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: 10672261
• 负责人: Rumela Chakrabarti
• 金额: $ 35.81万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-26 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672261
• 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; Caspase; Cell Survival; Cells; Cessation of life; Chitinase; Clinic; Clinical; Coculture Techniques; Combined Modality Therapy; Data; Development; Feeds; Foundations; Future; Genes; Genome Stability; 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; Receptors, Tumor Necrosis Factor, Type II; 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; breast cancer progression; cancer cell; cancer genome; cancer stem cell; cancer subtypes; chemokine; chemotherapy; comparison control; conditional knockout; disease heterogeneity; in vivo; inhibitor; 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.

项目摘要 乳腺癌仍然是一个主要的健康威胁，是第二大癌症相关死亡的原因， 美国的女性。三阴性乳腺癌（TNBC）患者的治疗特别重要。 由于疾病的异质性和癌细胞的可塑性，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， 预后TNBC的可塑性和异质性使得它们难以在治疗上靶向。安装 有证据表明，肿瘤微环境（TME）中的正常细胞在肿瘤发生中起着重要作用。 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 使它们成为药物治疗的理想靶点， 靶向癌细胞。TME内的免疫细胞在肿瘤进展中起重要作用， 转移此外，一种免疫细胞亚型，髓源性抑制细胞的数量增加， （MDSC），在循环血液中与临床阶段，转移性肿瘤负荷和增加的数量相关。 循环肿瘤细胞（CTC），这表明它可能是一个有前途的乳腺癌患者的预后标志物。 然而，目前尚不清楚MDSC是否被募集到TNBC的TME和/或它们是否有助于TNBC的肿瘤转移。 进展和转移。使用人类患者样本，我们发现TNBC中MDSC的数量增加， 与其他乳腺癌亚型相比，此外，我们还发现， 在具有高度MDSC浸润的TNBC患者样本中，提出了MDSC 募集和/或存活可能由TNBC患者中的JNp63表达驱动。为了支持，我们的出版物 初步研究表明，降低TNBC中p-Np63的水平可以减少肿瘤生长， 进展和转移，并与MDSC浸润减少有关。此外，我们发现， 与对照组相比，在JNP63-KD TNBC细胞中趋化因子和肿瘤坏死因子（TNF）途径基因的表达 细胞，从而鉴定了JNP63 + TNBC细胞可以调节趋化因子依赖性的潜在途径。 在TNBC中MDSC的募集和TNF介导的存活。最后，我们发现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，在NPNp63 + TNBC之间存在一种新的串扰。 细胞和MDSC，这可以促进TNBC肿瘤的侵袭性，从而增加TNBC肿瘤的侵袭性。 转移和患者死亡率。根据这些数据，本提案的目标是 Np63 + TNBC细胞介导趋化因子和TNF信号传导促进的新机制 MDSC浸润和存活，然后反馈给TNBC细胞以促进癌症进展 和转移。