Intratumoural Heterogeneity Underlies Distinct Therapy Responses and Treatment Resistance in Glioblastoma
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ABSTRACT:
PROVIDER: EGAS00001003438 | EGA |
REPOSITORIES: EGA
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Project description:Large-scale genomic profiling efforts have facilitated the characterization of molecular alterations in cancers and aided the development of targeted kinase inhibitors for a wide array of cancer types. However, resistance to these targeted therapies invariably develops and limits their clinical efficacy. Targeting tumours with kinase inhibitors induces complex adaptive survival programs that promote the persistence of a fraction of the original cancer cell population, facilitating the eventual outgrowth of inhibitor-resistant tumour clones following clonal evolution. Here we show that the addition of a newly identified transcriptional repressor, THZ1, to targeted cancer therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in cellular and in vivo cancer models with diverse genetic dependencies. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant. THZ1 can exploit this dependency by blocking dynamic transcriptional responses, remodelling of enhancers and key signalling outputs required for tumour cell survival in the setting of targeted cancer therapies. These findings suggest that the addition of THZ1 to targeted cancer therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations.
2017-10-23 | GSE89128 | GEO
Project description:Large-scale genomic profiling efforts have facilitated the characterization of molecular alterations in cancers and aided the development of targeted kinase inhibitors for a wide array of cancer types. However, resistance to these targeted therapies invariably develops and limits their clinical efficacy. Targeting tumours with kinase inhibitors induces complex adaptive survival programs that promote the persistence of a fraction of the original cancer cell population, facilitating the eventual outgrowth of inhibitor-resistant tumour clones following clonal evolution. Here we show that the addition of a newly identified transcriptional repressor, THZ1, to targeted cancer therapy enhances cell killing and impedes the emergence of drug-resistant cell populations in cellular and in vivo cancer models with diverse genetic dependencies. We propose that targeted therapy induces a state of transcriptional dependency in a subpopulation of cells poised to become drug tolerant. THZ1 can exploit this dependency by blocking dynamic transcriptional responses, remodelling of enhancers and key signalling outputs required for tumour cell survival in the setting of targeted cancer therapies. These findings suggest that the addition of THZ1 to targeted cancer therapies is a promising broad-based strategy to hinder the emergence of drug-resistant cancer cell populations.
2017-10-23 | GSE89127 | GEO
Project description:Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer with high intra-tumoral heterogeneity, frequently resistant to treatment and no known targeted therapy available to improve patient outcomes. It has been hypothesized that the genomic architecture of a TNBC tumour evolves over time, both before, and during therapy, leading to therapy resistance and a high propensity to relapse. Whether this is an inherent property of the tumour or acquired over time is not well characterized. Despite this important clinical implication, limited studies have been carried out to unravel temporal evolution of TNBC over time. Herein, we report an OMICS based analysis of three TNBC patients who were longitudinally sampled during their treatment at different times of relapse. We recruited three TNBC patients at the time of their first relapse who were then followed-up through the course of their treatment. We obtained retrospective samples (tumour samples) from patient tumours at diagnosis (before neo-adjuvant chemotherapy - NACT) at surgery (post NACT) and prospectively sampled them at each subsequent relapse (tumour, blood plasma, and buffy coat) as determined by RECIST criteria. Tumor and buffy coat DNA were subjected to whole exome sequencing (WES) at 200x, and SNP arrays for copy number variation (CNV) analysis. RNA from tumour samples at relapse was subjected to whole transcriptome sequencing. Pathogenic germline BRCA1 variants identified in WES were validated using Sanger sequencing. 1084 somatic mutations identified in whole exome sequencing of all tumour tissues (n=13) from three patients, were subjected to a custom amplicon ultra-deep sequencing assay at 30,000X in their germline DNA (n=3), tumour DNA (n=10), and cfDNA from plasma samples at relapse (n=8). Copy number corrected allele frequencies, tumour ploidy, tumour purity, and ultra-deep sequencing assay derived variant allele frequencies were used to infer clonal and phylogenetic architecture of each patient as it evolved under selective pressure of therapy over time. Clonality analysis incorporating allele fractions from ultra-deep sequencing identified clones comprising of mutations that are present throughout the course of therapy which we term as founding clones and stem mutations respectively. Such founding clones comprising of stem mutations in all 3 patients were present throughout the course of treatment, irrespective of change in treatment modalities. These stem clones included well characterized cancer related genes like PDGFRB & ARID2 (Patient 02), TP53, BRAF & CSF3R (Patient 04) and ESR1, APC, EZH2 & TP53 (Patient 07). Such branching evolution is seen in all three patients wherein the dominant clone (stem clone) acquires additional mutations to form sub-clones, while persisting over time. These sub-clones may be chemo and radio resistant, while also providing for organ specific metastatic potential. Allele fractions of expressed variants inferred from RNA-Seq data co-related with allele fractions from WES data indicating that all somatic.
