Similar Datasets
Project description:We investigate non-genomic mechanisms determining cellular response to EGFR inhibitors in triple negative breast cancer (TNBC). We integrate methods for cellular barcoding and single-cell transcriptomics to enable cell lineage tracing and explore the subclonal evolution of adaptation in an established preclinical model of TNBC in response to incremental concentrations of Afatinib, a second generation EGFR-TKI that irreversibly inhibits both EGFR and HER2. Retrospective lineage tracing data analysis uncovered a pre-existing subpopulation of rare Afatinib-tolerant cells displaying distinct biological features, such as elevated mRNA levels of the IGFBP2 gene. Furthermore, we investigated temporal coordination of transcriptional programs in drug resistant clones with high replication fitness by reordering cells along a pseudotime trajectory. Interestingly, it revealed the activation of biological processes, such as fatty acid metabolism, which have previously been linked to EGFR-TKIs resistance mechanisms.
2024-03-25 | GSE228154 | GEO
Project description:Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer.
| PRJNA949598 | ENA
Project description:Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer
| PRJNA948402 | ENA
Project description:Colon cancers are composed of phenotypically heterogeneous tumor cell subpopulations with variable expression of putative stem cell and differentiation antigens. While in normal colonic mucosa, clonal repopulation occurs along differentiation gradients from crypt base toward crypt apex, the clonal architecture of colon cancer and the relevance of tumor cell subpopulations for clonal outgrowth are poorly understood. Using a multicolor lineage tracing approach in colon cancer xenografts that reflect primary colon cancer architecture, we here demonstrate that clonal outgrowth is mainly driven by tumor cells located at the leading tumor edge with clonal axis formation toward the tumor center. While our findings are compatible with lineage outgrowth in a cancer stem cell model, they suggest that in colorectal cancer tumor cell position may be more important for clonal outgrowth than tumor cell phenotype.
| S-EPMC5681634 | biostudies-literature
Project description:Triple negative breast cancer (TNBC) is marked by a lack of expression of the Estrogen Receptor, Progesterone Receptor, and human epidermal growth factor receptor 2. Therefore, targeted therapies are being investigated based on the expression profiles of tumors. Due to the potential for acquired and intrinsic resistance, there is a need for combination therapy to overcome resistance. In the article by Lee et al., the authors identify that, while prexasertib (a CHK1 inhibitor) lacks efficacy alone, combination with an EGFR inhibitor provides synergistic anti-tumor effects. Advances in targeted therapy for TNBC will benefit the clinical landscape for this disease, with this study initiating a new avenue of investigation.
| S-EPMC8992589 | biostudies-literature
Project description:Current EGFR-targeted therapy for triple negative breast cancer (TNBC) has produced disappointing results. A rational therapeutic strategy to improve EGFR-targeted treatment for TNBC is therefore needed. In this study we evaluated the feasibility of treating TNBC using photoacoustic imaging (PAI)-guided near-infrared photothermal therapy (NIR-PTT) with anti-EGFR-conjugated gold nanorods (anti-EGFR-GN). NIR-PTT combined with anti-EGFR-GN exerted synergistic anti-proliferative and apoptotic actions through upregulation of HSP70 and cleaved caspase-3, downregulation of Ki-67 and EGFR, and inhibition of several intracellular signaling molecules (mTOR, AKT, ERK1/2 and FAK). These combined effects give this approach significant efficacy. Our findings suggest PAI-guided NIR-PTT using anti-EGFR-GN represent a novel and effective strategy for EGFR-targeted therapy in TNBC.
