Impact of EMT-driven plasticity on phenotypic diversity dynamics under chemotherapy [organoids]
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1098863 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28622003.fastq.gz | Fastqsanger.gz | |||
| SRR28622004.fastq.gz | Fastqsanger.gz | |||
| SRR28622005.fastq.gz | Fastqsanger.gz | |||
| SRR28622006.fastq.gz | Fastqsanger.gz | |||
| SRR28622007.fastq.gz | Fastqsanger.gz |
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Project description:Impact of EMT-driven plasticity on phenotypic diversity dynamics under chemotherapy [spontaneous]
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Project description:Triple negative breast cancer (TNBC) is the most lethal breast cancer subgroup, as lack of targeted therapies and drug resistance reduce survival rates. Cellular plasticity enables cells to adapt non-genetically and overcome therapeutic pressure, thereby embodying a critical clinical hurdle. The epithelial-mesenchymal transition (EMT) is an example of phenotypic reprogramming linked to plasticity, drug resistance and metastasis. However, its exact impact on population diversity under therapeutic pressure is unknown. Here, we used single cell transcriptomics to investigate phenotypic diversity dynamics upon drug treatment in two human in vitro models of TNBC plasticity.
2024-12-04 | GSE263728 | GEO
Project description:Triple negative breast cancer (TNBC) is the most lethal breast cancer subgroup, as lack of targeted therapies and drug resistance reduce survival rates. Cellular plasticity enables cells to adapt non-genetically and overcome therapeutic pressure, thereby embodying a critical clinical hurdle. The epithelial-mesenchymal transition (EMT) is an example of phenotypic reprogramming linked to plasticity, drug resistance and metastasis. However, its exact impact on population diversity under therapeutic pressure is unknown. Here, we used single cell transcriptomics to investigate phenotypic diversity dynamics upon drug treatment in two human in vitro models of TNBC plasticity.
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Project description:The resistance of cancer cells to therapy is responsible for the death of most cancer patients. Epithelial-to-mesenchymal transition (EMT) has been associated with resistance to therapy in different cancer cells. However, the mechanisms by which EMT mediates resistance to therapy remain poorly understood. Here, using a mouse model of skin squamous cell carcinoma (SCC) undergoing spontaneous EMT during tumorigenesis, we found that EMT tumor cells were highly resistant to a wide range of anti-cancer therapy both in-vivo and in-vitro. Using gain and loss of function in vitro and in vivo, we uncovered that RhoJ, a small GTPase preferentially expressed in EMT cancer cells, controls resistance to therapy. Using genome-wide transcriptomic and proteomic profiling, we found that RhoJ regulates EMT associated resistance to chemotherapy by promoting DNA damage response and the formation of new replication forks allowing tumor cells to repair DNA lesions more rapidly and survive under the replicative stress induced by chemotherapy. Using affinity-purification followed by mass spectrometry, we found that RhoJ interacts with proteins regulating nuclear actin and the inhibition of actin polymerization sensitizes EMT tumor cells to chemotherapy induced cell death in a Rhoj dependent manner. Altogether, our study uncovers the role and the mechanisms by which RhoJ acts as a key regulator of EMT associated resistance to chemotherapy.
2023-01-13 | PXD038278 | Pride
Project description:The resistance of cancer cell to therapy is responsible of the death of most cancer patients. Epithelial to mesenchymal transitions (EMT) has been associated with resistance to therapy in different cancer cells. However, the mechanisms by which EMT mediates resistance to therapy remain poorly understood. Here, using a mouse model of skin squamous cell carcinoma (SCC) undergoing spontaneous EMT during tumorigenesis, we identified EMT tumor subpopulations displaying different intrinsic resistance mechanisms to a wide range of anti-cancer therapy both in-vivo and in-vitro. We found that RhoJ, a small GTPase, preferentially expressed in EMT cancer cells controls resistance to therapy. Using genome-wide transcriptomic and proteomic profiling combined with functional assays following loss of RhoJ functions, we found that RhoJ regulated EMT associated resistance to chemotherapy by promoting DNA damage response and the formation of new replication forks allowing EMT tumor cells to repair DNA lesions more rapidly and survive under the replicative stress induced by chemotherapy. Altogether, our study uncovers RhoJ as a key regulator of EMT associated resistance to chemotherapy with important implications for the development of new strategies to overcome resistance to therapy in cancer.
