Activation of IFN/STAT1 signaling is a hallmark of response to chemotherapy in patient-derived xenografts of triple-negative breast cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE58990 | GEO | 2015/12/31
SECONDARY ACCESSION(S): PRJNA254062
REPOSITORIES: GEO
Similar Datasets
Project description:By using patient-derived xenografts (PDXs) as living surrogate of the clinical practice, we identify here induction of genes related to the IFN pathway as an early and specific predictor of tumor response to treatment. Gene expression profile of tumor cells after laser-capture microdissection of residual tumor foci to characterize the molecular changes occurring in residual tumor cells surviving chemotherapy RNA was extracted from microdissected areas using the RNeasy Mini kit (Qiagen, Valencia, CA). This approach allowed isolating foci of human tumor cells from the murine stroma. Gene expression analysis was performed with Affymetrix Exon 1.0 ST microarrays. Hybridization, data normalization and statistical analysis were outsourced to GenoSplice Technology (Paris, France).
2015-12-31 | E-GEOD-58990 | biostudies-arrayexpress
Project description:Patient-derived tumor xenografts (PDXs) increasingly are being used as preclinical models to study human cancers and to evaluate novel therapeutics, as they reflect clinical cancers more closely than established tumor cell lines. With >100 PDXs established from resected non-small cell lung carcinomas (NSCLC), we reported previously that xenograftability correlates significantly with poorer patient prognosis. In this study, genomic, transcriptomic, and proteomic profiling of 36 PDXs showed greater similarity in somatic alterations between PDX and primary tumors than with cell lines, using publicly available data on the latter. A higher number of somatic alterations among 865 frequently altered genes in the PDX tumors was associated with better overall patient survival (HR=0.15, p=0.00015) compared to patients with corresponding PDXs characterized by a lower number of alterations; this was validated with the TCGA lung cancer patient dataset (HR=0.28, p=0.000022). These passenger-like alterations, identified in PDXs, link cell-cell signaling and adhesion to patient prognosis. Total RNAs from xenograftswere amplified by DASL kit and hybridized to Illumina HT12v4 chip
2016-10-26 | E-GEOD-68929 | biostudies-arrayexpress
Project description:Invasive lobular carcinoma (ILC) is the most frequent specific histological subtype of breast cancer (BC). It has distinct clinical features from other estrogen receptor positive (ER+) BCs but the molecular mechanisms underlying the characteristic biology are unclear because we lack experimental models to study it. Here, we generate xenograft models with ILC-derived SUM-44 PE and MDA-MB-134-VI cells by grafting them to mouse milk ducts that recapitulate the human disease including metastasis to visceral organs. Transcriptomic analysis of intraductal ER+ PDXs reveals extracellular matrix modulation as an ILC-specific trait. This signature confirms in patient datasets. The collagen modifying enzyme LOXL1 is overexpressed specifically in ILCs by tumor cells; treatment with a LOX inhibitor, BAPN, and LOXL1 silencing decrease tumor growth and inhibit metastasis by disrupting ECM structure/fibrils with down modulation of ER, IGFR, and FGFR signaling. Hence inhibition of LOXL1 is a promising therapeutic strategy for ILC.
2020-12-09 | GSE149675 | GEO
Project description:Invasive lobular carcinoma (ILC) is the most frequent specific histological subtype of breast cancer (BC). It has distinct clinical features from other estrogen receptor positive (ER+) BCs but the molecular mechanisms underlying the characteristic biology are unclear because we lack experimental models to study it. Here, we generate xenograft models with ILC-derived SUM-44 PE and MDA-MB-134-VI cells by grafting them to mouse milk ducts that recapitulate the human disease including metastasis to visceral organs. Transcriptomic analysis of intraductal ER+ PDXs reveals extracellular matrix modulation as an ILC-specific trait. This signature confirms in patient datasets. The collagen modifying enzyme LOXL1 is overexpressed specifically in ILCs by tumor cells; treatment with a LOX inhibitor, BAPN, and LOXL1 silencing decrease tumor growth and inhibit metastasis by disrupting ECM structure/fibrils with down modulation of ER, IGFR, and FGFR signaling. Hence inhibition of LOXL1 is a promising therapeutic strategy for ILC.
