OrgTIP: A transplantable organoid-to-in vivo pipeline for targeting phospholipid metabolism to stop colorectal carcinoma

OrgTIP：一种可移植的类器官到体内的管道，用于靶向磷脂代谢以阻止结直肠癌

• 批准号: MR/T040769/1
• 负责人: David Bryant
• 金额: $ 157.27万
• 依托单位: University of Glasgow
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT040769%2F1
• 关键词: OrgTIP; transplantable; organoid; vivo; pipeline

Bowel carcinoma is the 4th most common cancer in the UK, accounting for 1 out of 10 deaths from any type of cancer. While 6 out of 10 patients will respond well to current therapies, which can include surgery, radiotherapy and chemotherapy depending on the patient, 4 out of 10 patients will not respond to treatment. These non-responding patients have a very poor outlook and no current effective therapies. We therefore need to develop new therapies to treat these patients. One of the ways to do this is to: 1) look in bowel cancer cells that have the same gene signature as these poor outlook patients, 2) identify which genes are changed commonly, and 3) work out whether using drugs to turn the products of these genes on or off can stop the tumour from growing or spreading. One family of genes that are commonly altered in many cancers, and particularly in bowel cancer, are called Phosphoinositide-modifying enzymes, which can be more easily referred to as PIP-MEs. PIP-MEs are like factory workers in an assembly chain: they each act in a sequence to modify one key part of something being built. The 'something' is a set of molecules that is essential for whether a cell lives, dies, or behaves in a certain way; the item being 'built' is a set of lipid molecules called phosphoinositides (PIPs). In bowel cancer, the PIP-MEs become uncontrolled such that they no longer work, or work when they shouldn't. The end result is that bowel cells have a PIP-ME factory that is either making too much of a particular PIP or making a PIP when it shouldn't. Targeting this PIP-ME factory may be a new way to treat bowel cancer. One major stumbling block is that this PIP-ME factory is also important for normal cells. A key question to understand is how do we treat only bowel cancer cells with drugs that target PIP-MEs and not damage healthy cells? I aim to tackle this in this proposal. My previous research has focused on 2 complementary areas which form the basis of being able to address this question. First, I have developed new ways to map what products (which PIPs) are being mis-produced when PIP-MEs become disrupted in cancer. Second, I have developed computer-assisted ways to identify the consequence for cells of altering PIP-MEs, growing and analysing hundreds-to-thousands of 'mini-bowel' tissues in a dish in the lab. I have identified that the balance between two particular steps in the PIP-ME factory is essential to determine whether such mini-tissues undergo normal or tumour-like behaviour (e.g. grow too much or spread to where they shouldn't). How certain PIPs are made may depend on whether the cells are normal or cancerous. Tumours may depend on ways of making certain PIPs that normal cells do not need as much of. Therefore, I propose that certain PIP-MEs can be targeted to stop tumour growth, and this will preferentially affect tumour cells (rather than normal cells). I aim to develop the skills in this proposal to extend our studies from mini-tissues in the lab by transplanting mini-tissues back into the bowel of mice and testing whether our approaches in the dish in a lab hold true inside a living organism. This will move us a step closer towards understanding how we drug PIP-MEs in bowel cancer patients. In addition, I will work with a biotechnology industry company partner to find ways to move our approaches beyond my research lab, to provide our tools for the entire research community to develop new ways to combat cancer. My long-term goal is to identify improved ways to tackle bowel cancer by inhibiting PIP-MEs, and to provide the tools to enable other researchers to find treatments for bowel and other cancers.

