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Deciphering the function of DNp63 and MDSCs in tumor promotion and metastasis of TNBCs

破译DNp63和MDSCs在TNBCs肿瘤促进和转移中的功能

基本信息

批准号：
10174878
负责人：
Rumela Chakrabarti
金额：
$ 25.18万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2022-01-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10174878
关键词：
Aggressive course Antibodies Back Binding Biological Assay Blood Breast Cancer Cell Breast Cancer Patient Breast Cancer cell line CASP8 and FADD-like apoptosis regulating protein CASP8 gene CCL22 gene CXCL2 gene Cancer Etiology Cell Survival Cells Cessation of life Chitinase Clinic Clinical Coculture Techniques Combined Modality Therapy Data Development Feeds Foundations Future Genes Genome Goals Health Heterogeneity Human Immune Immunocompetent Immunophenotyping Immunosuppression Immunotherapy In Vitro Infiltration Knockout Mice Label MMP9 gene Malignant Neoplasms Measures Mediating Molecular Monoclonal Antibodies Mouse Mammary Tumor Virus Mus Myeloid-derived suppressor cells Natural Killer Cells Nature Neoplasm Circulating Cells Neoplasm Metastasis Normal Cell Oncogenic Pathway interactions Patients Play Primary Neoplasm Production Prognosis Prognostic Marker Property Proteins Publishing Recombinants Regulation Role Sampling Shapes Signal Transduction T-Lymphocyte TNF gene TNFRSF1B gene Testing Therapeutic Time Transgenic Organisms Tumor Burden Tumor Promotion Tumor Volume Tumor stage Tumor-Derived United States Up-Regulation WNT Signaling Pathway Woman angiogenesis base breast cancer progression cancer cell cancer genome cancer stem cell cancer subtypes chemokine chemotherapy conditional knockout disease heterogeneity in vivo inhibitor/antagonist knock-down malignant breast neoplasm mortality mouse model neoplastic cell novel overexpression peripheral blood pre-clinical receptor recruit response small hairpin RNA stem cell function stemness targeted cancer therapy targeted treatment transcriptome sequencing triple-negative invasive breast carcinoma tumor tumor growth tumor initiation tumor microenvironment tumor progression

项目摘要

Project Summary Breast cancer remains a major health threat and is the second leading cause of cancer-related death in women in the United States. Treatment of triple negative breast cancer (TNBC) patients is particularly challenging due to the heterogeneity of the disease and plasticity of the cancer cells. TNBC represents about 15% of all breast cancers and is a particularly aggressive subtype, with limited treatment options and very poor prognosis. The plasticity and heterogeneity of TNBCs makes them difficult to target therapeutically. Mounting evidence suggests that normal cells within the tumor microenvironment (TME) play an important role in dictating tumor cell fate. Compared to the unstable genome of cancer cells, the stable genomes of normal cells within the TME make them ideal targets for drug therapies that can be used in combination with therapies targeting cancer cells. Immune cells within the TME play an essential role in tumor progression and metastasis. Moreover, increased numbers of one subtype of immune cell, myeloid-derived suppressor cells (MDSCs), in circulating blood correlates with clinical stage, metastatic tumor burden and increased numbers of circulating tumor cells (CTCs), suggesting it may be a promising prognostic marker in breast cancer patients. However, it is currently unclear if MDSCs are recruited to the TME of TNBC and/or if they contribute to tumor progression and metastasis. Using human patient samples, we found increased numbers of MDSCs in TNBC patient tumors compared to other breast cancer subtypes. Moreover, we found increased expression of Np63 in TNBC patient samples with a high degree of MDSC infiltration, raising the intriguing possibility that MDSC recruitment and/or survival may be driven by Np63 expression in TNBC patients. In support, our published and preliminary studies demonstrate that reducing the level of Np63 in TNBCs decreases tumor growth, progression and metastasis and is associated with reduced MDSC infiltrate. Additionally, we showed reduction of chemokine and Tumor necrosis Factor (TNF) pathway genes in Np63-KD TNBC cells compared to control cells, thus identifying a potential pathways by which Np63+ TNBC cells may regulate chemokine-dependent recruitment and TNF-mediated survival of MDSCs in TNBCs. Finally, we show that MDSCs can promote cancer stem cell function of TNBC cells. Together, our data indicates a novel crosstalk between Np63+ TNBC cells and MDSCs in TNBCs, which could promote the aggressive nature of TNBC tumors, thereby increasing metastasis and mortality of patients. Based on these data, the goal of the current proposal is to delineate a novel mechanism by which Np63+ TNBC cells mediated chemokine and TNF signaling promotes MDSC infiltration and survival, which then feeds back to TNBC cells to promote cancer progression and metastasis.

项目总结