| Accession |
PRJCA029962 |
| Title |
Mechanism exploration and model construction for small cell transformation in EGFR-mutant lung adenocarcinomas |
| Relevance |
Medical |
| Data types |
Transcriptome or Gene expression
|
| Organisms |
Homo sapiens
|
| Description |
Small-cell lung cancer (SCLC) transformation accounts for 3-14% of resistance in patients with EGFR-TKI relapsed lung adenocarcinomas (LUADs), with unknown molecular mechanisms and optimal treatment strategies. We performed transcriptomic analyses (including bulk and spatial transcriptomics) and multiplex immunofluorescence on pre-treated samples from LUADs that were not transformed after EGFR-TKI treatment (LUAD-NT), primary SCLCs (SCLC-P) and LUADs with SCLC transformation after EGFR-TKI treatment (before transformation: LUAD-BT; after transformation: SCLC-AT). We found LUAD-BT exhibited potential transformation characteristics compared with LUAD-NT, while SCLC-AT showed features of both LUAD-BT and SCLC-P with an intermediate phenotype. We identified several pathways that shifted during transformation. 17.5% of differential expressed genes were transcriptional regulation factors, and HDAC10 was the key regulation factors of transformation. SCLC-AT was less dependent on EGF-EGFR and its downstream pathways and more dependent on FGF-FGFR pathway, while VEGF-VEGFR pathway remained active as LUAD-BT, indicating potential optimal treatment after transformation. The decreasing of Tc-effect/Tc-exhausted ratio during transformation was associated with time to transformation, indicating an immuno-exhausted status in transformed-SCLCs which was associated with the duration of EGFR-TKI before transformation. Compared with SCLC-P, SCLC-AT showed significant down-regulation in cell cycle, immunity, DNA repair, and SCLC-related pathways. Besides, SCLC-AT exhibited distinct molecular subtypes from SCLC-P. Moreover, we constructed an ideal 4-marker model based on transcriptomic and IHC data to predict SCLC transformation. From an expanded validation cohort of 60 LUADs, the model obtained a sensitivity of 100% and 87.5%, a specificity of 95.7% and 100% in the training and test cohorts, respectively. We provided insights into the molecular mechanisms of SCLC transformation and the differences between SCLC-AT and SCLC-P, which might shed light on prevention strategies and subsequent therapeutic strategies for SCLC transformation in the future. |
| Sample scope |
Multiisolate |
| Release date |
2024-09-11 |
| Publication |
| PubMed ID |
Article title |
Journal name |
DOI |
Year |
| 39353908
|
Mechanism exploration and model construction for small cell transformation in EGFR-mutant lung adenocarcinomas
|
Signal Transduction and Targeted Therapy
|
10.1038/s41392-024-01981-3
|
2024
|
|
|
| Grants |
| Agency |
program |
Grant ID |
Grant title |
| National Natural Science Foundation of China (NSFC)
|
|
82172876
|
|
| Chinese Academy of Medical Sciences (CAMS)
|
|
2021-1-I2M-012
|
|
| CAMS | Cancer Institute and Hospital, Chinese Academy of Medical Sciences (Cancer Institute and Hospital)
|
|
LC2022A20
|
|
| CAMS | Cancer Institute and Hospital, Chinese Academy of Medical Sciences (Cancer Institute and Hospital)
|
|
LC2019L04
|
|
|
|
| Submitter |
Puyuan
Xing (xingpuyuan@cicams.ac.cn)
|
| Organization |
Cancer Hospital, Chinese Academy of Medical Sciences |
| Submission date |
2024-09-07 |
