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：
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
项目类别：
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

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.

项目摘要乳腺癌仍然是主要的健康威胁，是与癌症相关死亡的第二大原因在美国的妇女。尤其是三重阴性乳腺癌（TNBC）患者的治疗由于疾病的异质性和癌细胞的可塑性而挑战。 TNBC代表所有乳腺癌的15％，是一种特别具有侵略性的亚型，治疗选择有限，而且很差预后。 TNBC的可塑性和异质性使它们难以靶向治疗。安装有证据表明，肿瘤微环境（TME）中的正常细胞在决定肿瘤细胞命运。与癌细胞不稳定的基因组相比，正常细胞的稳定基因组在TME内部，它们使其成为可以与疗法结合使用的药物疗法的理想靶标靶向癌细胞。 TME内的免疫细胞在肿瘤进展中起着至关重要的作用转移。此外，增加了一种亚型的免疫电池亚型，髓样衍生的抑制细胞（MDSC），在循环血液中与临床阶段，转移性肿瘤伯恩（Burnen）相关，数量增加循环肿瘤细胞（CTC），这表明它可能是乳腺癌患者的有前途的预后标记。但是，目前尚不清楚MDSC是否招募到TNBC的TME和/或它们是否有助于肿瘤进展和转移。使用人类患者样品，我们发现TNBC中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患者样品中，增加了MDSC的有趣可能性 TNBC患者中的NP63表达可以驱动招募和/或生存。为了支持，我们出版了初步研究表明，降低TNBC中NP63的水平会下降肿瘤的生长，进展和转移，与降低的MDSC浸润有关。此外，我们显示还原与对照相比，NP63-KD TNBC细胞中趋化因子和肿瘤坏死因子（TNF）途径基因细胞，因此鉴定了NP63+ TNBC细胞可能调节趋化因子依赖性的潜在途径 MDSC在TNBC中的募集和TNF介导的存活率。最后，我们表明MDSC可以促进 TNBC细胞的癌症干细胞功能。一起，我们的数据表明NP63+ TNBC之间的新串扰 TNBC中的细胞和MDSC，可以促进TNBC肿瘤的侵略性，从而增加患者的转移和死亡率。基于这些数据，当前建议的目的是描述 NP63+ TNBC细胞介导的趋化因子和TNF信号传导的一种新型机制促进 MDSC浸润和生存，然后将其反馈到TNBC细胞以促进癌症进展和转移。