2022-12-30 | E-MTAB-11909 | biostudies-arrayexpress
Project description:Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer with high intra-tumoral heterogeneity, frequently resistant to treatment and no known targeted therapy available to improve patient outcomes. It has been hypothesized that the genomic architecture of a TNBC tumour evolves over time, both before, and during therapy, leading to therapy resistance and a high propensity to relapse. Whether this is an inherent property of the tumour or acquired over time is not well characterized. Despite this important clinical implication, limited studies have been carried out to unravel temporal evolution of TNBC over time. Herein, we report an OMICS based analysis of three TNBC patients who were longitudinally sampled during their treatment at different times of relapse. We recruited three TNBC patients at the time of their first relapse who were then followed-up through the course of their treatment. We obtained retrospective samples (tumour samples) from patient tumours at diagnosis (before neo-adjuvant chemotherapy - NACT) at surgery (post NACT) and prospectively sampled them at each subsequent relapse (tumour, blood plasma, and buffy coat) as determined by RECIST criteria. Tumor and buffy coat DNA were subjected to whole exome sequencing (WES) at 200x, and SNP arrays for copy number variation (CNV) analysis. RNA from tumour samples at relapse was subjected to whole transcriptome sequencing. Pathogenic germline BRCA1 variants identified in WES were validated using Sanger sequencing. 1084 somatic mutations identified in whole exome sequencing of all tumour tissues (n=13) from three patients, were subjected to a custom amplicon ultra-deep sequencing assay at 30,000X in their germline DNA (n=3), tumour DNA (n=10), and cfDNA from plasma samples at relapse (n=8). Copy number corrected allele frequencies, tumour ploidy, tumour purity, and ultra-deep sequencing assay derived variant allele frequencies were used to infer clonal and phylogenetic architecture of each patient as it evolved under selective pressure of therapy over time. Clonality analysis incorporating allele fractions from ultra-deep sequencing identified clones comprising of mutations that are present throughout the course of therapy which we term as founding clones and stem mutations respectively. Such founding clones comprising of stem mutations in all 3 patients were present throughout the course of treatment, irrespective of change in treatment modalities. These stem clones included well characterized cancer related genes like PDGFRB & ARID2 (Patient 02), TP53, BRAF & CSF3R (Patient 04) and ESR1, APC, EZH2 & TP53 (Patient 07). Such branching evolution is seen in all three patients wherein the dominant clone (stem clone) acquires additional mutations to form sub-clones, while persisting over time. These sub-clones may be chemo and radio resistant, while also providing for organ specific metastatic potential. Allele fractions of expressed variants inferred from RNA-Seq data co-related with allele fractions from WES data indicating that all somatic.