| S-EPMC5689707 | biostudies-literature
Project description:Tumour cells are subjected to evolutionary selection pressures during progression from initiation to metastasis. We analysed the clonal evolution of squamous skin carcinomas induced by DMBA/TPA treatment using the K5CreER-Confetti mouse and stage-specific lineage tracing. We show that benign tumours are polyclonal, but only one population contains the Hras driver mutation. Thus, benign papillomas are monoclonal in origin but recruit neighbouring epithelial cells during growth. Papillomas that never progress to malignancy retain several distinct clones, whereas progression to carcinoma is associated with a clonal sweep. Newly generated clones within carcinomas demonstrate intratumoural invasion and clonal intermixing, often giving rise to metastases containing two or more distinct clones derived from the matched primary tumour. These data demonstrate that late-stage tumour progression and dissemination are governed by evolutionary selection pressures that operate at a multicellular level and, therefore, differ from the clonal events that drive initiation and the benign-malignant transition.
| S-EPMC6400587 | biostudies-literature
Project description:A quantum-dot (QD)-based micelle conjugated with an anti-epidermal growth factor receptor (EGFR) nanobody (Nb) and loaded with an anticancer drug, aminoflavone (AF), has been engineered for EGFR-overexpressing cancer theranostics. The near-infrared (NIR) fluorescence of the indium phosphate core/zinc sulfide shell QDs (InP/ZnS QDs) allowed for in vivo nanoparticle biodistribution studies. The anti-EGFR nanobody 7D12 conjugation improved the cellular uptake and cytotoxicity of the QD-based micelles in EGFR-overexpressing MDA-MB-468 triple-negative breast cancer (TNBC) cells. In comparison with the AF-encapsulated nontargeted (i.e., without Nb conjugation) micelles, the AF-encapsulated Nb-conjugated (i.e., targeted) micelles accumulated in tumors at higher concentrations, leading to more effective tumor regression in an orthotopic triple-negative breast cancer xenograft mouse model. Furthermore, there was no systemic toxicity observed with the treatments. Thus, this QD-based Nb-conjugated micelle may serve as an effective theranostic nanoplatform for EGFR-overexpressing cancers such as TNBCs.
| S-EPMC5918284 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC), which lacks estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), accounts for about 15-20% of breast cancers and is the most aggressive breast cancer subtype. There are currently no effective therapies against metastatic TNBC. Compared with other breast cancer subtypes, EGFR is frequently overexpressed in TNBC and a potential therapeutic target for this disease. There are two types of EGFR inhibitors, small molecular tyrosine kinase inhibitor (TKI) and monoclonal antibody (mAb), for the treatment of cancers, such as non-small cell lung cancer and colorectal cancer. For breast cancer, however, the clinical trials of EGFR inhibitors have failed due to low response rates. Because a small portion of patients do demonstrate response to EGFR inhibitors, it may be necessary to stratify patients to enhance the efficacy of EGFR inhibitors in TNBC and to develop the effective combination therapy for this patient population. In this review, we describe some of the molecular mechanisms underlying EGFR inhibitor sensitivity and further discuss the possible therapeutic strategies to increase the efficacy of EGFR inhibitors in TNBC.
| S-EPMC5004067 | biostudies-literature
Project description:Activation of MAPK signaling via BRAF mutations may limit the activity of EGFR inhibitors in EGFR-mutant lung cancer patients. However, the impact of BRAF mutations on the selection and fitness of emerging resistant clones during anti-EGFR therapy remains elusive. We tracked the evolution of subclonal mutations by whole-exome sequencing and performed clonal analyses of individual metastases during therapy. Complementary functional analyses of polyclonal EGFR-mutant cell pools showed a dose-dependent enrichment of BRAFV600E and a loss of EGFR inhibitor susceptibility. The clones remain stable and become vulnerable to combined EGFR, RAF, and MEK inhibition. Moreover, only osimertinib/trametinib combination treatment, but not monotherapy with either of these drugs, leads to robust tumor shrinkage in EGFR-driven xenograft models harboring BRAFV600E mutations. These data provide insights into the dynamics of clonal evolution of EGFR-mutant tumors and the therapeutic implications of BRAF co-mutations that may facilitate the development of treatment strategies to improve the prognosis of these patients.
| S-EPMC8683498 | biostudies-literature