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Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer.

ABSTRACT: Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer.

PROVIDER: PRJNA949598 | ENA |

REPOSITORIES: ENA

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Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer

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

Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer

Project description:Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer

| PRJNA948402 | ENA

Single cell lineage tracing reveals clonal dynamics of anti-EGFR therapy resistance in triple negative breast cancer.

Project description:This SuperSeries is composed of the SubSeries listed below.

2024-03-25 | GSE228382 | GEO

cIAP1 regulates the EGFR/Snai2 axis in triple negative breast cancer cells

Project description:Inhibitor of apoptosis (IAP) proteins constitute a conserved family of molecules which regulate both apoptosis and receptor signaling. They are often deregulated in cancer cells and represent potential targets for therapy. In our work, we investigated the effect of IAP inhibition in vivo to identify novel downstream genes expressed in an IAP-dependent manner that could contribute to cancer aggressiveness. To this end, immunocompromised mice engrafted subcutaneously with the triple negative breast cancer MDA-MB231 cell line were treated with SM83, a pan-IAP inhibitor developed by us, and tumor nodules were profiled for gene expression. Our work suggests that IAP-targeted therapy could contribute to EGFR inhibition and the reduction of its downstream mediators. This approach could be particularly effective in cells characterized by high levels of EGFR and Snai2, such as triple negative breast cancer.

2018-12-06 | GSE98691 | GEO

Monomeric EGFR-mediated activation of STAT3 promotes triple-negative breast cancer progression

Project description:Dimerization is believed necessary for receptor tyrosine kinases (RTKs) activation. Here we report that monomeric epidermal growth factor receptor (EGFR) directly phosphorylates the signal transducer and activator of transcription-3 (STAT3) in the absence of transmembrane protein TMEM25 (hereafter referred to as TAMER (Transmembrane protein Antagonizing Monomeric EGF Receptor signaling) to reflect its molecular function). We identified TAMER as a checkpoint for the monomeric-EGFR/STAT3 signaling, and downregulation of TAMER in triple-negative breast cancer (TNBC) results in a persistent activation of STAT3 that is required for TNBC progression, which gives a good explanation why targeting EGFR dimerization by antibodies showed no significant benefit to TNBC patients in clinical trials. Remarkably, supply of TAMER strongly suppressed TNBC progression, presenting a promising targeted therapy for TNBC. Hence, our study demonstrated the first RTK monomer-mediated signaling pathway, introducing an unprecedented pattern of RTK signaling that may play key roles in certain physiological or pathological contexts, which might need to be inspected for therapeutically targeting RTKs in the future.In this paper, RNA-seq were used to identify different gene expression in WT and TMEM25 knockout MDA-MB-231 cells.

2024-07-28 | GSE180989 | GEO

Clonal lineage tracing reveals shared origin of conventional and plasmacytoid dendritic cells

Project description:Developmental origins of dendritic cells (DCs) including conventional DCs (cDCs, comprising cDC1 and cDC2 subsets) and plasmacytoid DCs (pDCs) remain unclear. We studied DC development in unmanipulated adult mice using inducible lineage tracing combined with clonal DNA "barcoding" and single-cell transcriptome and phenotype analysis (CITE-Seq). Inducible tracing of Cx3cr1+ hematopoietic progenitors in the bone marrow showed that they simultaneously produce all DC subsets including pDCs, cDC1s and cDC2s. Clonal tracing of hematopoietic stem cells (HSCs) and of Cx3cr1+ progenitors revealed clone sharing between cDC1s and pDCs, but not between the two cDC subsets or between pDCs and B cells. Accordingly, CITE-Seq analyses of differentiating HSCs and Cx3cr1+ progenitors identified progressive stages of pDC development including Cx3cr1+ Ly-6D+ propDCs that were distinct from lymphoid progenitors. These results reveal the shared origin of pDCs and cDCs, and suggest a revised scheme of DC development whereby pDCs share clonal relationship with cDC1s

2022-02-16 | GSE193733 | GEO

High-resolution clonal mapping of multi-organ metastasis in triple negative breast cancer

Project description:Most triple negative breast cancers (TNBCs) are aggressively metastatic with a high degree of intratumoral heterogeneity. We employed patient-derived xenograft models established from the breast tumors of patients with treatment-naïve metastatic TNBC to study clonal dynamics during metastasis. Genomic sequencing coupled with high-complexity barcode-mediated clonal tracking revealed robust alterations in clonal architecture between primary tumors and corresponding metastases that were deterministic rather than stochastic. The presence of numerous rare subclones in each metastatic lesion demonstrated that polyclonal seeding occurred and that heterogeneous populations of low-abundance clones were maintained in metastases. An identical population of subclones was enriched in lung, liver, and brain metastases, demonstrating that primary tumor clones harbor properties enabling them to seed and thrive in multiple organ sites. Further, clones that dominated multi-organ metastases shared a genomic lineage. Thus, intrinsic properties of rare primary tumor subclones enable the seeding and colonization of metastases in multiple organ sites.

2018-12-11 | GSE120753 | GEO

Impairment of autophagic flux by combined EGFR and ROCK inhibition leads to triple-negative breast cancer cell death

Project description:Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with very limited therapeutic options. We have recently shown that the combined inhibition of EGFR and ROCK in TNBC cells results in cell cycle arrest and ultimately cell death. However, the underlying mechanisms by which co-inhibition of EGFR and ROCK induces cell death remain unclear. To investigate the synergistic effect of the combination treatment on TNBC cells, in the present study we applied a mass spectrometry-based proteomic approach to identify proteins altered upon single and combination treatments.

2019-12-04 | PXD013821 | Pride

Monomeric EGFR-mediated activation of STAT3 promotes triple-negative breast cancer progression

Project description:Monomeric EGFR-mediated activation of STAT3 promotes triple-negative breast cancer progression

| PRJNA750318 | ENA

Cooperative regulation of coupled oncoprotein synthesis and stability in triple-negative breast cancer by EGFR and CDK12/13

Project description:Evidence has long suggested that epidermal growth factor receptor (EGFR) may play a prominent role in triple-negative breast cancer (TNBC) pathogenesis, but clinical trials of EGFR inhibitors have yielded disappointing results. Using a candidate drug screen, we discovered that inhibition of cyclin-dependent kinases 12 and 13 (CDK12/13) dramatically sensitizes diverse models of TNBC to EGFR blockade. This combination therapy drives cell death through the 4E-BP1-dependent suppression of the translation and translation-linked turnover of driver oncoproteins, including MYC. A genome-wide CRISPR/Cas9 screen identified the CCR4-NOT complex as a major determinant of sensitivity to the combination therapy whose loss renders 4E-BP1 unresponsive to drug-induced dephosphorylation, thereby rescuing MYC translational suppression and promoting MYC stability. The central roles of CCR4-NOT and 4E-BP1 in response to the combination therapy were further underscored by the observation of CNOT1 loss and rescue of 4E-BP1 phosphorylation in TNBC cells that naturally evolved therapy resistance. Thus, pharmacological inhibition of CDK12/13 reveals a long proposed EGFR dependence in TNBC that functions through the cooperative regulation of translation-coupled oncoprotein stability.

2023-09-27 | GSE221475 | GEO

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