2020-12-09 | GSE149671 | GEO
Project description:EGFR blockade by the monoclonal antibodies cetuximab or panitumumab causes objective tumor regressions in selected patients with metastatic colorectal cancer (mCRC). However, residual disease reservoirs almost invariably remain even after maximal response to therapy, leading to treatment failure and tumor relapse. Using mCRC patient-derived xenografts (PDXs), we observed that residual cancer cells surviving EGFR inhibition exhibited gene expression patterns reminiscent of a quiescent subpopulation of normal intestinal secretory precursors with Paneth-cell traits. These drug-tolerant cells had reduced expression of EGFR-activating ligands, consistent with lower EGFR dependence, and displayed higher HER2/HER3 pathway activity and persistent PI3K signaling. Mechanistically, cell fate reprogramming towards the Paneth cell-like phenotype was mediated by inactivation of YAP – a master regulator of intestinal epithelium recovery after injury – following cetuximab-induced neutralization of the MAPK cascade. Clinically, tumors from patients in whom cetuximab was not effective were enriched for markers of secretory commitment/Paneth-cell differentiation. In PDX therapeutic experiments, Pan-HER antibodies minimized residual disease burden and induced long-term tumor control after treatment discontinuation. We propose that tolerance to EGFR inhibition in CRC is typified by the adaptive disengagement of an in-built lineage program that jointly drives intestinal regenerative signaling and tumorigenesis. Further, our findings motivate therapeutic strategies to pre-emptively target residual disease before acquisition of irreversible resistance.
2020-05-06 | GSE108277 | GEO
Project description:The majority of EGFR mutant lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors (TKIs). However, most of these responses are partial with drug tolerant residual disease remaining even at the time of maximal response. This residual disease ultimately leads to relapses which eventually develop in most patients. To investigate the cellular and molecular properties of residual tumor cells in vivo, we leveraged patient-derived models of EGFR mutant lung cancer. Subcutaneous EGFR mutant PDXs were treated with the 3rd generation TKI osimertinib until maximal tumor regression. Residual tissue inevitably harbored tumor cells that were transcriptionally, but not mutationally, distinct from bulk pre-treatment tumor. Using single cell transcriptional profiling we found evidence of cells matching the profiles of drug-tolerant cells present in the pre-treatment tumor. In one of the PDXs analyzed, osimertinib treatment caused dramatic transcriptomic changes that featured upregulation of the neuroendocrine lineage transcription factor ASCL1. Mechanistically, we found that ASCL1 confers drug tolerance by initiating an epithelial-to-mesenchymal gene expression program in permissive cellular contexts. Our study reveals fundamental insights into the biology of drug tolerance, the plasticity of cells through TKI treatment and explains why specific phenotypes are only observed in certain tumors.
2024-02-06 | GSE243562 | GEO
Project description:The majority of EGFR mutant lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors (TKIs). However, most of these responses are partial with drug tolerant residual disease remaining even at the time of maximal response. This residual disease ultimately leads to relapses which eventually develop in most patients. To investigate the cellular and molecular properties of residual tumor cells in vivo, we leveraged patient-derived models of EGFR mutant lung cancer. Subcutaneous EGFR mutant PDXs were treated with the 3rd generation TKI osimertinib until maximal tumor regression. Residual tissue inevitably harbored tumor cells that were transcriptionally, but not mutationally, distinct from bulk pre-treatment tumor. Using single cell transcriptional profiling we found evidence of cells matching the profiles of drug-tolerant cells present in the pre-treatment tumor. In one of the PDXs analyzed, osimertinib treatment caused dramatic transcriptomic changes that featured upregulation of the neuroendocrine lineage transcription factor ASCL1. Mechanistically, we found that ASCL1 confers drug tolerance by initiating an epithelial-to-mesenchymal gene expression program in permissive cellular contexts. Our study reveals fundamental insights into the biology of drug tolerance, the plasticity of cells through TKI treatment and explains why specific phenotypes are only observed in certain tumors.
