박주경 (성균관대학교 의과대학, 삼성서울병원)

한빛사논문

조회270

박주경Joo Kyung Park

성균관대학교 의과대학, 삼성서울병원

Mol. Cancer, May 03 2024, 23 (1) 87 | https://doi.org/10.1186/s12943-024-02003-0 Single-cell transcriptome analysis reveals subtype-specific clonal evolution and microenvironmental changes in liver metastasis of pancreatic adenocarcinoma and their clinical implications

Joo Kyung Park^1,2†, Hyoung‑oh Jeong^3†, Hyemin Kim^1†, Jin Ho Choi¹, Eun Mi Lee¹, Seunghoon Kim³, Jinho Jang³, David Whee‑Young Choi³, Se‑Hoon Lee^1,2, Kyoung Mee Kim⁴, Kee‑Taek Jang⁴, Kwang Hyuck Lee¹, Kyu Taek Lee¹, Min Woo Lee^5*, Jong Kyun Lee^1* and Semin Lee^3*

¹Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

²Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences & Technology (SAIHST), Sungkyunkwan University, Seoul, Republic of Korea.

³Department of Biomedical Engineering, College of Information-Bio Convergence Engineering, Ulsan National Institute of Science and Technology (UNIST), Ulsan, Republic of Korea.

⁴Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

⁵Department of Radiology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

^†Joo Kyung Park, Hyoung-oh Jeong, and Hyemin Kim contributed equally to this work.

^*Correspondence: Min Woo Lee, Jong Kyun Lee, Semin Lee

Abstract

Background: Intratumoral heterogeneity (ITH) and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) play important roles in tumor evolution and patient outcomes. However, the precise characterization of diverse cell populations and their crosstalk associated with PDAC progression and metastasis is still challenging.

Methods: We performed single-cell RNA sequencing (scRNA-seq) of treatment-naïve primary PDAC samples with and without paired liver metastasis samples to understand the interplay between ITH and TME in the PDAC evolution and its clinical associations.

Results: scRNA-seq analysis revealed that even a small proportion (22%) of basal-like malignant ductal cells could lead to poor chemotherapy response and patient survival and that epithelial-mesenchymal transition programs were largely subtype-specific. The clonal homogeneity significantly increased with more prevalent and pronounced copy number gains of oncogenes, such as KRAS and ETV1, and losses of tumor suppressor genes, such as SMAD2 and MAP2K4, along PDAC progression and metastasis. Moreover, diverse immune cell populations, including naïve SELLhi regulatory T cells (Tregs) and activated TIGIThi Tregs, contributed to shaping immunosuppressive TMEs of PDAC through cellular interactions with malignant ductal cells in PDAC evolution. Importantly, the proportion of basal-like ductal cells negatively correlated with that of immunoreactive cell populations, such as cytotoxic T cells, but positively correlated with that of immunosuppressive cell populations, such as Tregs.

Conclusion: We uncover that the proportion of basal-like subtype is a key determinant for chemotherapy response and patient outcome, and that PDAC clonally evolves with subtype-specific dosage changes of cancer-associated genes by forming immunosuppressive microenvironments in its progression and metastasis.

논문정보

형식Research article
게재일2024년 05월 (BRIC 등록일 2024-05-07)
연구진국내 연구진
분야 생명과학 > 유전학

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