Lui, A. J. W. | Search bioRxiv

bioRxiv2026

Chemotherapy reshapes cellular clonal landscape via persister programs in breast cancer xenografts

Tumor ecosystems evolve in response to chemotherapy, but how treatment reshapes clonal architecture and the transcriptional programs of distinct cell states remains unclear. To investigate the response to chemotherapy by individual single cell-derived clones, we used a high-complexity lentiviral barcoding strategy by genetically labelling with unique, heritable and expressible barcode sequences individual cells from four human breast cancer patient-derived tumor xenograft models. We tracked 3,248 single cell-derived clones across 39 xenografts and profiled 676,292 cells with single cell RNA sequencing. The most striking changes following chemotherapy occurred in non-responsive xenografts, attributed to the emergence of previously minor cell clones that are chemotherapy resistant. In a triple negative model, epithelial and mesenchymal cell states showed distinct sensitivities to chemotherapy. ER+/HER2-models activated stress adaptive programs in response to carboplatin, highlighting DUSP1 and KLF4 as markers of platinum tolerance and a slow cycling, persister-like state. Together, these findings reveal that chemotherapy triggers an immediate and substantial reorganization of the cellular clonal landscape, driven by the selective engagement of stress response programs in cell clones that survive treatment.

cancer biology↗

bioRxiv2020

Establishment of multiple novel patient-derived models of desmoplastic small round cell tumor enabling functional characterization of ERBB pathway signaling and pre-clinical evaluation of a novel targeted therapy approach

Desmoplastic small round cell tumor (DSRCT) is characterized by the t(11;22)(p13;q12) chromosomal translocation, which fuses the transcriptional regulatory domain of EWSR1 with the zinc finger DNA-binding domain of WT1, resulting in the oncogenic transcription factor EWS-WT1. DSRCT primarily affects young males and has a 5-year overall survival of about 15%. Typical treatment approaches for patients with DSRCT involve a multi-modal combination of surgery, chemotherapy and radiation. The paucity of DSRCT disease models has hampered functional and pre-clinical therapeutic studies in this aggressive cancer. Here, we developed robust preclinical disease models and mined DSRCT expression profiling data to identify genetic vulnerabilities that could be leveraged for the identification of rational therapies. Specifically, we developed four new DSRCT cell lines and one patient-derived xenograft (PDX) model. Transcriptomic and proteomic profiling showed evidence of activation of the ERBB pathway. Ectopic expression of EWSR1-WT1 resulted in upregulation of ERRB family ligands and downstream signaling. Treatment of DSRCT cell lines with ERBB ligands resulted in activation of EGFR, ERBB2, ERK1/2 and AKT, and stimulation of cell growth. Conversely, targeting of EGFR using shRNA, small molecule inhibitors (afatinib, neratinib) or an anti-EGFR antibody (cetuximab) inhibited growth and induced apoptosis in DSRCT cells. Finally, treatment of mice bearing DSRCT xenografts with a combination of cetuximab and afatinib significantly reduced tumor growth. These data provide a rationale for the clinical evaluation of EGFR antagonists in patients with DSRCT.

cancer biology↗