Molecular Regulation of Breast Cancer Progression

背景：乳腺癌(BRCA)是女性最常见的肿瘤，对黑人女性影响最大 严重；BRCA在女军人中也更为普遍和病态。局限性的原发癌通常是 找到并移除，治愈了高达80%的女性患者和极少数男性患者。一旦癌症扩散， 目前的治疗方法，甚至是较新的生物制剂和免疫疗法，只能延长几年的生命。信号和信元 能够使播散性肿瘤转移存活和生长的行为是关键的转折点。 我们在本年度和以前获奖期间的调查表明，一旦传播到 异位微环境，实质细胞引导肿瘤细胞重新表达上皮标记物 包括具有定义意义的E-钙粘素。此细胞-细胞内聚标记形成异型绑定，从而使 肿瘤细胞对化疗和死亡细胞因子的杀伤更具抵抗力，并下调靶点 免疫疗法。这种对死亡信号的保护是通过E-钙粘素触发的信号进行的，包括 至少是PI3激酶-AKT通路，这里针对的是特定的通路。 我们还研究了这种上皮逆转也可能导致肿瘤细胞休眠，这是一种并发症 肿瘤扩散。我们已经对此进行了建模，以证明整个器官的静止是 休眠，但这种非增殖状态是可塑性的，刺激的细胞被唤醒并重新获得 继发于支持的非实质细胞活化的侵袭性间充质表型 特定的应激源会导致炎症引发的生长，本文将对此进行研究。 假设：我们的基本模型假设E-钙粘素连接信号促进肿瘤细胞休眠 以及通过选择信号通路存活，这些信号通路可以被靶向逆转化疗耐药性，并可能 免疫逃脱。通过识别操作信号和路径，我们可以开发新的方法来 靶向新生乳腺癌细胞的微转移。肿瘤细胞与肿瘤细胞的相互作用 转移微环境决定了肿瘤靶向治疗的反应性和休眠/ 外延生长。这一假说引出了两个相互关联的问题--产生抵抗力的机制是什么 为什么肿瘤细胞随后从这个休眠阶段出来，生长为致命的肿瘤。 这些主题将导致新的方法，通过这些新出现的癌细胞将成为靶点。 具体目标：将同时追求两个相互关联但独立的目标： I.确定在微转移中提供抗杀伤性的关键肿瘤细胞机制 并确定以它们为靶点是否可以增强化疗敏感性。E-钙粘附素促进生存，在 至少部分是通过规范的AKT途径发出信号，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疗耐药。然而，不同的AKT亚型 混淆了药效。将在临床前模型的组合中建立增强的化学敏化 在培养和创新的体外微生理系统/生物反应器中，然后在动物模型中进行验证。 确定激活微转移生态位以触发从休眠中苏醒的线索。 从休眠中苏醒预示着播散性乳腺癌的致命阶段。我们发现微小的- 转移的生态位既反映并支持休眠期间的静止，也反映并支持驱动生长的激活。 我们将确定炎症反应/肿瘤生长事件中的关键信号，以开发生物标记物和 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线索 在乳腺癌中被颠覆以促进进展的细胞行为。偶数分量的验证 我们的基础模型和我们最初的翻译工作将突出Rational的未来途径 对癌症治疗难治阶段、临床无法检测到的微转移的干预。

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.