2023-08-09 | E-MTAB-11375 | biostudies-arrayexpress
Project description:Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer with high intra-tumoral heterogeneity, frequently resistant to treatment and no known targeted therapy available to improve patient outcomes. It has been hypothesized that the genomic architecture of a TNBC tumour evolves over time, both before, and during therapy, leading to therapy resistance and a high propensity to relapse. Whether this is an inherent property of the tumour or acquired over time is not well characterized. Despite this important clinical implication, limited studies have been carried out to unravel temporal evolution of TNBC over time. Herein, we report an OMICS based analysis of three TNBC patients who were longitudinally sampled during their treatment at different times of relapse. We recruited three TNBC patients at the time of their first relapse who were then followed-up through the course of their treatment. We obtained retrospective samples (tumour samples) from patient tumours at diagnosis (before neo-adjuvant chemotherapy - NACT) at surgery (post NACT) and prospectively sampled them at each subsequent relapse (tumour, blood plasma, and buffy coat) as determined by RECIST criteria. Tumor and buffy coat DNA were subjected to whole exome sequencing (WES) at 200x, and SNP arrays for copy number variation (CNV) analysis. RNA from tumour samples at relapse was subjected to whole transcriptome sequencing. Pathogenic germline BRCA1 variants identified in WES were validated using Sanger sequencing. 1084 somatic mutations identified in whole exome sequencing of all tumour tissues (n=13) from three patients, were subjected to a custom amplicon ultra-deep sequencing assay at 30,000X in their germline DNA (n=3), tumour DNA (n=10), and cfDNA from plasma samples at relapse (n=8). Copy number corrected allele frequencies, tumour ploidy, tumour purity, and ultra-deep sequencing assay derived variant allele frequencies were used to infer clonal and phylogenetic architecture of each patient as it evolved under selective pressure of therapy over time. Clonality analysis incorporating allele fractions from ultra-deep sequencing identified clones comprising of mutations that are present throughout the course of therapy which we term as founding clones and stem mutations respectively. Such founding clones comprising of stem mutations in all 3 patients were present throughout the course of treatment, irrespective of change in treatment modalities. These stem clones included well characterized cancer related genes like PDGFRB & ARID2 (Patient 02), TP53, BRAF & CSF3R (Patient 04) and ESR1, APC, EZH2 & TP53 (Patient 07). Such branching evolution is seen in all three patients wherein the dominant clone (stem clone) acquires additional mutations to form sub-clones, while persisting over time. These sub-clones may be chemo and radio resistant, while also providing for organ specific metastatic potential. Allele fractions of expressed variants inferred from RNA-Seq data co-related with allele fractions from WES data indicating that all somatic.
2023-08-09 | E-MTAB-11379 | biostudies-arrayexpress
Project description:Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer with high intra-tumoral heterogeneity, frequently resistant to treatment and no known targeted therapy available to improve patient outcomes. It has been hypothesized that the genomic architecture of a TNBC tumour evolves over time, both before, and during therapy, leading to therapy resistance and a high propensity to relapse. Whether this is an inherent property of the tumour or acquired over time is not well characterized. Despite this important clinical implication, limited studies have been carried out to unravel temporal evolution of TNBC over time. Herein, we report an OMICS based analysis of three TNBC patients who were longitudinally sampled during their treatment at different times of relapse. We recruited three TNBC patients at the time of their first relapse who were then followed-up through the course of their treatment. We obtained retrospective samples (tumour samples) from patient tumours at diagnosis (before neo-adjuvant chemotherapy - NACT) at surgery (post NACT) and prospectively sampled them at each subsequent relapse (tumour, blood plasma, and buffy coat) as determined by RECIST criteria. Tumor and buffy coat DNA were subjected to whole exome sequencing (WES) at 200x, and SNP arrays for copy number variation (CNV) analysis. RNA from tumour samples at relapse was subjected to whole transcriptome sequencing. Pathogenic germline BRCA1 variants identified in WES were validated using Sanger sequencing. 1084 somatic mutations identified in whole exome sequencing of all tumour tissues (n=13) from three patients, were subjected to a custom amplicon ultra-deep sequencing assay at 30,000X in their germline DNA (n=3), tumour DNA (n=10), and cfDNA from plasma samples at relapse (n=8). Copy number corrected allele frequencies, tumour ploidy, tumour purity, and ultra-deep sequencing assay derived variant allele frequencies were used to infer clonal and phylogenetic architecture of each patient as it evolved under selective pressure of therapy over time. Clonality analysis incorporating allele fractions from ultra-deep sequencing identified clones comprising of mutations that are present throughout the course of therapy which we term as founding clones and stem mutations respectively. Such founding clones comprising of stem mutations in all 3 patients were present throughout the course of treatment, irrespective of change in treatment modalities. These stem clones included well characterized cancer related genes like PDGFRB & ARID2 (Patient 02), TP53, BRAF & CSF3R (Patient 04) and ESR1, APC, EZH2 & TP53 (Patient 07). Such branching evolution is seen in all three patients wherein the dominant clone (stem clone) acquires additional mutations to form sub-clones, while persisting over time. These sub-clones may be chemo and radio resistant, while also providing for organ specific metastatic potential. Allele fractions of expressed variants inferred from RNA-Seq data co-related with allele fractions from WES data indicating that all somatic.
