Paracrine Role of Endothelial Cells in HER3-Mediated Colon Cancer Cell Survival

项目：结直肠癌(CRC)仍然是美国癌症相关死亡的第二大原因 各州。更好地了解结直肠癌细胞化疗耐药的调节将导致新的 治疗策略和改善多发性结肠癌患者的预后。我们的初步研究表明 ECS向条件培养液(CM)分泌可溶性因子，进而通过激活提高癌细胞的存活率 人表皮生长因子受体3(HER3，又称ERBB3)在RAS野生型和突变型大肠癌中的表达 细胞。然而，激活HER3的EC分泌因子(S)和激活HER3的机制(S)在 CRC信元是未知的。我们假设CRC相关的HER3介导EC旁分泌效应。 促进不依赖RAS突变的结直肠癌细胞存活。在目标1中，我们将确定HER3在 EC诱导结直肠癌细胞在体内外存活。在目标2中，我们将确定EC分泌因子(S)， 在CRC细胞中激活HER3。在目标3中，我们将确定CRC细胞中与之耦合并激活的辅助因子 HER3.我们这个项目的长期目标是确定和验证开发潜力的新目标。 多发性结直肠癌患者的治疗方法。这项提案中的研究将有助于我们更好地理解 HER3，一种与其他HER受体相比尚未得到很好研究的受体。该项目将作为 利用HER3抗体/抑制剂治疗mCRC患者的新疗法的基础 已经在对各种癌症类型的临床试验中进行评估。应聘者：我的长期职业目标是 独立调查员进行翻译研究和教学/辅导，重点研究 将有助于更好地了解结直肠癌生物学，并有助于改善多发性结直肠癌患者的临床治疗， 而且可能与其他癌症类型有关。职业发展计划：除了进行研究和职业生涯 在提案中描述的与发展相关的培训，我将向每个委员会学习具体的科目 成员。我的导师Lee Ellis博士将教我有关结直肠癌的临床问题和实际问题 与医学肿瘤学家合作开发临床试验。(2)我的共同导师仙杜赖·马尼博士将 告诉我微环境影响癌细胞功能的机制。(3)我的委员 洪绵杰博士将教我HER3对癌细胞功能的影响。环境：诊所- M.D.安德森癌症中心(MDACC)的定向环境，我目前的实验室为我提供了 充分的机会了解复杂的癌症生物学和临床方面的结直肠癌。MDACC为 位于德克萨斯医疗中心(TMC)的中心，该中心拥有54个与医学相关的机构， 方圆5英里内。除了使用MDACC的可用资源外，我还将参加TMC主办的研究- 与职业发展有关的研讨会，并在必要时使用其他机构的核心设施。我的 专注于翻译性CRC研究，并热衷于建立一个独立资助的 这一领域的研究实验室非常符合NCI的使命和K99/R00奖的目标。

Project: Colorectal cancer (CRC) remains the second-leading cause of cancer-related death in the United States. Having a better understanding of the regulation of chemoresistance in CRC cells would lead to new therapeutic strategies and improve outcomes for patients with mCRC. Our preliminary studies showed that ECs secrete soluble factors to conditioned medium (CM), in turn, increased cancer cell survival by activating human epidermal growth factor receptor 3 (HER3, also known as ERBB3) in RAS wildtype and mutant CRC cells. However, the EC-secreted factor(s) for HER3 activation and the mechanism(s) of activating HER3 in CRC cells are unknown. We hypothesize CRC-associated HER3 mediates the EC paracrine effects on promoting CRC cell survival independent of RAS mutations. In Aim 1, we will determine the role of HER3 in EC-induced CRC cell survival in in vitro and in vivo. In Aim 2, we will identify the EC-secreted factor(s) that activate HER3 in CRC cells. In Aim 3, we will identify the co-factors in CRC cells that couple with and activate HER3. Our long term goal of this project is to identify and validate new targets for developing potential therapeutic approaches for patients with mCRC. Studies in this proposal will help us to better understand HER3, a receptor that is not well studied compared to other HER receptors. This project will serve as the foundation of novel therapies for treating patients with mCRC utilizing HER3 antibodies/inhibitors that are already being assessed in clinical trials for various cancer types. Candidate: My long-term career goal is to be an independent investigator conducting translational research and teaching/mentoring focusing on studies that will lead to a better understanding of CRC biology and help improving clinical therapy for patients with mCRC, and potentially with other cancer types. Career Development plan: In addition to conduct research- and career development-related trainings described in the proposal, I will learn specific subjects from each committee member. (1) My mentor Dr. Lee Ellis will teach me clinical problems related to CRC and the practical aspects of developing clinical trials in collaboration with Medical Oncologists. (2) My co-mentor Dr. Sendurai Mani will teach me the mechanisms by which microenvironment affects cancer cell functions. (3) My committee member Dr. Mien-Chie Hung will teach me the effects of HER3 on cancer cell functions. Environment: The clinic- orientated environment at M.D. Anderson Cancer Center (MDACC) and my current laboratory has offered me ample opportunities to understand the complicities of cancer biology and clinical aspects of CRC. MDACC is located in the center of the Texas Medical Center (TMC), which has 54 medicine-related institutions that are all within a 5-mile radius. In addition to use resources available at MDACC, I will attend TMC-hosted research- and career development-related seminars, and use core facilities from other institutions, when necessary. My concentration on translational CRC research and enthusiasm for establishing an independently funded research laboratory in this area fit well with the mission of NCI and with the objectives of the K99/R00 award.