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Reprogramming anchorage dependency by adherent-to-suspension transition promotes metastatic dissemination

Authors
 Hyunbin D Huh  ;  Yujin Sub  ;  Jongwook Oh  ;  Ye Eun Kim  ;  Ju Young Lee  ;  Hwa-Ryeon Kim  ;  Soyeon Lee  ;  Hannah Lee  ;  Sehyung Pak  ;  Sebastian E Amos  ;  Danielle Vahala  ;  Jae Hyung Park  ;  Ji Eun Shin  ;  So Yeon Park  ;  Han Sang Kim  ;  Young Hoon Roh  ;  Han-Woong Lee  ;  Kun-Liang Guan  ;  Yu Suk Choi  ;  Joon Jeong  ;  Junjeong Choi  ;  Jae-Seok Roe  ;  Heon Yung Gee  ;  Hyun Woo Park 
Citation
 MOLECULAR CANCER, Vol.22(1) : 63, 2023-03 
Journal Title
MOLECULAR CANCER
Issue Date
2023-03
MeSH
Animals ; Breast Neoplasms* / genetics ; Breast Neoplasms* / pathology ; Cell Line, Tumor ; Female ; Humans ; Lung Neoplasms* / pathology ; Melanoma* / metabolism ; Mice ; Neoplasm Metastasis ; Neoplastic Cells, Circulating* / pathology
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.

© 2023. The Author(s).
Files in This Item:
T202302122.pdf Download
DOI
10.1186/s12943-023-01753-7
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Surgery (외과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Han Sang(김한상) ORCID logo https://orcid.org/0000-0002-6504-9927
Park, Hyun Woo(박현우)
Oh, Jongwook(오종욱)
Jeong, Joon(정준) ORCID logo https://orcid.org/0000-0003-0397-0005
Gee, Heon Yung(지헌영) ORCID logo https://orcid.org/0000-0002-8741-6177
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/195278
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