Molecular Regulation of Breast Cancer Progression

背景：乳腺癌（BrCa）是女性最常见的肿瘤，影响黑人女性最多 严重; BrCa在女军人中也更普遍和病态。局限性原发癌通常 发现并切除，治愈了80%的女性和少数男性患者。一旦癌细胞扩散， 目前的治疗方法，甚至是更新的生物制剂和免疫疗法，只能延长几年的生命。信号和细胞 使转移性存活和扩散性肿瘤生长的行为是关键的转变点。 我们在当前和以前的颁奖期间进行的调查表明， 异位微环境，实质细胞指导肿瘤细胞重新表达上皮标志物 包括决定性的E-钙粘蛋白这种细胞-细胞凝聚标记物形成异型结合，使得细胞间的粘附性增加。 肿瘤细胞对化疗和死亡细胞因子的杀伤更具抗性，并下调肿瘤细胞的靶点。 免疫疗法这种对死亡信号的保护通过E-钙粘蛋白触发的信号传导进行， 至少PI 3激酶-AKT途径，其中特定途径是本文所靶向的。 我们还研究了这种上皮细胞的逆转也可能导致肿瘤细胞休眠，这是一种并发症。 肿瘤播散我们对此进行了建模，以证明整个器官的静止是 休眠，但这种非增殖状态是可塑的，受刺激的细胞被“唤醒”并恢复活力。 侵袭性间充质表型继发于支持性非实质细胞的活化， 特定的应激源导致炎症触发的生长，这将在本文中进行研究。 假设：我们的基础模型假定E-钙粘蛋白配体信号促进肿瘤细胞休眠 通过选择信号通路，可以靶向逆转化疗耐药性， 免疫逃逸通过识别操作信号和途径，我们可以开发新的方法， 在靶向新出现的乳腺癌细胞中的微转移。肿瘤细胞与癌细胞的相互作用 转移性微环境决定了对肿瘤靶向治疗的反应性和休眠/ 结果这一假设引出了两个相关的问题--是什么机制赋予了耐药性 以及为什么肿瘤细胞后来从这个休眠阶段出现，成为致命的肿瘤。 这些主题将导致新的方法，这些新兴的癌细胞将被靶向。 具体目标：将同时追求两个相互联系但又相互独立的目标： I.定义在微转移性肿瘤中提供杀伤抗性的关键肿瘤细胞机制 并确定是否靶向它们可以增强化学敏感性。E-钙粘蛋白促进生存，在 至少部分是通过经典的AKT通路进行信号传导，我们的初步数据支持这种靶向 这些中间激酶可以消除转移的化学抗性。然而，不同的AKT亚型 混淆疗效。将在临床前模型的组合中建立增强的化学增敏作用 在培养中，和创新的离体微生理系统/生物反应器，然后在动物模型中验证。 二.确定激活微转移小生境以触发从休眠中出现的线索。 从休眠中出现预示着扩散性乳腺癌的致命阶段。我们发现微- 转移生态位反映和支持休眠期间的静止和驱动生长的激活。 我们将确定炎症反应/肿瘤生长事件中的关键信号，用于生物标志物的开发， 使用患者来源的肿瘤细胞和血清样本进行干预，在临床前模型中进行验证。 这些实验的成功完成将为如何操纵分子控制提供新的思路 在乳腺癌中被破坏的细胞行为，以促进进展。偶数组件的验证 我们的基础模型和我们最初的翻译工作将突出未来的合理途径， 癌症的治疗难治性阶段的干预，临床上检测不到的微转移。

Background: Cancer of the breast (BrCa) is the most frequent tumor in women, affecting black women most severely; BrCa is also more prevalent and morbid in military women. Localized primary carcinomas are often found and removed, curing up to 80% of the women and few men afflicted. Once the cancer has disseminated, current therapies, even newer biologics and immunotherapies, prolong life for just a few years. Signals and cell behaviors that enable metastatic survival and outgrowth of disseminated tumors are critical transition points. Our investigations during the present and previous Award periods demonstrated that upon dissemination to the ectopic microenvironment, the parenchymal cells direct the tumor cells to re-express epithelial markers including the defining E-cadherin. This cell-cell cohesion marker forms heterotypic binding that renders the tumor cells more resistant to killing by chemotherapies and death cytokines and down-regulate targets of immunotherapy. This protection from death signals proceeds through E-cadherin-triggered signaling involving at least the PI3 kinase-AKT pathway with the specific pathways being targeted herein. We also investigate that this epithelial reversion also likely leads to tumor cell dormancy, a complication of tumor dissemination. We have modeled this to demonstrate that quiescence of the entire organ underlies the dormancy, but that this non-proliferative state is plastic with stimulated cells being `awakened' and regaining an aggressive mesenchymal phenotype secondary to activation of the supporting nonparenchymal cells by specific stressors leads to inflammation-triggered outgrowth that will be investigated herein. Hypothesis: Our foundational model posits that E-cadherin-ligandation signals promote tumor cell dormancy and survival via select signaling pathways that can be targeted to reverse the chemo-resistance and possibly immune-escape. By discerning the operative signals and pathways we can develop novel approaches to micrometastases in targeting the emergent breast cancer cells. The interplay of tumor cells with cells of the metastatic microenvironment dictates both responsiveness to tumor-targeted therapies and dormancy/ outgrowth. This hypothesis leads to two linked questions – what are the mechanisms that confer the resistance of metastasis, and why do the tumor cells then later emerge from this dormant stage to grow as lethal tumors. These topics will lead to novel approaches by which these emergent carcinoma cells will be targeted. Specific Aims: Two linked but independent aims will be pursued simultaneously: I. Define the key tumor cell mechanisms that provide for resistance to killing in the micrometastatic niche and determine if targeting them can enhance chemosensitivity. E-cadherin promotes survival, at least in part, by signaling via the canonical AKT pathway, with our preliminary data supporting that targeting these intermediary kinases can abrogate the chemoresistance of metastasis. However, different AKT isoforms confound the efficacy. Enhanced chemo-sensitization will be established in a combination of preclinical models in culture, and innovative ex vivo microphysiological systems/bioreactor, and then validated in animal models. II. Determine the cues that activate the micrometastatic niche to trigger emergence from dormancy. Emergence from dormancy heralds the lethal stage of disseminated breast cancer. We found that the micro- metastatic niche both reflects and supports the quiescent during dormancy and activation driving outgrowth. We will determine critical signals in inflammatory response/tumor growth event for biomarker development and intervention using patient-derived tumor cells and serum specimens, validating in preclinical models. The successful completion of these experiments will shed new light on how to manipulate molecular controls of cell behavior that are subverted in breast carcinoma to promote progression. Validation of even components of our foundational model and our initial translational effort would highlight future avenues for rational interventions for the therapeutically refractory stage of cancer, clinically undetectable micrometastases.