Reprogramming anchorage dependency by adherent-to-suspension transition promotes metastatic dissemination
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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2023-03-01
|
| Series: | Molecular Cancer |
| Online Access: | https://doi.org/10.1186/s12943-023-01753-7 |
| _version_ | 1827635315183976448 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Hyunbin D. Huh |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T15:26:03Z |
| format | Article |
| id | doaj.art-2729d7d0a8664b44a4f7f9838e5393ba |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-03-09T15:26:03Z |
| publishDate | 2023-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-2729d7d0a8664b44a4f7f9838e5393ba2023-11-26T12:31:44ZengBMCMolecular Cancer1476-45982023-03-0122111510.1186/s12943-023-01753-7Reprogramming anchorage dependency by adherent-to-suspension transition promotes metastatic disseminationHyunbin D. Huh0Yujin Sub1Jongwook Oh2Ye Eun Kim3Ju Young Lee4Hwa-Ryeon Kim5Soyeon Lee6Hannah Lee7Sehyung Pak8Sebastian E. Amos9Danielle Vahala10Jae Hyung Park11Ji Eun Shin12So Yeon Park13Han Sang Kim14Young Hoon Roh15Han-Woong Lee16Kun-Liang Guan17Yu Suk Choi18Joon Jeong19Junjeong Choi20Jae-Seok Roe21Heon Yung Gee22Hyun Woo Park23Department of Biochemistry, College of Life Science and Biotechnology, Brain Korea 21 Project, Yonsei UniversityDepartment of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of MedicineDepartment of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of MedicineDepartment of Biochemistry, College of Life Science and Biotechnology, Brain Korea 21 Project, Yonsei UniversityDepartment of Biochemistry, College of Life Science and Biotechnology, Brain Korea 21 Project, Yonsei UniversityDepartment of Biochemistry, College of Life Science and Biotechnology, Brain Korea 21 Project, Yonsei UniversityDepartment of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of MedicineDepartment of Biochemistry, College of Life Science and Biotechnology, Brain Korea 21 Project, Yonsei UniversityCytogenSchool of Human Sciences, University of Western AustraliaSchool of Human Sciences, University of Western AustraliaDepartment of Biochemistry, College of Life Science and Biotechnology, Brain Korea 21 Project, Yonsei UniversityDepartment of Biochemistry, College of Life Science and Biotechnology, Brain Korea 21 Project, Yonsei UniversityDepartment of Biochemistry, College of Life Science and Biotechnology, Brain Korea 21 Project, Yonsei UniversityYonsei 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 MedicineDepartment of Biotechnology, College of Life Science and Biotechnology, Yonsei UniversityDepartment of Biochemistry, College of Life Science and Biotechnology, Brain Korea 21 Project, Yonsei UniversityDepartment of Pharmacology and Moores Cancer Center, University of California San DiegoSchool of Human Sciences, University of Western AustraliaDepartments of Surgery, Gangnam Severance Hospital, Yonsei University College of MedicineCollege of Pharmacy, Yonsei Institute of Pharmaceutical Sciences, Yonsei UniversityDepartment of Biochemistry, College of Life Science and Biotechnology, Brain Korea 21 Project, Yonsei UniversityDepartment of Pharmacology, Graduate School of Medical Science, Brain Korea 21 Project, Yonsei University College of MedicineDepartment of Biochemistry, College of Life Science and Biotechnology, Brain Korea 21 Project, Yonsei UniversityAbstract 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.https://doi.org/10.1186/s12943-023-01753-7 |
| spellingShingle | 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 Reprogramming anchorage dependency by adherent-to-suspension transition promotes metastatic dissemination Molecular Cancer |
| title | Reprogramming anchorage dependency by adherent-to-suspension transition promotes metastatic dissemination |
| title_full | Reprogramming anchorage dependency by adherent-to-suspension transition promotes metastatic dissemination |
| title_fullStr | Reprogramming anchorage dependency by adherent-to-suspension transition promotes metastatic dissemination |
| title_full_unstemmed | Reprogramming anchorage dependency by adherent-to-suspension transition promotes metastatic dissemination |
| title_short | Reprogramming anchorage dependency by adherent-to-suspension transition promotes metastatic dissemination |
| title_sort | reprogramming anchorage dependency by adherent to suspension transition promotes metastatic dissemination |
| url | https://doi.org/10.1186/s12943-023-01753-7 |
| work_keys_str_mv | AT hyunbindhuh reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT yujinsub reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT jongwookoh reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT yeeunkim reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT juyounglee reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT hwaryeonkim reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT soyeonlee reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT hannahlee reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT sehyungpak reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT sebastianeamos reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT daniellevahala reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT jaehyungpark reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT jieunshin reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT soyeonpark reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT hansangkim reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT younghoonroh reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT hanwoonglee reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT kunliangguan reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT yusukchoi reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT joonjeong reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT junjeongchoi reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT jaeseokroe reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT heonyunggee reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination AT hyunwoopark reprogramminganchoragedependencybyadherenttosuspensiontransitionpromotesmetastaticdissemination |