Genomic alterations and transcriptional phenotypes in circulating tumor DNA and matched metastatic tumor
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1125929 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Genomic alterations and transcriptional phenotypes in circulating tumor DNA and matched metastatic tumor
| PRJNA1125930 | ENA
Project description:BackgroundProfiling circulating cell-free DNA (cfDNA) has become a fundamental practice in cancer medicine, but the effectiveness of cfDNA at elucidating tumor-derived molecular features has not been systematically compared to standard single-lesion tumor biopsies in prospective cohorts of patients. The use of plasma instead of tissue to guide therapy is particularly attractive for patients with small cell lung cancer (SCLC), a cancer whose aggressive clinical course making it exceedingly challenging to obtain tumor biopsies.MethodsHere, a prospective cohort of 49 plasma samples obtained before, during, and after treatment from 20 patients with recurrent SCLC, we study cfDNA low pass whole genome (0.1X coverage) and exome (130X) sequencing in comparison with time-point matched tumor, characterized using exome and transcriptome sequencing.ResultsDirect comparison of cfDNA versus tumor biopsy reveals that cfDNA not only mirrors the mutation and copy number landscape of the corresponding tumor but also identifies clinically relevant resistance mechanisms and cancer driver alterations not found in matched tumor biopsies. Longitudinal cfDNA analysis reliably tracks tumor response, progression, and clonal evolution. Genomic sequencing coverage of plasma DNA fragments around transcription start sites shows distinct treatment-related changes and captures the expression of key transcription factors such as NEUROD1 and REST in the corresponding SCLC tumors, allowing prediction of SCLC neuroendocrine phenotypes and treatment responses.ConclusionsThese findings have important implications for non-invasive stratification and subtype-specific therapies for patients with SCLC, now treated as a single disease.
| S-EPMC11185519 | biostudies-literature
Project description:BackgroundProfiling circulating cell-free DNA (cfDNA) has become a fundamental practice in cancer medicine, but the effectiveness of cfDNA at elucidating tumor-derived molecular features has not been systematically compared to standard single-lesion tumor biopsies in prospective cohorts of patients. The use of plasma instead of tissue to guide therapy is particularly attractive for patients with small cell lung cancer (SCLC), due to the aggressive clinical course of this cancer, which makes obtaining tumor biopsies exceedingly challenging.MethodsIn this study, we analyzed a prospective cohort of 49 plasma samples obtained before, during, and after treatment from 20 patients with recurrent SCLC. We conducted cfDNA low-pass whole genome sequencing (0.1X coverage), comparing it with time-point matched tumor characterized using whole-exome (130X) and transcriptome sequencing.ResultsA direct comparison of cfDNA and tumor biopsy revealed that cfDNA not only mirrors the mutation and copy number landscape of the corresponding tumor but also identifies clinically relevant resistance mechanisms and cancer driver alterations not detected in matched tumor biopsies. Longitudinal cfDNA analysis reliably tracks tumor response, progression, and clonal evolution. Sequencing coverage of plasma DNA fragments around transcription start sites showed distinct treatment-related changes and captured the expression of key transcription factors such as NEUROD1 and REST in the corresponding SCLC tumors. This allowed for the prediction of SCLC neuroendocrine phenotypes and treatment responses.ConclusionscfDNA captures a comprehensive view of tumor heterogeneity and evolution. These findings have significant implications for the non-invasive stratification of SCLC, a disease currently treated as a single entity.
| S-EPMC11863907 | biostudies-literature
Project description:We profiled the tumor heterogeneity of individual primary tumor and matched metastatic cells of breast cancer using a set of patient derived xenograft models with different metastatic potentials. This data set gives insights into the transcriptional tumor heterogeneity, the transcriptional differences between primary tumor and matched metastatic cells and how these are changing in regard to varying metastatic phenotypes.
2022-08-15 | GSE211146 | GEO
Project description:Circulating Tumor Cells (CTCs) are shed from primary tumors into the bloodstream, mediating the hematogenous spread of cancer to distant organs. Using a pancreatic cancer mouse model, we applied a microfluidic device to isolate CTCs independently of tumor epitopes, subjecting these to single cell RNA-sequencing. This study was conducted to determine the heterogeneity of pancreatic CTCs and to compare these CTCs to matched primary tumors, cell line controls (NB508 cancer cell line and MEF non-cancer cell line), primary tumor single cells, and normal leukocytes/WBCs. We profiled RNA from 75 single cells circulating in mouse blood enriched for circulating tumor cells from 5 mice, 12 single cells from a mouse embryonic fibroblast cell line, 16 single cells from the nb508 mouse pancreatic cancer cell line, 12 single mouse white blood cells, 18 single GFP lineage-traced circulating tumor cells from two mice, 20 single GFP lineage-traced cancer cells from the primary pancreatic tumor of a mouse, and 34 dilutions to 10 or 100 picograms of total RNA from mouse primary pancreatic tumors from 4 mice.
