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NOTCH3 Blockade Inhibits Cancer Cell Plasticity through a NOTCH3/PD-L1 Oncogenic Axis in Triple Negative Breast Cancer

ABSTRACT: NOTCH3 Blockade Inhibits Cancer Cell Plasticity through a NOTCH3/PD-L1 Oncogenic Axis in Triple Negative Breast Cancer

PROVIDER: PRJNA989131 | ENA |

REPOSITORIES: ENA

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NOTCH3 Blockade Inhibits Cancer Cell Plasticity through a NOTCH3/PD-L1 Oncogenic Axis in Triple Negative Breast Cancer

Project description:Triple negative breast cancer (TNBC) accounts for 15-20% of all breast cancers and mainly affects pre-menopausal and minority women. Therapeutic options are yet limited, in part because of acquisition of tumor cells with cancer stem cell (CSC) properties, leading to intrinsic resistance to chemotherapeutic agents and immune evasion capacity. Dysregulated Notch signaling has been linked to breast cancer and in this study, we demonstrate the pivotal role of NOTCH3 in inducing the enrichment of chemoresistant ALDHhigh CSCs. Significantly, selective targeting of NOTCH3 with AV-353, a novel humanized monoclonal antibody, or by shRNA-mediated knockdown, impaired the enrichment of ALDHhigh CSCs with high self-renewal capacity, induced apoptosis and enhanced chemosensitivity. AV-353 treatment similarly reduced growth of xenografted tumors in vivo. Moreover, blocking NOTCH3 by AV-353 or shRNA reduced PD-L1 expression in TNBC cells, which was linked to the inhibition of tumor growth and enhancement of CD8+ T-cell infiltration. Taken together, these findings provide preclinical evidence for NOTCH3 as a novel therapeutic target in TNBC and reveal a novel NOTCH3/PD-L1 oncogenic axis as a platform for the betterment of TNBC therapy.

2024-06-28 | GSE236140 | GEO

PD-L1 blockade-induced temporal single cell dynamics in triple negative breast cancer

Project description:PD-L1 blockade-induced temporal single cell dynamics in triple negative breast cancer

| PRJNA715775 | ENA

PD-L1 blockade-induced temporal single cell dynamics in triple negative breast cancer

Project description:Despite the progress in immunotherapies, leading immune checkpoint inhibitors are only effective in a subset of patients. The efficacy of atezolizumab, an anti-PD-L1 antibody, in triple negative breast cancer (TNBC) is limited for unknown reasons. We utilized single-cell RNA- and ATAC-sequencing to examine the dynamics of immune cells in metastatic TNBC patients treated with paclitaxel or its combination with atezolizumab. We found that paclitaxel selectively damaged tumor-reactive T cells while atezolizumab was effective in a small set of patients with high levels of baseline B cells and CXCL13+ T cells. B cells concertedly expanded with CXCL13+ T cells in responsive patients following paclitaxel plus atezolizumab treatment. Our data highlight the importance of potential tumor-reactive T cells and their orchestrators in the effective response to anti-PD-L1 therapies, and reveal drawbacks of existing clinical trials for TNBC.

2021-09-15 | GSE169246 | GEO

NOTCH3-IC

Project description:NOTCH3-IC

| PRJNA480489 | ENA

AKT dependent Notch3 activation drives tumor progression in a model of mesenchymal colorectal cancer subtype

Project description:Recently a consensus molecular subtype (CMS) classification of colorectal cancer (CRC) has been established that is based on the transcriptional rather than the genetic profile of an individual tumor and which may ultimately help to individualize CRC therapy. So far, however, the lack of appropriate animal models that faithfully recapitulate the different molecular subtypes impedes adequate preclinical testing of stratified therapeutic concepts. Here we demonstrate that constitutive AKT activation in intestinal epithelial cells markedly enhances colonic tumor invasion and metastasis in Trp53DIEC mice (Trp53ΔIECAktE17K) upon challenge with the carcinogen azoxymethane (AOM). Gene-expression profiling indicates that Trp53ΔIECAktE17K tumors closely resemble the human mesenchymal colorectal cancer subtype (CMS4), which is characterized by the poorest survival rate among the four consensus molecular subtypes of CRC. Trp53ΔIECAktE17K tumors are further characterized by a NOTCH pathway gene signature and a distinct cell autonomous upregulation of Notch3 in tumor epithelia while treatment of Trp53ΔIECAktE17K mice with a NOTCH3-inhibiting antibody reduces invasion and metastasis. Conversely, selective activation of NOTCH3 by overexpression of NOTCH3-IC in Akt wt tumor organoids strongly promotes development of metastasis in an orthotopic transplantation model. In CRC patients NOTCH3 expression correlates positively with tumor grading and the presence of lymph node as well as distant metastases and is specifically upregulated in CMS4 tumors. Therefore, we suggest NOTCH3 as a putative target for advanced CMS4 CRC patients.