2023-08-18 | E-MTAB-11376 | biostudies-arrayexpress
Project description:The naïve polyclonal CD4 T cell repertoire can differentiate into multiple lineages during acute viral infection, with some T cell clones exhibiting a preferred lineage choice. TCR α CDR3 motifs can partially influence a clone-intrinsic lineage preference towards TFH fate.
2020-11-10 | GSE158896 | GEO
Project description:<p>Although multi-agent combination chemotherapy is curative in a significant fraction of childhood acute lymphoblastic leukemia (ALL) patients, 20% of cases relapse and most die due to chemo-refractory disease. Here we used whole-exome and whole-genome sequencing to analyze the mutational landscape and pattern of clonal evolution at relapse in pediatric ALL cases. These analyses showed that ALL relapses originate from a common ancestral precursor clone of the diagnosis and relapsed populations and frequently harbor mutations implicated in chemotherapy resistance. RAS-MAPK pathway activating mutations in NRAS, KRAS and PTPN11 were present in 24/55 (44%) cases in our series. Notably, while some cases showed emergence of RAS mutant clones at relapse, in others, RAS mutant clones present at diagnosis were replaced by RAS wild type populations. Mechanistically, functional dissection of mouse and human wild type Kras and mutant Kras (Kras G12D) isogenic leukemia cells demonstrated induction of methotrexate resistance, but also improved response to vincristine, in mutant Kras- expressing lymphoblasts. These results identify chemotherapy driven selection as a central mechanism of leukemia clonal evolution and pave the road for the development of tailored personalized therapies for the treatment of relapsed ALL. </p>
| phs001072 | dbGaP
Project description:Cancer cells exhibit dramatic differences in gene expression at the single-cell level which can predict whether they become resistant to treatment. Treatment perpetuates this heterogeneity, resulting in a diversity of cell states among resistant clones. However, it remains unclear whether these differences lead to distinct responses when another treatment is applied or the same treatment is continued. In this study, we combined single-cell RNA-sequencing with barcoding to track resistant clones through prolonged and sequential treatments. We found that cells within the same clone have similar gene expression states after multiple rounds of treatment. Moreover, we demonstrated that individual clones have distinct and differing fates, including growth, survival, or death, when subjected to a second treatment or when the first treatment is continued. By identifying gene expression states that predict clone survival, this work provides a foundation for selecting optimal therapies that target the most aggressive resistant clones within a tumor.
2024-01-23 | GSE253739 | GEO
Project description:Multiple BRAF inhibitor resistance mechanisms have been described, however their relative frequency, clinical correlates, and effect on subsequent therapy have not been assessed in patients with metastatic melanoma. Excised progressing BRAFV600 mutant melanoma metastases (Prog) from patients treated with dabrafenib (n=22) or vemurafenib (n=8) were analyzed for known resistance mechanisms. Oncogenic signaling in Prog and matched pre-treatment tumors was examined using gene expression analysis. Resistance mechanisms were correlated with clinicopathologic features and outcome. A resistance mechanism was identified in 21/38 (55%) Prog samples from 30 patients; BRAF splice variants (n=12, 32%), N-RAS mutations (n=3, 8%), BRAF amplification (n=3, 8%), MEK1/2 mutations (n=3, 8%) and an AKT1 mutation (n=1, 3%). Four Progs tumours displayed multiple resistance mechanisms, and four patients with multiple Progs demonstrated inter-tumoral heterogeneity of resistance mechanisms. Six (21%) of 29 Progs showed loss of MAPK activity by gene expression analysis. These MAPK-inhibited Progs had unknown resistance mechanisms, and these patients had a shorter progression-free survival than patients with MAPK re-activated Progs. There were no responses to subsequent targeted therapy, even when the identified mechanism of resistance was predicted to be responsive. Heterogeneity of resistance mechanisms was common between patients, within patients and within individual tumors. The MAPK pathway remained inhibited in a subset of resistant tumors with unknown mechanisms of resistance, and the outcomes of patients with these tumors are poor. The use of sequential targeted therapies based on the molecular characteristics of a single progressing biopsy is unlikely to provide improved clinical outcomes. Total RNA was obtained from fresh-frozen melanoma tumour samples from patients before commencing treatment with dabrafenib or vemurafenib and at time of tumour progression.
2014-02-19 | E-GEOD-50509 | biostudies-arrayexpress