2024-02-06 | GSE243568 | GEO
Project description:The majority of EGFR mutant lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors (TKIs). However, most of these responses are partial with drug tolerant residual disease remaining even at the time of maximal response. This residual disease ultimately leads to relapses which eventually develop in most patients. To investigate the cellular and molecular properties of residual tumor cells in vivo, we leveraged patient-derived models of EGFR mutant lung cancer. Subcutaneous EGFR mutant PDXs were treated with the 3rd generation TKI osimertinib until maximal tumor regression. Residual tissue inevitably harbored tumor cells that were transcriptionally, but not mutationally, distinct from bulk pre-treatment tumor. Using single cell transcriptional profiling we found evidence of cells matching the profiles of drug-tolerant cells present in the pre-treatment tumor. In one of the PDXs analyzed, osimertinib treatment caused dramatic transcriptomic changes that featured upregulation of the neuroendocrine lineage transcription factor ASCL1. Mechanistically, we found that ASCL1 confers drug tolerance by initiating an epithelial-to-mesenchymal gene expression program in permissive cellular contexts. Our study reveals fundamental insights into the biology of drug tolerance, the plasticity of cells through TKI treatment and explains why specific phenotypes are only observed in certain tumors.
2024-02-06 | GSE243565 | GEO
Project description:The majority of EGFR mutant lung adenocarcinomas respond well to EGFR tyrosine kinase inhibitors (TKIs). However, most of these responses are partial with drug tolerant residual disease remaining even at the time of maximal response. This residual disease ultimately leads to relapses which eventually develop in most patients. To investigate the cellular and molecular properties of residual tumor cells in vivo, we leveraged patient-derived models of EGFR mutant lung cancer. Subcutaneous EGFR mutant PDXs were treated with the 3rd generation TKI osimertinib until maximal tumor regression. Residual tissue inevitably harbored tumor cells that were transcriptionally, but not mutationally, distinct from bulk pre-treatment tumor. Using single cell transcriptional profiling we found evidence of cells matching the profiles of drug-tolerant cells present in the pre-treatment tumor. In one of the PDXs analyzed, osimertinib treatment caused dramatic transcriptomic changes that featured upregulation of the neuroendocrine lineage transcription factor ASCL1. Mechanistically, we found that ASCL1 confers drug tolerance by initiating an epithelial-to-mesenchymal gene expression program in permissive cellular contexts. Our study reveals fundamental insights into the biology of drug tolerance, the plasticity of cells through TKI treatment and explains why specific phenotypes are only observed in certain tumors.
2024-02-06 | GSE243564 | GEO
Project description:Patient-derived tumor xenografts (PDXs) increasingly are being used as preclinical models to study human cancers and to evaluate novel therapeutics, as they reflect clinical cancers more closely than established tumor cell lines. With >100 PDXs established from resected non-small cell lung carcinomas (NSCLC), we reported previously that xenograftability correlates significantly with poorer patient prognosis. In this study, genomic, transcriptomic, and proteomic profiling of 36 PDXs showed greater similarity in somatic alterations between PDX and primary tumors than with cell lines, using publicly available data on the latter. A higher number of somatic alterations among 865 frequently altered genes in the PDX tumors was associated with better overall patient survival (HR=0.15, p=0.00015) compared to patients with corresponding PDXs characterized by a lower number of alterations; this was validated with the TCGA lung cancer patient dataset (HR=0.28, p=0.000022). These passenger-like alterations, identified in PDXs, link cell-cell signaling and adhesion to patient prognosis.
2016-10-26 | GSE68929 | GEO