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

• 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
• 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

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.

项目概要 乳腺癌仍然是一个主要的健康威胁，并且是癌症相关死亡的第二大原因 美国的女性。三阴性乳腺癌（TNBC）患者的治疗尤其重要 由于疾病的异质性和癌细胞的可塑性，具有挑战性。 TNBC 代表约 占所有乳腺癌的 15%，是一种特别具有侵袭性的亚型，治疗选择有限且效果非常差 预后。 TNBC 的可塑性和异质性使其难以靶向治疗。安装 有证据表明肿瘤微环境（TME）内的正常细胞在 决定肿瘤细胞的命运。与癌细胞的不稳定基因组相比，正常细胞的稳定基因组 TME 内的药物使它们成为可与疗法联合使用的理想靶点 针对癌细胞。 TME 内的免疫细胞在肿瘤进展和 转移。此外，一种免疫细胞亚型——骨髓源性抑制细胞——的数量增加 （MDSC），在循环血液中与临床分期、转移性肿瘤负荷和增加的数量相关 循环肿瘤细胞（CTC），表明它可能是乳腺癌患者的一个有前途的预后标志物。 然而，目前尚不清楚 MDSC 是否被招募到 TNBC 的 TME 中和/或它们是否有助于肿瘤 进展和转移。使用人类患者样本，我们发现 TNBC 中的 MDSC 数量增加 与其他乳腺癌亚型相比，患者肿瘤。此外，我们发现 Np63 的表达增加 在具有高度 MDSC 浸润的 TNBC 患者样本中，提出了 MDSC 的有趣可能性 TNBC 患者的招募和/或生存可能由 Np63 表达驱动。为了支持，我们发布了 初步研究表明，降低 TNBC 中 Np63 的水平可降低肿瘤生长， 进展和转移，并与 MDSC 浸润减少相关。此外，我们还展示了减少 与对照相比，Np63-KD TNBC 细胞中趋化因子和肿瘤坏死因子 (TNF) 途径基因的变化 细胞，从而确定了 Np63+ TNBC 细胞调节趋化因子依赖性的潜在途径 TNBC 中 MDSC 的募集和 TNF 介导的存活。最后，我们证明 MDSC 可以促进 TNBC 细胞的癌症干细胞功能。总之，我们的数据表明 Np63+ TNBC 之间存在一种新颖的串扰 TNBC 中的细胞和 MDSC，可以促进 TNBC 肿瘤的侵袭性，从而增加 患者的转移和死亡率。基于这些数据，当前提案的目标是描绘 Np63+ TNBC 细胞介导的趋化因子和 TNF 信号传导促进的新机制 MDSC 浸润和存活，然后反馈给 TNBC 细胞，促进癌症进展 和转移。