Understanding metabolic heterogeneity in pancreatic cancer

项目总结/摘要 胰腺导管腺癌（PDAC）是一种五年生存率极低的癌症， 大多数患者被诊断患有无法治愈的转移性疾病。新疗法旨在针对不同的 需要PDAC细胞的生物学特性，因为目前的治疗提供的存活益处很少。治疗目的是 靶向癌症独特的代谢已经在其他癌症中取得成功，并可应用于 PDAC的治疗使PDAC肿瘤中代谢研究复杂化的是，大多数肿瘤 由基质细胞如成纤维细胞组成，而几乎没有肿瘤由癌细胞组成。到 为了更好地了解PDAC代谢并开发适当的治疗方法，我们必须了解代谢 癌症和基质细胞之间的差异。 本研究的主要目的是研究胰腺癌的代谢异质性。以来 单层贴壁细胞培养系统在建模异质性方面有局限性，该提案概述了一种 研究类器官共培养物和小鼠模型中分选的PDAC细胞类型代谢的新方法。 通过研究13 C标记的营养素掺入稳定的大分子，我们可以绕过所提出的问题 代谢反应的短时间尺度。这个项目的目标是检查代谢差异 PDAC癌细胞和原发性肿瘤中的成纤维细胞之间的差异（目的1），并比较这些细胞的代谢 细胞与转移性肿瘤内的肿瘤细胞和成纤维细胞的差异（Aim 2）。首先，我将使用13 C-营养追踪 在类器官共培养物和PDAC小鼠模型中转化为稳定的大分子， PDAC细胞类型之间的使用不同。然后，我将使用Crispr-Cas9来检查不同的 癌细胞和基质中的代谢酶。最后，我将使用这种方法来探讨 原发性肿瘤内癌细胞和成纤维细胞之间的代谢与这些细胞的代谢有关， 体内转移。 拟议的培训计划将支持我向独立过渡。我召集了一队 科学家与科学和职业指导的杰出记录，以帮助我实现我的目标， 成为一名独立的科学家：泰勒杰克斯博士，开发癌症小鼠模型的领导者。 大卫Tuveson，在胰腺癌和间质的专家，和布赖恩沃尔平博士，临床医生广泛 胰腺癌的治疗方法这些科学家将作为合作者定期与我会面， 我的职业指导委员会成员我的培训计划还概述了我将培养科学 和职业导师，提高我的科学沟通技能，发展教学和指导技能，建立 我的网络，学习实验室管理技能。科学的建议和职业发展计划 将给我的培训和专业知识，我需要成为一个成功的独立调查员在该领域的 癌症生物学

Project Summary/Abstract Pancreatic ductal adenocarcinoma (PDAC) is a cancer with an extremely low five-year survival rate, with most patients diagnosed with incurable metastatic disease. New therapies aimed at targeting the distinctive biology of PDAC cells are needed since current treatments offer little survival benefit. Therapies aimed at targeting cancer's unique metabolism have been successful in other cancers and can be applied to the treatment of PDAC. Complicating the study of metabolism in PDAC tumors is the fact that most of the tumor is composed of stromal cells such as fibroblasts, whereas little of the tumor is composed of cancer cells. To better understand PDAC metabolism and develop appropriate therapies, we must understand the metabolic differences between cancer and stromal cells. The main goal of this proposal is to investigate metabolic heterogeneity in pancreatic cancer. Since monolayer adherent cell culture systems have limitations in modeling heterogeneity, this proposal outlines a new approach for studying metabolism in sorted PDAC cell types in organoid co-cultures and mouse models. By studying 13C-labeled nutrient incorporation into stable macromolecules, we can bypass the problem posed by the short timescale of metabolic reactions. The goals of this project are to examine metabolic differences between PDAC cancer cells and fibroblasts in primary tumors (Aim 1) and compare the metabolism of these cells to that of tumor cells and fibroblasts within metastatic tumors (Aim 2). First, I will use 13C-nutrient tracing into stable macromolecules in organoid co-cultures and mouse models of PDAC to understand how nutrient use differs between PDAC cell types. I will then use Crispr-Cas9 to examine the requirement for different metabolic enzymes in cancer cells and stroma. Finally, I will use this method to explore differences in metabolism between cancer cells and fibroblasts within a primary to tumor to the metabolism of these cells in metastases in vivo. The proposed training plan will support me in my transition to independence. I have assembled a team of scientists with an outstanding track record of scientific and career mentoring to help me achieve my goal of becoming an independent scientist: Dr. Tyler Jacks, a leader in developing mouse models of cancer, Dr. David Tuveson, an expert in pancreatic cancer and stroma, and Dr. Brian Wolpin, a clinician with extensive expertise in pancreatic cancer treatment. These scientists will meet with me regularly as collaborators and members of my career mentoring committee. My training plan also outlines ways that I will cultivate scientific and career mentors, improve my science communication skills, develop teaching and mentoring skills, build my network, and learn lab management skills. Together, the scientific proposal and career development plan will give me the training and expertise I need to become a successful independent investigator in the field of cancer biology.