Single-cell decoding of drug induced transcriptomic reprogramming in triple negative breast cancers

Background The encoding of cell intrinsic drug resistance states in breast cancer reflects the contributions of genomic and non-genomic variations and requires accurate estimation of clonal fitness from co-measurement of transcriptomic and genomic data. Somatic copy number (CN) variation is the dominant mutational mechanism leading to transcriptional variation and notably contributes to platinum chemotherapy resistance cell states. Here, we deploy time series measurements of triple negative breast cancer (TNBC) single-cell transcriptomes, along with co-measured single-cell CN fitness, identifying genomic and transcriptomic mechanisms in drug associated transcriptional cell states. Results We present scRNA-seq data (53,641 filtered cells) from serial passaging TNBC patient-derived xenograft (PDX) experiments spanning 2.5 years, matched with genomic single-cell CN data from the same samples. Our findings reveal distinct clonal responses within TNBC tumors exposed to platinum. Clones with high drug fitness undergo clonal sweeps and show subtle transcriptional reversion, while those with weak fitness exhibit dynamic transcription upon drug withdrawal. Pathway analysis highlights convergence on epithelial-mesenchymal transition and cytokine signaling, associated with resistance. Furthermore, pseudotime analysis demonstrates hysteresis in transcriptional reversion, indicating generation of new intermediate transcriptional states upon platinum exposure. Conclusions Within a polyclonal tumor, clones with strong genotype-associated fitness under platinum remained fixed, minimizing transcriptional reversion upon drug withdrawal. Conversely, clones with weaker fitness display non-genomic transcriptional plasticity. This suggests CN-associated and CN-independent transcriptional states could both contribute to platinum resistance. The dominance of genomic or non-genomic mechanisms within polyclonal tumors has implications for drug sensitivity, restoration and re-treatment strategies.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