2014-09-22 | E-GEOD-51372 | biostudies-arrayexpress
Project description:Extracellular vesicles (EVs) secreted by tumors are abundant in plasma, but their potential for multi-omic profiling remains widely unexplored. Here, we pursued next-generation sequencing of circulating EV-DNA and EV-RNA in metastatic prostate cancer (mPC), using a range of in-vitro and in-vivo models, validating our findings in 35 mPC patients with longitudinal samples collected during androgen receptor signaling inhibitor (ARSI) therapy. EV-DNA copy-number (CN) profiles matched same-patient biopsies and ctDNA (p<0.001) and EV-DNA tumor fraction (TF) associated with shorter time to progression. We developed a novel approach for studying mRNA in circulating EVs (RExCuE), showing high correlation between EV-RNA and tumor biopsies (r>0.7, p<0.001). EV-RNAseq signatures at 4 weeks of therapy associated with clinical responses. Last, we derived a specific signature of ARSI response in EV-RNA in vivo that predicted response to therapy. In conclusion, EV profiling enables the study of mPC evolution at transcriptomics level in liquid biopsies.
2024-06-30 | GSE221709 | GEO
Project description:While cytotoxic CD4+ tumor-infiltrating lymphocytes have anti-cancer activity in patients, whether these can be non-invasively monitored and how these are regulated remains obscure. By matching single cells with T cell receptors (TCR) in tumor and blood of bladder cancer patients, we identified distinct pools of tumor-matching cytotoxic CD4+ T cells in the periphery directly reflecting the predominant antigenic specificities of intratumoral CD4+ TILs. On one hand, the granzyme B (GZMB)-expressing cytotoxic CD4+ subset proliferated in blood in response to PD-1 blockade, but was separately regulated by the killer cell lectin-like receptor G1 (KLRG1) which inhibited their killing by interacting with E-cadherin. Conversely, a clonally related, granzyme K (GZMK)-expressing circulating CD4+ population demonstrated basal proliferation and a memory phenotype that may result from activation of GZMB+ cells, but was not directly mobilized by PD-1 blockade. As KLRG1 marked the majority of circulating tumor TCR-matched cytotoxic CD4+ T cells, this work nominates KLRG1 as a means to isolate them from blood and provide a window into intratumoral CD4+ recognition, as well as a putative regulatory receptor to mobilize the cytolytic GZMB+ subset for therapeutic benefit. Our findings also underscore the ontogenic relationship of GZMB- and GZMK-expressing populations and the distinct cues that regulate their activity.
2025-04-04 | GSE293860 | GEO
Project description:Identification and regulation of circulating tumor TCR-matched cytotoxic CD4+ lymphocytes by KLRG1 in bladder cancer
| PRJNA1246607 | ENA
Project description:Self-sufficiency (autonomy) in growth signaling, the earliest recognized hallmark of cancer, is fuelled by the tumor cell’s ability to ‘secrete-and-sense’ growth factors; this translates into cell survival and proliferation that is self-sustained by auto-/paracrine secretion. Using breast cancer cells that are either endowed or inept in growth signaling autonomy, here we reveal how tumor cell autonomy impacts cancer progression. Autonomy is associated with enhanced molecular programs for stemness, immune evasiveness, and epithelial-mesenchymal plasticity (EMP) across the entire mesenchymal spectrum. Autonomy is both necessary and sufficient for anchorage-independent growth factor-restricted growth, resistance to anti-cancer drugs and metastatic progression. Transcriptomic and proteomic studies show that autonomy is associated with self-sustained EGFR/ERBB signaling, a required signal for re-epithelialization. A gene expression signature was derived (a.k.a., autonomy signature) which revealed that autonomy is induced in circulating tumor cells (CTCs), the precursor tumor cells that re-epithelialize to initiate metastases. Autonomy in CTCs tracks therapeutic response and prognosticates outcome. Autonomy is present during reversible (but not stable) EMT and requires EGFR/ERBB signaling. These data support a role for growth signaling autonomy in the blood-borne dissemination of human breast cancer.
2023-02-06 | PXD037253 | Pride
Project description:Metastasis accounts for the majority of all cancer deaths, yet the process remains poorly understood. A pivotal step in the metastasis process is the exiting of tumor cells from the circulation, a process known as extravasation. However, it is unclear how tumor cells extravasate, and if multicellular clusters of tumor cells posses the ability to exit as a whole or must first disassociate. In this study, we use in vivo zebrafish and mouse models to elucidate the mechanism tumor cells use to extravasate. We found that circulating tumor cells exit the circulation using the recently identified extravasation mechanism, angiopellosis, and do as both clusters and individual cells. We further show that when melanoma and cervical cancer cells utilize this extravasation method to exit as clusters, they exhibit an increased ability to form tumor at distant sites through the expression of unique genetic profiles. Collectively, we present a new model for tumor cell extravasation of both individual and multicellular circulating tumor cells.
2019-08-26 | GSE132583 | GEO