2021-09-08 | PXD014778 | Pride

Exercise inhibits tumor progression and improves the therapeutic efficacy of PD-1 blockade in colorectal cancer preclinical models

Project description:Exercise training (ExT) has shown antitumor effects in many preclinical cancer models. In the present study, we utilize MC38 and CT26 cells, which represent MSI and MSS colorectal carcinomas respectively, to study the effects and mechanisms of ExT alone or in combination with PD-1 based immunotherapy. Using treadmill running and PD-1/PD-L1 blockade, we demonstrated that post-implant exercise training has broad anticancer activities in murine models of CRC. Specifically, in MSI CRC models, ExT induces beneficial metabolic and immunological adaptations, leading to a more significant inhibition in tumors treated with PD-1/PD-L1 blockade, suggesting a genotype-directed combinatory therapy for the subgroup of CRC patients. Moreover, ExT might be a safe and alternative anticancer strategy for cancers resistant to the PD-1 based immunotherapy, such as patients with MSS CRC tumors.

2021-04-16 | GSE172162 | GEO

Notch3 signaling promotes tumor cell adhesion and progression in a murine epithelial ovarian cancer model

Project description:High grade serous ovarian cancer (HGSC) is the most common and deadly type of ovarian cancer, largely due to difficulties in early diagnosis and rapid metastasis throughout the peritoneal cavity. Previous studies have shown that expression of Notch3 correlates with worse prognosis and increased tumorigenic cell behaviors in HGSC. We investigated the mechanistic role of Notch3 in a model of metastatic ovarian cancer using the murine ovarian surface epithelial cell line, ID8 IP2. Notch3 was activated in ID8 IP2 cells via expression of the Notch3 intracellular domain (Notch3IC). Notch3IC ID8 IP2 cells injected intraperitoneally caused accelerated ascites and reduced survival compared to control ID8 IP2, particularly in early stages of disease. We interrogated downstream targets of Notch3IC in ID8 IP2 cells by RNA sequencing and found significant induction of genes that encode adhesion and extracellular matrix proteins. Notch3IC ID8 IP2 showed increased expression of ITGA1 mRNA and cell-surface protein. Notch3IC-mediated increase of ITGA1 was also seen in two human ovarian cancer cells. Notch3IC ID8 IP2 cells showed increased adhesion to collagens I and IV in vitro. We propose that Notch3 activation in ovarian cancer cells causes increased adherence to collagen-rich peritoneal surfaces. Thus, the correlation between increased Notch3 signaling and poor prognosis may be influenced by increased dissemination and metastasis of HGSC via increased attachment to the peritoneum. Implications: Expression of Notch3 accelerates the progression of ovarian cancer by increasing the adherence of disseminating cells to new metastatic sites.

2020-05-19 | GSE132737 | GEO

Gene expression profiles of PD-L1 SP142 expression in triple-negative breast cancer

Project description:The SP142 PD-L1 assay is a companion diagnostic for atezolizumab in metastatic triple-negative breast cancer (TNBC). The VENTANA SP142 assay was used to identify PD-L1 expression from TMA slides where PD-L1-positivity for an individual sample was defined as ≥1% of tumor-infiltrating immune cells as having PD-L1 expression. The PD-L1-positive gene signature consisted of 94 immune-related genes. The PD-L1-positive signature was predictive of pathologic complete response and survival outcome in multiple TNBC cohorts. In other malignancies treated with ICIs, the PD-L1-positive signature was associated with response and improved survival.

2021-07-14 | GSE157284 | GEO

Gene expression comparison of exhausted CD8 T cells after PD-L1 blockade alone or PD-L1 blockade combined with LPS

Project description:Gene expression comparison of exhausted CD8 T cells after PD-L1 blockade alone or PD-L1 blockade combined with LPS

| PRJNA507717 | ENA

Aurora A Kinase Inhibition Induces Accumulation of Tumor Cells in Mitosis with Restored Interferon Signaling to Potentiate Response to PD-L1 Immune Checkpoint Blockade [RNA-seq]

Project description:By arresting tumor cells in mitosis, aurora A kinase inhibition restores interferon signaling in small cell lung cancer tumor cells and cooperates with PD-L1 immune checkpoint blockade.

2023-09-26 | GSE214613 | GEO

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