mutations in significantly mutated genes. Messenger RNA–protein abundance correlations revealed potential prognostic biomarkers correlated with patient survival. Integrated clustering of mRNA, protein and phosphorylation data identified six PDAC subtypes. Cellular pathways represented by mRNA and protein signatures, defining the subtypes and compositions of cell types in the subtypes, characterized them as classical progenitor (TS1), squamous (TS2–4), immunogenic progenitor (IS1) and exocrine-like (IS2) subtypes. Compared with the mRNA data, protein and phosphorylation data further classified the squamous subtypes into activated stroma-enriched (TS2), invasive (TS3) and invasive-proliferative (TS4) squamous subtypes. Orthotopic mouse PDAC models revealed a higher number of pro-tumorigenic immune cells in TS4, inhibiting T cell proliferation. Our proteogenomic analysis provides significantly mutated genes/biomarkers, cellular pathways and cell types as potential therapeutic targets to improve stratification of patients with PDAC.",

author = "Hyeon, {Do Young} and Dowoon Nam and Youngmin Han and Kim, {Duk Ki} and Gibeom Kim and Daeun Kim and Jingi Bae and Seunghoon Back and Mun, {Dong Gi} and Madar, {Inamul Hasan} and Hangyeore Lee and Kim, {Su Jin} and Hokeun Kim and Sangyeop Hyun and Kim, {Chang Rok} and Choi, {Seon Ah} and Kim, {Yong Ryoul} and Juhee Jeong and Suwan Jeon and Choo, {Yeon Woong} and Lee, {Kyung Bun} and Wooil Kwon and Seunghyuk Choi and Taewan Goo and Taesung Park and Suh, {Young Ah} and Hongbeom Kim and Ku, {Ja Lok} and Kim, {Min Sik} and Eunok Paek and Daechan Park and Keehoon Jung and Baek, {Sung Hee} and Jang, {Jin Young} and Daehee Hwang and Lee, {Sang Won}",

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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AU - Hyeon, Do Young

AU - Nam, Dowoon

AU - Han, Youngmin

AU - Kim, Duk Ki

AU - Kim, Gibeom

AU - Kim, Daeun

AU - Bae, Jingi

AU - Back, Seunghoon

AU - Mun, Dong Gi

AU - Madar, Inamul Hasan

AU - Lee, Hangyeore

AU - Kim, Su Jin

AU - Kim, Hokeun

AU - Hyun, Sangyeop

AU - Kim, Chang Rok

AU - Choi, Seon Ah

AU - Kim, Yong Ryoul

AU - Jeong, Juhee

AU - Jeon, Suwan

AU - Choo, Yeon Woong

AU - Lee, Kyung Bun

AU - Kwon, Wooil

AU - Choi, Seunghyuk

AU - Goo, Taewan

AU - Park, Taesung

AU - Suh, Young Ah

AU - Kim, Hongbeom

AU - Ku, Ja Lok

AU - Kim, Min Sik

AU - Paek, Eunok

AU - Park, Daechan

AU - Jung, Keehoon

AU - Baek, Sung Hee

AU - Jang, Jin Young

AU - Hwang, Daehee

AU - Lee, Sang Won

PY - 2023/2

Y1 - 2023/2

N2 - We report a proteogenomic analysis of pancreatic ductal adenocarcinoma (PDAC). Mutation–phosphorylation correlations identified signaling pathways associated with somatic mutations in significantly mutated genes. Messenger RNA–protein abundance correlations revealed potential prognostic biomarkers correlated with patient survival. Integrated clustering of mRNA, protein and phosphorylation data identified six PDAC subtypes. Cellular pathways represented by mRNA and protein signatures, defining the subtypes and compositions of cell types in the subtypes, characterized them as classical progenitor (TS1), squamous (TS2–4), immunogenic progenitor (IS1) and exocrine-like (IS2) subtypes. Compared with the mRNA data, protein and phosphorylation data further classified the squamous subtypes into activated stroma-enriched (TS2), invasive (TS3) and invasive-proliferative (TS4) squamous subtypes. Orthotopic mouse PDAC models revealed a higher number of pro-tumorigenic immune cells in TS4, inhibiting T cell proliferation. Our proteogenomic analysis provides significantly mutated genes/biomarkers, cellular pathways and cell types as potential therapeutic targets to improve stratification of patients with PDAC.

AB - We report a proteogenomic analysis of pancreatic ductal adenocarcinoma (PDAC). Mutation–phosphorylation correlations identified signaling pathways associated with somatic mutations in significantly mutated genes. Messenger RNA–protein abundance correlations revealed potential prognostic biomarkers correlated with patient survival. Integrated clustering of mRNA, protein and phosphorylation data identified six PDAC subtypes. Cellular pathways represented by mRNA and protein signatures, defining the subtypes and compositions of cell types in the subtypes, characterized them as classical progenitor (TS1), squamous (TS2–4), immunogenic progenitor (IS1) and exocrine-like (IS2) subtypes. Compared with the mRNA data, protein and phosphorylation data further classified the squamous subtypes into activated stroma-enriched (TS2), invasive (TS3) and invasive-proliferative (TS4) squamous subtypes. Orthotopic mouse PDAC models revealed a higher number of pro-tumorigenic immune cells in TS4, inhibiting T cell proliferation. Our proteogenomic analysis provides significantly mutated genes/biomarkers, cellular pathways and cell types as potential therapeutic targets to improve stratification of patients with PDAC.

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ER -

Proteogenomic landscape of human pancreatic ductal adenocarcinoma in an Asian population reveals tumor cell-enriched and immune-rich subtypes

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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