Targeting cooperative mechanisms of metastatic colonization in osteosarcoma

在研究骨肉瘤转移机制的同时，我们发现单个肿瘤细胞对肿瘤转移的反应， 在暴露于外来肺环境时会有不同的变化。我们的早期数据提出了一个假设： 一组肿瘤细胞通过停止细胞分裂和大量产生 炎性细胞因子这些罕见的“锚”细胞的反应改变了周围的肺组织， 使其通过快速增殖的肿瘤细胞（“生长”细胞）为定植做好准备。释放的细胞因子 锚细胞似乎可以改变周围肺细胞的行为，促进伤口愈合反应。 然而，与正常的伤口愈合反应不同，这种伤口永远不会愈合。 这种创伤反应所产生的环境与正常健康的肺明显不同。 最重要的是，构成伤口的细胞和细胞因子创造了一个环境， 存活，但迅速增殖，胜过锚细胞，成为细胞内的优势亚型。 转移性肿瘤在这里，我们概述了一个研究计划，以测试这一假设，严格评估我们的建议， 建立早期转移小生境的机制，并询问化疗是否选择性地杀死生长 细胞，无意中留下完整的锚细胞以在治疗停止后重新建立转移。 该项目分为三个目标。目的1检验与锚细胞机制相关的假设 通过激活肺的伤口愈合机制来创建肥沃的转移性小生境， 识别肺肿瘤信号，使其成为生长细胞的肥沃环境。 在第二个目标，我们将确定如何锚和生长细胞来约-是否不同的克隆来 预编程的锚或生长细胞活性或动态发育过程是否调节 维持每个肿瘤内的亚群。理解这一点对于设计治疗方案非常重要 维持疗效同时最小化毒性的方案。 最后，我们将评估直接或间接靶向锚细胞的药理学抑制剂的使用，看看是否 这些可以增强传统疗法的效果，并克服耐药性和复发。通过识别 选择性靶向锚细胞的药物，我们可以开发靶向两组 肿瘤细胞，使耐药疾病可治疗。 具有离散行为的癌细胞之间的合作对于治疗和治疗具有直接意义。 提示需要开发靶向生长细胞和锚细胞的策略。这项工作可以推动一个 这将彻底改变骨肉瘤患者的护理模式。

While studying mechanisms of metastasis in osteosarcoma, we discovered that individual tumor cells respond differently when exposed to the foreign lung environment. Our early data suggest a hypothesis: that a small group of tumor cells survives the initial encounter with the lungs by stopping cell division and liberally producing inflammatory cytokines. The reaction of these rare “anchor” cells changes the surrounding lung tissue in ways that prepare it for colonization by rapidly proliferating tumor cells (“growth” cells). The cytokines released by anchor cells appear to alter the behavior of the surrounding lung cells, prompting a wound healing response. Unlike the normal wound healing response, however, this wound never heals. The environment created by this wound response is markedly different from that of the normal, healthy lung. Most importantly, cells and cytokines that make up the wound create an environment where growth cells not only survive, but proliferate rapidly, outcompeting the anchor cells to become the dominant subtype within the metastatic tumor. Here, we outline a research plan to test this hypothesis, rigorously evaluating our proposed mechanisms that establish the early metastatic niche and asking whether chemotherapy selectively kills growth cells, inadvertently leaving anchor cells intact to re-establish metastases once therapy ceases. The project is divided into three Aims. Aim 1 tests hypotheses relating to the mechanisms by which anchor cells create a fertile metastatic niche by activating the wound-healing machinery of the lung and facilitates identification of the lung-to-tumor signals that make this a fertile environment for growth cells. In the second Aim, we will determine how anchor and growth cells come about—whether distinct clones come pre-programmed for anchor or growth cell activity or whether dynamic developmental processes regulate maintenance of subpopulations within each tumor. Understanding this will be important for designing treatment regimens that maintain efficacy while minimizing toxicity. Finally, we will evaluate the use of pharmacologic inhibitors that target anchor cells directly or indirectly to see if these can augment the effects of conventional therapies and overcome resistance and relapse. By identifying agents that selectively target anchor cells, we can develop combination regimens that target both groups of tumor cells, rendering resistant disease treatable. The cooperation between cancer cells with discrete behaviors has immediate implications for treatment and suggests a need to develop strategies that target both growth cells and anchor cells. This work could drive a paradigm shift that would revolutionize the care of patients with osteosarcoma.