Targeting cooperative mechanisms of metastatic colonization in osteosarcoma

在研究骨肉瘤的转移机制时，我们发现单个肿瘤细胞对 当暴露在外来的肺部环境中时，情况会有所不同。我们早期的数据提出了一个假设：一个小的 一组肿瘤细胞通过停止细胞分裂和大量产生，在最初与肺部相遇时幸存下来 炎性细胞因子。这些罕见的“锚定”细胞的反应改变了周围的肺组织 通过快速增殖的肿瘤细胞(“生长”细胞)为其定植做好准备。这些细胞因子是由 锚定细胞似乎改变了周围肺细胞的行为，促使伤口愈合反应。 然而，与正常的伤口愈合反应不同，这种伤口永远不会愈合。 这种创伤反应所创造的环境与正常、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种环境，在这种环境中，生长的细胞不仅 生存，但迅速增殖，竞争超过锚定细胞，成为 转移性肿瘤。在这里，我们概述了一项测试这一假设的研究计划，严格评估了我们提出的 建立早期转移生态位的机制和询问化疗是否选择性地扼杀生长 细胞，不经意间保持锚定细胞完好无损，一旦治疗停止，重新建立转移。 该项目分为三个目标。目标1测试与锚定细胞的机制有关的假设 通过激活肺的伤口愈合机制来创造肥沃的转移利基，并促进 识别肺到肿瘤的信号，使之成为生长细胞的肥沃环境。 在第二个目标中，我们将确定锚定细胞和生长细胞是如何产生的--是否有不同的克隆 预先编程的锚定或生长细胞活动，或者动态发育过程是否调节 维持每个肿瘤内的亚群。了解这一点对设计治疗方案将是重要的 在保持疗效的同时将毒性降至最低的方案。 最后，我们将评估直接或间接靶向锚定细胞的药物抑制剂的使用，看看是否 这些疗法可以增强传统疗法的效果，克服耐药性和复发。通过识别 选择性靶向锚定细胞的药物，我们可以开发针对这两组患者的联合方案 肿瘤细胞，使抗药性疾病可治愈。 具有离散行为的癌细胞之间的合作对治疗和 这表明有必要制定同时针对生长细胞和锚定细胞的策略。这项工作可能会驾驶一辆 范式的转变将彻底改变骨肉瘤患者的护理。

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.