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

项目摘要 乳腺癌仍然是一个主要的健康威胁，是#年与癌症相关的死亡的第二大原因。 美国的女性。三阴性乳腺癌(TNBC)患者的治疗尤为重要 由于疾病的异质性和癌细胞的可塑性而具有挑战性。TNBC代表大约 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，而且非常差 预后。TNBCs的可塑性和异质性使其很难作为治疗的靶点。安装 有证据表明，肿瘤微环境(TME)中的正常细胞在 决定了肿瘤细胞的命运。与癌细胞的不稳定基因组相比，正常细胞的稳定基因组 在TME内使他们成为药物治疗的理想靶点，可以与治疗结合使用 靶向癌细胞。TME内的免疫细胞在肿瘤进展和 转移。此外，免疫细胞的一种亚型，髓系来源的抑制细胞的数量增加 (MDSCs)，循环血中的MDSCs与临床分期、转移肿瘤负担和增加的肿瘤数目有关。 循环肿瘤细胞(CTCs)，提示它可能是一个有希望的乳腺癌患者的预后标志物。 然而，目前尚不清楚MDSCs是否被招募到TNBC的TME和/或它们是否对肿瘤有贡献 进展和转移。使用人类患者样本，我们发现TNBC中MDSCs的数量增加 患者肿瘤与其他乳腺癌亚型的比较。此外，我们还发现np63的表达增加 在具有高度MDSC渗透的TNBC患者样本中，MDSC增加了耐人寻味的可能性 Np63在TNBC患者中的表达可能推动了患者的募集和/或生存。作为支持，我们出版的 初步研究表明，降低TNBCs中Np63的水平会减少肿瘤的生长， 进展和转移，并与MDSC浸润率降低有关。此外，我们还显示出减少 趋化因子和肿瘤坏死因子途径基因在Np63-KD细胞中的表达 从而确定了Np63+TnBC细胞调节趋化因子依赖的潜在途径 肿瘤坏死因子介导的MDSCs在TNBCs中的募集和存活。最后，我们证明了MDSCs可以促进 肿瘤干细胞的TNBC细胞功能。总而言之，我们的数据表明np63+tnbc之间存在新的串扰。 TNBCs中的细胞和MDSCs，这可能促进TNBC肿瘤的侵袭性，从而增加 患者的转移和死亡率。根据这些数据，当前提案的目标是划定 Np63+TnBC细胞介导趋化因子和肿瘤坏死因子信号转导的新机制 MDSC的侵袭和存活，然后反馈给TNBC细胞促进癌症进展 和转移。

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.