Project 1: How tumor ensemble models with two experimental models predict tumor dormancy & reactivation in cancers with gender and/or ethnic disparities

癌症是世界上主要的健康问题之一。化疗或手术后，一些癌症，例如， 乳腺癌和黑色素瘤，由于一种仍然神秘的机制，在过去几年里一直存在，显然处于休眠状态。 出现远处转移，肿瘤重新激活和生长。潜伏的肿瘤细胞可以通过它们的微环境存活- 环境部分排除了会攻击它们的T细胞。移植研究表明，不是静态的 静止期，这些细胞和免疫系统处于动态平衡和周期性的细胞分裂爆发 消除有时会改变看不见的微转移，这些微转移积累了遗传的、表观遗传的和 蛋白质组学变化为大转移。目前还缺乏细节和完整的机制。 很少有实验或理论模型来概括潜伏期或潜伏期的重新激活。一 小鼠乳腺癌模型表现出短期潜伏期和复发。典型的癌症数学模型 描述单个肿瘤的生长和/或转移的产生或几个突变的可能性，但不是 曼西。我们假设了一个新的数学种群模型，用于大型系综的动力学(从一个或一个 许多患者)各种大小的肿瘤都会有丝分裂，细胞死亡(免疫、化疗或免疫治疗、死亡)。 SIS等)和转移。整体自然地包含了类似肿瘤的反应变化。预测 是概率的，与任何初始大小分布的每个大小和时间的预期肿瘤数量成正比。 提顿。较小的肿瘤往往比较大的肿瘤对化疗的反应更好，这可能是因为后者的活性更强。 累积突变；肿瘤大小依赖的参数最简单地模拟了这一点。我们的模型发现了一个令人惊讶的 这些依赖于大小的过程之间的相互作用产生了耐人寻味的新的意想不到的结果 定性行为，例如，在肿瘤大小空间内的扩散首次预测休眠和复发。 该建议将这一新的数学模型与BALB/c小鼠乳腺癌和 清晰、无条纹的斑马鱼黑色素瘤系统；两者都允许实时非侵入性监测肿瘤数量 在没有动物牺牲的情况下，大小和时间。我们的模型适用于现有的人肝细胞癌和免疫缺陷。 免疫抑制和有能力的鱼类黑色素瘤直方图多次非常好，只有3个参数- 特斯。我们计划进行新的鱼类实验，以控制/调节免疫水平，以便访问和测试参数 预计会导致休眠和复发。我们将对小鼠乳腺癌进行详细的实验 系统，可以自然地表现出休眠和重复，并用它来测试我们的模型。我们还将尝试 调节其对进入和测试参数的免疫力，这些参数预计会产生休眠和复发。因为这两个 这些癌症表现出种族和性别差异，我们将使用带有SNPs的黑色素瘤细胞来概括 种族特定的遗传学和按性别分离(FISH)数据，以查看参数是否显示种族和/或 性别特异性；这将延续到休眠和复发。如果时间和资金允许，我们也将 开始观察肿瘤形状对其参数的肿瘤大小依赖关系的影响。

Cancer is one of the world's major health problems. After chemotherapy or surgery, some cancers, e.g., breast cancer and melanoma, by a still mysterious mechanism persist, apparently dormant, for years before distant metastases appear and tumors reactivate and grow. Latent tumor cells may survive by their microenvi- ronment partially excluding T-cells that would attack them. Transplant studies indicate that, rather than static quiescence, these cells and the immune system are in dynamic equilibrium and periodic bursts of cell division and elimination sometimes transform unobservable micrometastases that accumulate genetic, epigenetic and proteomic changes into macrometastases. Details and a complete mechanism are lacking. There is a paucity of experimental or theoretical models that recapitulate latency or its reactivation. One mouse breast cancer model exhibits short-term latency & recurrence. Mathematical cancer models typically describe single tumor growth and/or metastasis generation or the probability of several mutations, but not dor- mancy. We posit a new mathematical population model for the dynamics of a large ensemble (from one or many patients) of tumors of all sizes subject to mitosis, cell death (immunity, chemo or immunotherapy, necro- sis, etc.) and metastasis. Ensembles naturally incorporate response variations of similar tumors. Predictions are probabilistic, proportional to the expected tumor number of each size and time from any initial size distribu- tion. Smaller tumors often respond better to chemotherapy than larger ones, likely due to the latter's more ac- cumulated mutations; tumor-size-dependent parameters model this most simply. Our model finds a surprising interaction among these size-dependent processes in an ensemble that generates intriguing new unexpected qualitative behavior, e.g., diffusion in tumor size space that for the first time predicts dormancy & recurrence. This proposal intimately integrates this new mathematical model with the BALB/c murine breast cancer and the clear, stripeless zebrafish melanoma systems; both allow live non-invasive monitoring of tumor numbers and sizes vs time without animal sacrifice. Our model fits existing human hepatocellular carcinoma and im- mune-suppressed & competent fish melanoma histograms at many times extremely well with only 3 parame- ters. We plan new fish experiments to control/tune the level of immunity so as to access and test parameters predicted to yield dormancy & recurrence. We shall carry out detailed experiments on the mouse breast cancer system, which may exhibit dormancy & recurrence naturally, and use it to test our model. We shall also attempt to modulate its immunity to access and test parameters predicted to yield dormancy & recurrence. Since both these cancers show both ethnic and gender disparities, we shall use melanoma cell with snps that recapitulate ethnicity-specific genetics and segregate (fish) data by gender so as to see if parameters show ethnic and/or gender specificity; this would carry over to dormancy & recurrence. Time and funds permitting, we shall also begin to look at the effect of tumor shape on its parameters' tumor size dependences.