47 Datasets 1 Publication

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Dataset ID	Description	Technology	Samples
EGAD00001011209	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0063_000 for Triple negative breast cancer patient-derived xenograft SA609X3XB01584	NextSeq 500	1
EGAD00001011210	10x Single Cell Gene Expression library TENX068 for Triple negative breast cancer patient-derived xenograft SA609X4XB03080	NextSeq 500	1
EGAD00001011211	10x Single Cell Gene Expression library TENX069 for Triple negative breast cancer patient-derived xenograft SA609X4XB03083	NextSeq 500	1
EGAD00001011212	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0150_001 for Triple negative breast cancer sample SA609X5XB03230	Illumina HiSeq X	1
EGAD00001011213	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0150_002 for Triple negative breast cancer sample SA609X5XB03231	Illumina HiSeq 2500 Illumina HiSeq X	1
EGAD00001011214	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0146_002 for Triple negative breast cancer patient-derived xenograft SA609X5XB03223	Illumina HiSeq 2500	1
EGAD00001011215	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0152_001 for Triple negative breast cancer patient-derived xenograft SA609X6XB03401	Illumina HiSeq 2500	1
EGAD00001011216	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0152_002 for Triple negative breast cancer sample SA609X6XB03404	Illumina HiSeq 2500	1
EGAD00001011217	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0172_001 for Triple negative breast cancer sample SA609X6XB03447	Illumina HiSeq 2500	1
EGAD00001011218	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0163_002 for Triple negative breast cancer sample SA609X7XB03510	Illumina HiSeq 2500	1
EGAD00001011219	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0163_001 for Triple negative breast cancer patient-derived xenograft SA609X7XB03505	Illumina HiSeq 2500	1
EGAD00001011220	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0172_002 for Triple negative breast cancer sample SA609X7XB03554	Illumina HiSeq 2500	1
EGAD00001011221	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0148_001 for Triple negative breast cancer patient-derived xenograft SA535X4XB02498	Illumina HiSeq 2500	1
EGAD00001011222	10x Single Cell Gene Expression library TENX048 for Triple negative breast cancer sample SA535X5XB02895	NextSeq 500	1
EGAD00001011223	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0146_006 for Triple negative breast cancer sample SA535X6XB03099	Illumina HiSeq 2500	1
EGAD00001011224	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0175_001 for Triple negative breast cancer patient-derived xenograft SA535X6XB03101	BGISEQ-500 Illumina HiSeq 2500	1
EGAD00001011225	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0182_001 for Triple negative breast cancer patient-derived xenograft SA535X7XB03304	Illumina HiSeq 2500	1
EGAD00001011226	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0189_001 for Triple negative breast cancer patient-derived xenograft SA535X7XB03448	Illumina HiSeq 2500	1
EGAD00001011227	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0184_001 for Triple negative breast cancer sample SA535X7XB03305	Illumina HiSeq 2500	1
EGAD00001011228	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0146_004 for Triple negative breast cancer sample SA535X7XB03305	Illumina HiSeq 2500	1
EGAD00001011229	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0189_002 for Triple negative breast cancer patient-derived xenograft SA535X8XB03663	Illumina HiSeq 2500	1
EGAD00001011230	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0182_002 for Triple negative breast cancer sample SA535X8XB03431	Illumina HiSeq 2500	1
EGAD00001011231	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0184_002 for Triple negative breast cancer patient-derived xenograft SA535X8XB03434	Illumina HiSeq 2500	1
EGAD00001011232	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0173_002 for Triple negative breast cancer patient-derived xenograft SA535X9XB03617	Illumina HiSeq 2500	1
EGAD00001011233	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0173_001 for Triple negative breast cancer patient-derived xenograft SA535X9XB03616	Illumina HiSeq 2500	1
EGAD00001011234	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0195_001 for Triple negative breast cancer patient-derived xenograft SA535X8XB03664	Illumina HiSeq 2500	1
EGAD00001011235	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0206_002 for Triple negative breast cancer patient-derived xenograft SA535X10XB03696	Illumina HiSeq 2500	1
EGAD00001011236	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0206_001 for Triple negative breast cancer sample SA535X10XB03693	Illumina HiSeq 2500	1
EGAD00001011237	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0208_002 for Triple negative breast cancer patient-derived xenograft SA535X9XB03776	Illumina HiSeq 2500	1
EGAD00001011238	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0142_002 for Triple negative breast cancer sample SA1035X4XB02879	Illumina HiSeq 2500	1
EGAD00001011239	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0071_000 for Triple negative breast cancer sample SA1035X5XB03015	Illumina HiSeq 2500	1
EGAD00001011240	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0076_000 for Triple negative breast cancer sample SA1035X5XB03021	Illumina HiSeq 2500	1
EGAD00001011241	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0079_001 for Triple negative breast cancer sample SA1035X6XB03216	HiSeq X Ten Illumina HiSeq 2500	1
EGAD00001011242	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0079_002 for Triple negative breast cancer patient-derived xenograft SA1035X6XB03211	HiSeq X Ten Illumina HiSeq 2500	1
EGAD00001011243	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0142_004 for Triple negative breast cancer sample SA1035X6XB03209	Illumina HiSeq 2500	1
EGAD00001011244	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0145_001 for Triple negative breast cancer patient-derived xenograft SA1035X7XB03338	NextSeq 500	1
EGAD00001011245	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0145_002 for Triple negative breast cancer patient-derived xenograft SA1035X7XB03340	NextSeq 500	1
EGAD00001011246	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0162_002 for Triple negative breast cancer sample SA1035X7XB03502	Illumina HiSeq 2500	1
EGAD00001011247	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0151_001 for Triple negative breast cancer patient-derived xenograft SA1035X8XB03425	Illumina HiSeq 2500	1
EGAD00001011248	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0162_001 for Triple negative breast cancer sample SA1035X8XB03420	Illumina HiSeq 2500	1
EGAD00001011249	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0175_002 for Triple negative breast cancer patient-derived xenograft SA1035X8XB03631	Illumina HiSeq 2500	1
EGAD00001011250	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0164_002 for Triple negative breast cancer sample SA530X3XB03295	Illumina HiSeq 2500	1
EGAD00001011251	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0014_001 for Triple negative breast cancer patient-derived xenograft SA604X6XB01979	Illumina HiSeq 2500	1
EGAD00001011252	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0015_001 for Triple negative breast cancer patient-derived xenograft SA604X6XB01979	Illumina HiSeq 2500	1
EGAD00001011253	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0019_001 for Triple negative breast cancer patient-derived xenograft SA604X7XB02089	NextSeq 500	1
EGAD00001011254	10x Single Cell Gene Expression library SCRNA10X_SA_CHIP0020_002 for Triple negative breast cancer patient-derived xenograft SA604X8XB02164	Illumina HiSeq 2500	1
EGAD00001011268	10x Single Cell Gene Expression library TENX063 for Triple negative breast cancer patient-derived xenograft SA609X3XB01584	NextSeq 500	1

Publications	Citations
Single-cell decoding of drug induced transcriptomic reprogramming in triple negative breast cancers. Kabeer F, Tran H, Andronescu M, Singh G, Lee H, Salehi S, Wang B, Biele J, Brimhall J, Gee D, Cerda V, O'Flanagan C, Algara T, Kono T, Beatty S, Zaikova E, Lai D, Lee E, Moore R, Mungall AJ, IMAXT Consortium, Williams MJ, Roth A, Campbell KR, Shah SP, Aparicio S. Genome Biol 25: 2024 191	0