肠癌是英国第四常见的癌症，占任何类型癌症死亡人数的十分之一。虽然10名患者中有6名对目前的治疗反应良好，根据患者的不同，这些治疗可能包括手术、放疗和化疗，但10名患者中有4名对治疗没有反应。这些无反应的患者前景非常差，目前没有有效的治疗方法。因此，我们需要开发新的疗法来治疗这些患者。其中一种方法是：1）寻找与这些前景不佳的患者具有相同基因特征的肠癌细胞，2）确定哪些基因通常发生变化，3）确定使用药物打开或关闭这些基因的产物是否可以阻止肿瘤生长或扩散。在许多癌症中，特别是在肠癌中通常改变的一个基因家族被称为磷酸肌醇修饰酶，其可以更容易地被称为PIP-ME。PIP-ME就像装配链中的工厂工人：他们每个人都按顺序修改正在建造的东西的一个关键部分。“东西”是一组分子，对细胞的生存、死亡或以某种方式表现至关重要;“构建”的项目是一组称为磷酸肌醇（PIP）的脂质分子。在肠癌中，PIP-ME变得不受控制，以至于它们不再工作，或者在不应该工作的时候工作。最终的结果是，肠细胞有一个PIP-ME工厂，它要么制造过多的特定PIP，要么制造不应该制造的PIP。靶向这个PIP-ME工厂可能是治疗肠癌的一种新方法。一个主要的障碍是，这个PIP-ME工厂对正常细胞也很重要。要理解的一个关键问题是，我们如何用靶向PIP-ME的药物治疗肠癌细胞而不损害健康细胞？ 我的目的是在这个建议中解决这个问题。我以前的研究集中在两个互补的领域，它们构成了解决这个问题的基础。首先，我开发了新的方法来绘制当PIP-ME在癌症中被破坏时，哪些产品（哪些PIP）被错误地生产。其次，我开发了计算机辅助的方法来确定改变PIP-ME的细胞的后果，在实验室的培养皿中生长和分析数百到数千个“迷你肠”组织。我已经确定，PIP-ME工厂中两个特定步骤之间的平衡对于确定这种微型组织是否经历正常或肿瘤样行为（例如，生长过多或扩散到不应该的地方）至关重要。 特定PIP的产生可能取决于细胞是正常的还是癌细胞。肿瘤可能依赖于制造某些PIP的方式，而正常细胞并不需要那么多PIP。因此，我建议某些PIP-ME可以靶向阻止肿瘤生长，这将优先影响肿瘤细胞（而不是正常细胞）。 我的目标是发展这项提议中的技能，通过将微型组织移植回小鼠的肠道，并测试我们在实验室培养皿中的方法是否适用于活体组织，从而将我们的研究从实验室的微型组织中扩展出来。这将使我们更进一步了解我们如何在肠癌患者中使用PIP-ME。此外，我将与一家生物技术行业公司合作，寻找将我们的方法推广到我的研究实验室之外的方法，为整个研究界提供我们的工具，以开发对抗癌症的新方法。我的长期目标是通过抑制PIP-ME来确定治疗肠癌的改进方法，并提供工具，使其他研究人员能够找到治疗肠癌和其他癌症的方法。

项目成果

The small GTPase ARF3 controls metastasis and invasion modality by regulating N-cadherin levels

• DOI: 10.1101/2022.04.25.489355
• 发表时间: 2022-04
• 期刊: bioRxiv
• 作者: Emma Sandilands;Eva C. Freckmann;Álvaro Román-Fernández;L. Mcgarry;L. Galbraith;S. Mason;Rachana Patel;Jayanthi Anand;J. Cartwright;H. Leung;K. Blyth;David M. Bryant

An ARF GTPase module promoting invasion and metastasis through regulating phosphoinositide metabolism.

• DOI: 10.1038/s41467-021-21847-4
• 发表时间: 2021-03-12
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: Nacke M;Sandilands E;Nikolatou K;Román-Fernández Á;Mason S;Patel R;Lilla S;Yelland T;Galbraith LCA;Freckmann EC;McGarry L;Morton JP;Shanks E;Leung HY;Markert E;Ismail S;Zanivan S;Blyth K;Bryant DM
• 通讯作者: Bryant DM

Spatial regulation of the glycocalyx component podocalyxin is a switch for prometastatic function.

• DOI: 10.1126/sciadv.abq1858
• 发表时间: 2023-02-03
• 期刊: Science advances
• 影响因子: 13.6

Traject3d allows label-free identification of distinct co-occurring phenotypes within 3D culture by live imaging.

轨迹3D允许通过实时成像在3D培养中无标记鉴定3D培养物中不同的同时发生表型。

• DOI: 10.1038/s41467-022-32958-x
• 发表时间: 2022-09-09
• 期刊: Nature communications
• 影响因子: 16.6

Conversations with LGBT+ scientists about visibility, leadership and climbing the career ladder.

与 LGBT 科学家讨论知名度、领导力和攀登职业阶梯。

• DOI: 10.1242/jcs.259880
• 发表时间: 2022
• 期刊: Journal of cell science
• 影响因子: 4
• 作者: Bristow RG