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

肠癌是英国第四大最常见的癌症，每10例癌症死亡中就有1例是肠癌。虽然10名患者中有6名对目前的治疗（包括手术、放疗和化疗）反应良好，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很差，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)观察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)弄清楚使用药物打开或关闭这些基因的产物是否可以阻止肿瘤的生长或扩散。在许多癌症中，尤其是在肠癌中，有一个基因家族被称为磷酸肌醇修饰酶，它可以更容易地被称为PIP-MEs。PIP-MEs就像装配链上的工厂工人：他们每个人都按顺序行动，修改正在建造的东西的一个关键部分。“某物”是一组分子，它们对细胞的生存、死亡或某种行为至关重要；正在“构建”的是一组脂质分子，称为磷酸肌苷（PIPs）。在肠癌中，PIP-MEs变得不受控制，以至于它们不再起作用，或者在不应该起作用的时候不起作用。最终的结果是肠细胞有一个PIP- me工厂，要么产生过多的特定PIP，要么在不应该产生PIP的时候产生PIP。靶向这种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，我们如何只用靶向PIP-MEs的药物治疗肠癌细胞而不损害健康细胞？我打算在这个提案中解决这个问题。我之前的研究主要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-MEs在癌症中被破坏时，哪些产物（哪些pip）被错误地产生。其次，我开发了计算机辅助方法来识别改变PIP-MEs对细胞的影响，在实验室的培养皿中培养和分析了成百上千个“微型肠道”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些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。某些pip如何产生可能取决于细胞是正常的还是癌变的。肿瘤可能依赖于产生某些pip的方式，而正常细胞不需要那么多pip。因此，我建议某些PIP-MEs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）。我的目标是在这个提案中发展我们的技能，通过将微型组织移植回老鼠的肠道，并测试我们在实验室培养皿中的方法是否适用于活体生物体，将我们的研究从实验室的微型组织扩展到微型组织。这将使我们进一步了解如何在肠癌患者中使用PIP-MEs药物。此外，我将与一家生物技术行业公司合作，寻找将我们的方法转移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。我的长期目标是找到通过抑制PIP-MEs来治疗肠癌的改进方法，并为其他研究人员找到肠癌和其他癌症的治疗方法提供工具。

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.