Crucial Microenvironmental Cofactors for Pancreatic Cancer Pathogenesis

描述（由申请人提供）：胰腺导管腺癌（PDA）是一种致命的疾病，几乎没有有效的治疗方案。PDA癌细胞在由多种细胞类型与基质和信号蛋白混合组成的复杂微环境中培养。像大多数复杂的系统一样，很难在实验室中准确地模拟微环境。如果没有良好的模型，我们识别和治疗影响微环境目标的尝试在临床上已经并将继续失败，因此这一领域的需求是直接和真实的。 这一创新项目远远超出了裸鼠模型中人类异种移植物的不足，以了解和利用PDA细胞对微环境线索的先天依赖性。我们已经发明了灵活的体外和体内系统，以在稳健和动态的临床前模型中独立地改变微环境组成以及药物和肿瘤细胞基因组亚型的存在。 这些新的模型现在准备直接测试假设，即微环境在这种难以治疗的疾病中具有离散的，未被认可的治疗靶点，并且癌细胞的转录亚型可能独立地影响这种治疗在临床上的表现。我们计划在这个100%胰腺癌相关的项目中发现，优先考虑和利用关键的微环境辅助因子，通过两个具体目标，重点是按亚型对PDA微环境进行个性化治疗。 具体目标1：通过共同靶向激酶MEK和参与对MEK抑制剂（MEKi）耐药的细胞外相互作用，优化准间充质（QM-PDA）亚型的治疗。 目标1.1：通过鉴定所涉及的整合素亚单位并定义TGF <$在该过程中的作用，描述QM-PDA亚型中整合素<$V（ITGAV）依赖性的机制。 目的1.2：在QM-PDA模型中验证MEKi组合共靶向整合素或TGF β受体的体内功效。 具体目标2：确定和利用胰腺星状细胞（PSC）衍生的因子，改变药物反应和/或影响转移行为。 目标2.1：使用微环境微阵列识别和抑制支持生长并赋予MEK抑制剂抗性的新型PSC产生的信号，以模拟体外微环境。目标2.2：通过在同基因系统中改变和共移植活化的、遗传修饰的PSC，从遗传上定义影响体内转移过程的PSC衍生因子。

DESCRIPTION (provided by applicant): Pancreatic Ductal Adenocarcinoma (PDA) is a deadly disease with few effective treatment options. The PDA cancer cell is nurtured in a complex microenvironment comprised of multiple cell types admixed with matrix and signaling proteins. Like most complicated systems, it has been hard to accurately model the microenvironment in the lab. Our attempts to identify and therapeutically impact microenvironmental targets have and will continue to fail in the clinic without good models, so the need in this area is immediate and real. This innovative project goes far beyond insufficient human xenograft in nude mouse models to both understand and exploit innate dependencies that PDA cells have for cues from their microenvironment. We have invented flexible in vitro and in vivo systems to independently vary microenvironmental composition alongside the presence of drug and tumor cell genomic subtype in robust and dynamic preclinical models. These novel models are now poised to directly test the hypotheses that the microenvironment harbors discrete, unappreciated treatment targets in this difficult to treat disease, and that the transcriptional subtype of the cancer cell might independently impact how such treatments fare clinically. We plan to discover, prioritize and exploit crucial microenvironmental cofactors here i this 100% pancreatic cancer-relevant project through two specific aims focused on personalizing treatment of the PDA microenvironment by subtype. Specific Aim 1: To optimize treatment of the Quasi-Mesenchymal (QM-PDA) subtype by co-targeting the kinase MEK and extracellular interactions involved in resistance to inhibitors of MEK (MEKi). Aim 1.1: Describe the mechanism of Integrin ¿V (ITGAV) dependence in the QM-PDA subtype by identifying the ¿ integrin subunit(s) involved, and defining the role(s) of TGF¿ in the process. Aim 1.2: Validate the in vivo efficacy of MEKi combinations co-targeting either ¿V Integrin or TGF¿ receptors in a QM-PDA model. Specific Aim 2: To define and exploit pancreatic stellate cell (PSC)-derived factors that change drug response and/or affect metastatic behavior. Aim 2.1: Identify and inhibit novel PSC-generated signals that support growth and confer resistance to MEK inhibitors using Microenvironment Microarrays, to mimic the microenvironment in vitro. Aim 2.2: Genetically define PSC-derived factors affecting the metastatic process in vivo, by altering and co-transplanting activated, genetically modified PSCs in a syngeneic system.