한빛사논문
- 조회550
Hyunbin D. Huh1†, Yujin Sub2†, Jongwook Oh2†, Ye Eun Kim1, Ju Young Lee1, Hwa‑Ryeon Kim1, Soyeon Lee2, Hannah Lee1, Sehyung Pak3, Sebastian E. Amos4, Danielle Vahala4, Jae Hyung Park1, Ji Eun Shin1, So Yeon Park1, Han Sang Kim5, Young Hoon Roh6, Han‑Woong Lee1, Kun‑Liang Guan7, Yu Suk Choi4, Joon Jeong8, Junjeong Choi9, Jae‑Seok Roe1*, Heon Yung Gee2* and Hyun Woo Park1*
1Department of Biochemistry, College of Life Science and Biotechnology, Brain Korea 21 Project, Yonsei University, Seoul 03722, Republic of Korea.
2Department of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
3Cytogen, Seoul, Republic of Korea.
4School of Human Sciences, University of Western Australia, Crawley, WA 6009, Australia.
5Yonsei Cancer Center, Division of Medical Oncology, Department of Internal Medicine, Brain Korea 21 Plus Project for Medical Sciences, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
6Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
7Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
8Departments of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, Republic of Korea.
9College of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei University, Incheon, Republic of Korea.
†Hyunbin D. Huh, Yujin Sub and Jongwook Oh contributed equally to this work.
*Correspondence: Jae‑Seok Roe, Heon Yung Gee, Hyun Woo Park
Abstract
Background: Although metastasis is the foremost cause of cancer-related death, a specialized mechanism that reprograms anchorage dependency of solid tumor cells into circulating tumor cells (CTCs) during metastatic dissemination remains a critical area of challenge.
Methods: We analyzed blood cell-specific transcripts and selected key Adherent-to-Suspension Transition (AST) factors that are competent to reprogram anchorage dependency of adherent cells into suspension cells in an inducible and reversible manner. The mechanisms of AST were evaluated by a series of in vitro and in vivo assays. Paired samples of primary tumors, CTCs, and metastatic tumors were collected from breast cancer and melanoma mouse xenograft models and patients with de novo metastasis. Analyses of single-cell RNA sequencing (scRNA-seq) and tissue staining were performed to validate the role of AST factors in CTCs. Loss-of-function experiments were performed by shRNA knockdown, gene editing, and pharmacological inhibition to block metastasis and prolong survival.
Results: We discovered a biological phenomenon referred to as AST that reprograms adherent cells into suspension cells via defined hematopoietic transcriptional regulators, which are hijacked by solid tumor cells to disseminate into CTCs. Induction of AST in adherent cells 1) suppress global integrin/ECM gene expression via Hippo-YAP/TEAD inhibition to evoke spontaneous cell-matrix dissociation and 2) upregulate globin genes that prevent oxidative stress to acquire anoikis resistance, in the absence of lineage differentiation. During dissemination, we uncover the critical roles of AST factors in CTCs derived from patients with de novo metastasis and mouse models. Pharmacological blockade of AST factors via thalidomide derivatives in breast cancer and melanoma cells abrogated CTC formation and suppressed lung metastases without affecting the primary tumor growth.
Conclusion: We demonstrate that suspension cells can directly arise from adherent cells by the addition of defined hematopoietic factors that confer metastatic traits. Furthermore, our findings expand the prevailing cancer treatment paradigm toward direct intervention within the metastatic spread of cancer.
논문정보
- Research article
- 2023년 03월 (BRIC 등록일 2023-03-31)
- 국내(교신)+국외 연구진
- 생명과학 > 생화학
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