한빛사
>
한빛사논문
한빛사논문
- 조회274
J. Hematol. Oncol., Feb 05 2025, 18 (1) | https://doi.org/10.1186/s13045-025-01667-5
Transcriptional regulatory network analysis identifies GRN as a key regulator bridging chemotherapy and immunotherapy response in small cell lung cancer
Seungyeul Yoo1†, Ayushi S. Patel2,3†, Sarah Karam2,3, Yi Zhong1, Li Wang1, Feng Jiang2,3, Ranran Kong2,3,4, Sharon Bikvan2,3, Wenhui Wang1, Abhilasha Sinha2,3, Charles A. Powell2,3, Jun Zhu1,3*† and Hideo Watanabe2,3,5*†
1GeneDx, 333 Ludlow Street, North Tower, 6th Floor, Stamford, CT 06902, USA.
2Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY 10029, USA.
3Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
4Department of Thoracic Surgery, The Second Afliated Hospital of Xi’an Jiaotong University, Xi’an, China.
5Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY 10029, USA.
†Seungyeul Yoo and Ayushi Patel have contributed equally to this work.
Jun Zhu and Hideo Watanabe have jointly supervised this work.
*Correspondence: Jun Zhu, Hideo Watanabe
1GeneDx, 333 Ludlow Street, North Tower, 6th Floor, Stamford, CT 06902, USA.
2Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY 10029, USA.
3Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, 1425 Madison Avenue, New York, NY 10029, USA.
4Department of Thoracic Surgery, The Second Afliated Hospital of Xi’an Jiaotong University, Xi’an, China.
5Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, 1468 Madison Avenue, New York, NY 10029, USA.
†Seungyeul Yoo and Ayushi Patel have contributed equally to this work.
Jun Zhu and Hideo Watanabe have jointly supervised this work.
*Correspondence: Jun Zhu, Hideo Watanabe
Abstract
Small cell lung cancer (SCLC) is an aggressive and heterogeneous subtype, representing 15% of lung cancer cases. Although SCLC initially responds to etoposide and platinum (EP) chemotherapy, nearly all patients relapse with resistant tumors. While recent advances in immunotherapy have shown promise, only 10-20% of patients benefit, and effective stratification methods are lacking. The mechanisms of resistance to both therapeutics remain obscure. In this study, we aimed to gain insights into those leveraging a recent surge in the field of SCLC genomics. We constructed a regulatory network for SCLC and identified granulin precursor (GRN) as a hub of EP response associated genes. GRN-low patients showed improved survival with chemotherapy, while GRN-high patients exhibited resistance. GRN overexpression in SCLC cells conferred resistance to EP treatment and suppressed neuroendocrine features. GRN and its associated genes were linked to cancer cell intrinsic immunogenicity, and single-cell RNA-seq data revealed that GRN expression is particularly high in subsets of tumor-associated macrophages. In concordance with these findings, GRN-low tumors showed significantly better survival with chemo-immunotherapy, while GRN-high tumors did not benefit from additional immunotherapy. GRN-high tumors, associated with non-neuroendocrine (non-NE) subtypes, had a higher level of macrophage infiltration, potentially contributing to immunotherapy resistance. These results highlight GRN as a critical regulator of chemo-resistance and a potential biomarker for immunotherapy resistance in SCLC. Targeted therapeutic strategies for GRN-low patients could improve outcomes, while new approaches are needed for GRN-high patients. Overall, our findings implicate GRN as a bridge between chemotherapy and immunotherapy resistance through GRN-mediated mechanisms.
논문정보
- Research article
- 2025년 02월 (BRIC 등록일 2025-02-07)
- 국외 연구진
- 생명과학 > 분자생물학
댓글 작성 로그인
팝업 닫기관련 링크
연구자 키워드
관련분야 연구자보기
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기