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Project description:Cancer stem cells (CSCs) drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC), we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44highEpCAMlow/-CD24+ cell surface marker profile. Treatment with TGFβ and retinoic acid (RA) enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER) stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs. The CA1 OSCC cell line was sub-cloned to derive 4 clonal sub-lines, termed pEMT-P, pEMT-S, Epi-S and Epi-P (here 18, 23, 7 and 4 respectively).
2016-01-12 | E-GEOD-74578 | biostudies-arrayexpress
Project description:Cancer stem cells (CSCs) drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC), we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44highEpCAMlow/-CD24+ cell surface marker profile. Treatment with TGFβ and retinoic acid (RA) enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER) stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs. The clonal derivative of the CA1 OSCC cell line termed 18 here (otherwise termed pEMT-P) was treated with 0.5ng/ml TGFbeta and/or 5uM RA for eight days, with media changed every second day. The LM OSCC cell line was FACS sorted to recover the CD44highEpCAMlowCD24+ sub-population, which was then treated with 0.5ng/ml TGFbeta and/or 5uM RA for eight days, with media changed every second day. The parental CA1 and LM cell lines are included as reference samples.
2016-01-12 | E-GEOD-74580 | biostudies-arrayexpress
Project description:Cancer therapeutic resistance is mediated, in part, by phenotypic heterogeneity and the plasticity of tumor cells, the latter being enabled by Epithelial-Mesenchymal Transition (EMT). However, EMT in human cancer therapeutic response remain poorly understood. We developed patient-derived organoids (PDOs) from human triple-negative breast cancer (TNBC) and investigated their response to chemotherapy. We found that chemotherapy treatment kills the bulk of tumor cells in PDOs, but there is selective survival of malignant cells that had activated an EMT program, entered a quasi-mesenchymal, stem cell-like state and display primary cilia. We developed a family of small-molecule inhibitors of ciliogenesis and show that treatment with these inhibitors, or genetic ablation of primary cilia, is sufficient to suppress this chemoresistance via NFB-induced cell death. We conclude that an EMT-ciliary signaling axis induces chemoresistance in quasi-mesenchymal stem-like cells to help tumors evade chemotherapy and represents a druggable vulnerability in human TNBC.
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Project description:Cancer stem cells (CSCs) drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC), we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44highEpCAMlow/-CD24+ cell surface marker profile. Treatment with TGFβ and retinoic acid (RA) enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER) stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs.
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Project description:Cancer stem cells (CSCs) drive tumour spread and therapeutic resistance, and can undergo epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) to switch between epithelial and post-EMT sub-populations. Examining oral squamous cell carcinoma (OSCC), we now show that increased phenotypic plasticity, the ability to undergo EMT/MET, underlies increased CSC therapeutic resistance within both the epithelial and post-EMT sub-populations. The post-EMT CSCs that possess plasticity exhibit particularly enhanced therapeutic resistance and are defined by a CD44highEpCAMlow/-CD24+ cell surface marker profile. Treatment with TGFβ and retinoic acid (RA) enabled enrichment of this sub-population for therapeutic testing, through which the endoplasmic reticulum (ER) stressor and autophagy inhibitor Thapsigargin was shown to selectively target these cells. Demonstration of the link between phenotypic plasticity and therapeutic resistance, and development of an in vitro method for enrichment of a highly resistant CSC sub-population, provides an opportunity for the development of improved chemotherapeutic agents that can eliminate CSCs.
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