Stochastic fluctuations during mammary development and breast cancer morphogenesis

我们都从日常经验中知道，我们身体的某些部分可能会有略微不同的形状。这种差异部分是由于基因的差异，但也有一些是由于自然变异。这种可变性是由细胞内的随机(随机)物理过程引起的，细胞内相同的遗传程序可能导致略有不同的结果。虽然由相同的遗传程序决定，但健康和患病的器官表现出不同的形状和形式。目前，人们还不能很好地了解组织所表现出的变异性。在这项提案中，我们将量化和分析多细胞结构采用三维形状背后的随机性。我们预计，我们的工作将确定管理器官和癌症发展的基本原则。我们打算探索的可变性部分来自细胞如何施力并以机械方式相互作用，部分来自干细胞的动力学。细胞利用它们的细胞骨架--一种能够施加力的内部结构--来相互移动。此外，干细胞通过分裂和产生不同类型的细胞来确保组织正常运作。例如，在修复受损器官的过程中，干细胞会取代受损细胞。在癌症中也有干细胞，因此称为癌症干细胞，这些癌症干细胞(CSC)被认为是癌症扩散到身体其他部位(转移)所必需的，也与治疗后癌症的再次出现(复发)有关。目前还不可能研究活着的动物器官中所有细胞的位置和行为。在过去的几年里，在所谓的有机体中培养微小的器官状结构和三维癌症已经成为可能。类器官的细胞功能和相互作用与在活体动物中观察到的非常相似，因此类器官代表了一个研究细胞集体行为的独特系统。在这里，我们将探索乳腺类器官中的组织变异性是如何由细胞相互施加的机械力引起的，以及干细胞如何分裂并产生其他类型的细胞。我们将关注乳腺器官，因为乳腺癌是一种非常常见的疾病，每7名女性中就有一人患有乳腺癌。为了做到这一点，我们将开发一种系统，在很长一段时间内对有机物质进行成像，并使用它来研究干细胞在哪里，它们是如何分裂的，它们产生什么类型的子代细胞，以及干细胞和后代细胞如何在有机物质内部施加力，产生不同的器官和癌症形状。这种成像将使用定制的显微镜进行，分析将使用复杂的计算和物理建模方法。然后，我们将使用物理科学和数值模拟的方法来了解细胞行为的不确定性如何导致组织形状的可变性。来自理论物理的数学工具允许将物理系统在不同尺度上的行为联系起来。通过使用多学科方法，我们将应用这些工具来解决器官尺度的可变性问题。

We all know from everyday experience that parts of our body can have slightly different shapes. Some of this variance is due to differences in genes, but some is also due to natural variability. This variability, where the same genetic program within cells can lead to slightly different results, arises from random (stochastic) physical processes in cells. Although determined by the same genetic program, healthy and diseased organs show a variety of shapes and forms. At present the variability exhibited by tissues is not well understood. In this proposal we will quantify and analyse the stochasticity underlying the adoption of three-dimensional shapes by multicellular structures. We anticipate that our work will identify fundamental principles governing organ and cancer development. Part of the variability that we intend to explore arises from how cells exert forces and interact mechanically with each other, and part of it arises from the dynamics of stem cells. Cells use their cytoskeleton, an internal architecture capable of exerting forces, to move relative to each other. In addition, stem cells ensure that tissues function properly by dividing and giving rise to different cell types. For example, stem cells replace damaged cells during the repair of injured organs. Also in cancer there are stem cells, so call cancer stem cells, and these cancer stem cells (CSC) are believed to be required for cancer to spread to other sites in the body (metastasis) and are also linked to the re-emergence of cancer (relapse) after therapy. It is not currently possible to investigate the position and the behaviour of all cells in a living animal organ. In the last few years it has become possible to culture small organ-like structures and cancers in 3 dimensions, in so-called organoids. The cellular functions and interplay in organoids is very similar to what is observed in a living animal, thus organoids represent a unique system to study the collective behaviour of cells.Here we will explore how tissue variability in mammary gland organoids arises from mechanical forces exerted by cells on each other, and how stem cells divide and give rise to other cell types. We will look at mammary gland organoids because breast cancer is a very common disease and affects 1 in 7 woman. To do this, we will develop a system to image organoids over a prolonged period of time and use it to investigate where the stem cells are, how they divide, what type of progeny cells they generate, and how stem and progeny cells exert forces inside the organoid, to produce different organ and cancer shapes. This imaging will be performed using a custom-built microscope, and the analysis be performed using sophisticated computational and physical modelling approaches.We will then use methods from physical sciences and numerical simulations to understand how the uncertainty in cellular behaviour results in variability of tissue shapes. Mathematical tools from theoretical physics allow to connect the behaviour of a physical system at different scales. By using a multidisciplinary approach, we will apply these tools to address the question of organ-scale variability.