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| Status |
Public on May 20, 2024 |
| Title |
Single Cell Analysis of Treatment–Resistant Prostate Cancer: Implications of Cell State Changes for Cell Surface Antigen Targeted Therapies |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Targeting cell surface molecules using radioligand and antibody–based therapies has yielded considerable success across cancers. However, it remains unclear how the expression of putative lineage markers, particularly cell surface molecules, varies in the process of lineage plasticity, wherein tumor cells alter their identity and acquire new oncogenic properties. A notable example of lineage plasticity is the transformation of prostate adenocarcinoma (PRAD) to neuroendocrine prostate cancer (NEPC)––a growing resistance mechanism that results in the loss of responsiveness to androgen blockade and portends dismal patient survival. To understand how lineage markers vary across the evolution of lineage plasticity in prostate cancer, we applied single cell analyses to 21 human prostate tumor biopsies and two genetically engineered mouse models, together with tissue microarray analysis (TMA) on 131 tumor samples. Not only did we observe a higher degree of phenotypic heterogeneity in castrate–resistant PRAD and NEPC than previously anticipated, but also found that the expression of molecules targeted therapeutically, namely PSMA, STEAP1, STEAP2, TROP2, CEACAM5, and DLL3, varied within a subset of gene–regulatory networks (GRNs). We also noted that NEPC and small cell lung cancer (SCLC) subtypes shared a set of GRNs, indicative of conserved biologic pathways that may be exploited therapeutically across tumor types. While this extreme level of transcriptional heterogeneity, particularly in cell surface marker expression, may mitigate the durability of clinical responses to novel antigen–directed therapies, its delineation may yield signatures for patient selection in clinical trials, potentially across distinct cancer types.
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| Overall design |
Tumor biopsies were dissociated per previously published protocols (PMID: 35981096). Single cell data for HMP22, HMP23A, HMP23B, HMP24 has not previously been published and is deposited under this GEO ID. Data for HMP04, HMP05, HMP08, HMP11A, HMP11B, HMP13, HMP14, HMP16, HMP17, HMP19, HMP20, HMP25, and HMP26 were re–analyzed, but has previously been published in the context of JAK/STAT signaling in prostate cancer under GSE210358 (PMID 35981096). Data from HP95, HP96, HP97, HP99, HP100, and HP101 are also re–analyzed and has previously been published by our group in the context luminal regeneration under https://duos.broadinstitute.org/ (accession no. DUOS-000115). We have also included processed RDS files for combined samples (N=23) for all cells and tumor cells. Of note, HP and HMP IDs correspond to MSK–HP IDs as presented in this publication in Supplementary Table 3.
The list of the re-analyzed sample in GSE210358:
SRX16781303 GSM6428952 HMP04 SAMN30111353
SRX16781304 GSM6428953 HMP05 SAMN30111352
SRX16781305 GSM6428954 HMP08 SAMN30111351
SRX16781314 GSM6428955 HMP11_1 SAMN30111350
SRX16781315 GSM6428956 HMP11_2 SAMN30111349
SRX16781316 GSM6428957 HMP13 SAMN30111348
SRX16781317 GSM6428958 HMP14 SAMN30111347
SRX16781319 GSM6428960 HMP16 SAMN30111345
SRX16781318 GSM6428959 HMP15 SAMN30111346
SRX16781320 GSM6428961 HMP17 SAMN30111344
SRX16781321 GSM6428962 HMP19 SAMN30111343
SRX16781322 GSM6428963 HMP20 SAMN30111342
SRX16781323 GSM6428964 HMP25 SAMN30111341
SRX16781325 GSM6428965 HMP26 SAMN30111340
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| Contributor(s) |
Zaidi S, Park J, Haffner MC, Sawyers CL |
| Citation missing |
Has this study been published? Please login to update or notify GEO. |
| Submission date |
Apr 22, 2024 |
| Last update date |
May 20, 2024 |
| Contact name |
Samir Zaidi |
| E-mail(s) |
zaidis@mskcc.org
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| Organization name |
Memorial Sloan Kettering Cancer Center
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| Street address |
1275 York Avenue
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| City |
New York |
| ZIP/Postal code |
10065 |
| Country |
USA |
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| Platforms (1) |
| GPL24676 |
Illumina NovaSeq 6000 (Homo sapiens) |
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| Samples (4)
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| Relations |
| Reanalysis of |
GSM6428952 |
| Reanalysis of |
GSM6428953 |
| Reanalysis of |
GSM6428954 |
| Reanalysis of |
GSM6428955 |
| Reanalysis of |
GSM6428956 |
| Reanalysis of |
GSM6428957 |
| Reanalysis of |
GSM6428958 |
| Reanalysis of |
GSM6428959 |
| Reanalysis of |
GSM6428960 |
| Reanalysis of |
GSM6428961 |
| Reanalysis of |
GSM6428962 |
| Reanalysis of |
GSM6428963 |
| Reanalysis of |
GSM6428964 |
| Reanalysis of |
GSM6428965 |
| BioProject |
PRJNA1103171 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE264573_RAW.tar |
101.2 Mb |
(http)(custom) |
TAR (of MTX, TSV) |
| GSE264573_msk.integrated.remove.cellcycle.allcells.rds.gz |
30.0 Gb |
(ftp)(http) |
RDS |
| GSE264573_msk.integrated.remove.cellcycle.tumor.cells.rds.gz |
1.3 Gb |
(ftp)(http) |
RDS |
SRA Run Selector |
| Raw data are available in SRA |
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