Integrin control of epithelial polarity and glandular tissue morphogenesis

整合素控制上皮极性和腺组织形态发生

• 批准号: MR/P028411/1
• 负责人: Nasreen Akhtar
• 金额: $ 78.86万
• 依托单位: University of Sheffield
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FP028411%2F1
• 关键词: Integrin; control; epithelial; polarity; glandular

The majority of human cancers develop in specialized cells called epithelia, which are the most abundant cell type in the body. Internally epithelia are built into hollow tubes connected to ball-shaped alveoli, which form the common units of most organs. The hollow lumens within the tubes and alveoli are vital for correct tissue function, for example, alveoli in the breast secrete milk into the lumen which is then transported towards the nipple by connecting ducts. A common feature of epithelial tumours is that cells pile up in the lumen spaces blocking the ducts and alveoli. The displacement of cells might further contribute towards cancer progression. In this proposal we aim to explore the messages that control normal cell organization within breast tissue. This information is necessary so that we can identify and treat the defects that lead to breast cancer in future studies. Epithelia assemble within tissues by sticking to each other and a supportive matrix which coats the entire tissue. Attachments to the matrix occur through specific cell surface receptors called integrins. These receptors transmit information from the matrix to the cell. Adhesion to each other and the matrix create different instructions on each side of the cell, which means that epithelia accumulate distinct groups of proteins and fats on their top, bottom and sides, called epithelial polarization. This membrane configuration enables epithelia to form hollow spaces within tissues and secrete products into the lumen. How cells integrate many different signals from the matrix and interpret the messages to organize their membranes and position themselves properly within tissues remains poorly understood.Using a specialized 3D tissue culture technology where isolated breast epithelia form tiny organoids, we recently discovered that beta1 integrin is essential for breast alveolar organization. Without this integrin, the alveoli became disorganized with cells blocking the lumen spaces, resembling an early breast cancer phenotype. We further revealed that loss of beta1 integrin blinded the cells to the matrix causing them to flip their tops and bottoms to opposite ends. We then confirmed our findings by removing this integrin from breast tissue within mice and found a similar effect of disorder. However, we spotted one key difference, the cells although blocking the lumen spaces were not completely upside down as in the culture model. Understanding this is of medical importance because misorientation of the membranes might alter cell behaviour. For instance some aggressive breast cancers that spread to lymph nodes have upside down cells, which might enable them to stick better inside lymph vessels aiding the spread of cancer. We hypothesize that in an intact animal epithelia receive extra messages from the matrix made by surrounding cells known as myoepithelia, which might prevent them from flipping over. Our original 3D organoids were almost devoid of this cell type and we have now built new co-culture technology containing both cell types that resembles breast tissue more accurately. Our objectives are to build transgenic mouse models to test how beta1 integrin from the two cell types assemble breast tissue inside mice. In parallel studies, we will use the co-culture organoids to dissect further how different integrin systems from the two breast cell types contribute to tissue architecture and attempt to restore tissue architecture by recreating the hollow spaces in the integrin defective alveoli. Overall, the work in this project will decipher how epithelial cells unravel information from the microenvironment to organize themselves properly within the breast. Ultimately this will lead to better strategies for the diagnosis of cancers.

大多数人类癌症在称为上皮细胞的特化细胞中发展，上皮细胞是体内最丰富的细胞类型。在内部，上皮细胞被构建成连接到球形肺泡的中空管，球形肺泡形成大多数器官的共同单位。导管和肺泡内的中空腔对于正确的组织功能至关重要，例如，乳房中的肺泡将乳汁分泌到管腔中，然后通过连接导管将乳汁输送到乳头。上皮肿瘤的一个共同特征是细胞堆积在管腔空间中，阻塞导管和肺泡。细胞的移位可能进一步促进癌症进展。在这项提案中，我们的目标是探索控制乳腺组织内正常细胞组织的信息。这些信息是必要的，这样我们就可以在未来的研究中识别和治疗导致乳腺癌的缺陷。上皮细胞在组织内通过相互粘附和覆盖整个组织的支持性基质来组装。通过称为整合素的特异性细胞表面受体发生对基质的粘附。这些受体将信息从基质传递到细胞。相互粘附和基质在细胞的每一侧产生不同的指令，这意味着上皮细胞在其顶部，底部和侧面积累不同的蛋白质和脂肪组，称为上皮极化。这种膜结构使上皮细胞能够在组织内形成空腔并将产物分泌到管腔中。细胞如何整合来自基质的许多不同信号并解释这些信息以组织它们的膜并在组织内正确定位仍然知之甚少。使用专门的3D组织培养技术，分离的乳腺上皮形成微小的类器官，我们最近发现β 1整合素对乳腺肺泡组织至关重要。如果没有这种整合素，肺泡变得紊乱，细胞阻塞管腔空间，类似于早期乳腺癌表型。我们进一步发现，β 1整合素的丢失使细胞对基质失去了知觉，导致它们将顶部和底部翻转到相反的两端。然后，我们通过从小鼠乳腺组织中去除这种整合素来证实我们的发现，并发现了类似的紊乱效应。然而，我们发现了一个关键的区别，细胞虽然阻塞了管腔空间，但并不像培养模型中那样完全颠倒。理解这一点具有医学重要性，因为膜的错误取向可能会改变细胞行为。例如，一些扩散到淋巴结的侵袭性乳腺癌细胞倒置，这可能使它们能够更好地粘附在淋巴管内，帮助癌症扩散。我们假设，在一个完整的动物上皮细胞接收额外的信息，从周围的细胞称为肌上皮细胞，这可能会阻止他们翻转矩阵。我们最初的3D类器官几乎没有这种细胞类型，我们现在已经建立了包含两种细胞类型的新的共培养技术，更准确地类似于乳腺组织。我们的目标是建立转基因小鼠模型，以测试来自两种细胞类型的β 1整合素如何在小鼠体内组装乳腺组织。在平行研究中，我们将使用共培养类器官来进一步剖析来自两种乳腺细胞类型的不同整合素系统如何有助于组织结构，并试图通过在整合素缺陷的肺泡中重建中空空间来恢复组织结构。总的来说，这个项目的工作将破译上皮细胞如何从微环境中解开信息，以在乳房内正确组织自己。最终，这将导致更好的癌症诊断策略。

项目成果

Rac1 controls cell turnover and reversibility of the involution process in postpartum mammary glands.

• DOI: 10.1371/journal.pbio.3001583
• 发表时间: 2023-01
• 期刊: PLoS biology
• 影响因子: 9.8

Rac1 controls cell turnover and mammary gland reversibility in post-partum involution

Rac1 控制产后复旧过程中的细胞更新和乳腺可逆性

• DOI: 10.1101/2022.02.28.482219
• 发表时间: 2022
• 作者: Mironov A