Tumor Microenvironment Crosstalk Drives Early Lesions in Pancreatic Cancer

总体-摘要 胰腺导管腺癌（PDAC）是胰腺癌相关死亡的第三大常见原因。 美国，绝大多数患者表现为晚期疾病。侵入性 胰腺肿瘤是一个多步骤进展的顶点， 前驱病变仍然是早期发现和癌症拦截的未开发的“机会之窗”。 前体病变的两种主要组织学亚型被确认-更常见的非囊性途径， 以胰腺上皮内瘤变或PanIN病变为代表，估计发生在约90%的PDAC之前，以及 囊性途径，最常见的是导管内乳头状粘液性肿瘤或IPMN， 占剩下的10%。虽然这个团队的成员在描述 PanIN和IPMNs的组织学和遗传学，在分子生物学方面仍有许多有待阐明的问题。 维持早期胰腺肿瘤的依赖性，以及这些早期病变的信号线索 重新编程“前体微环境”（PME），包括“前体相关成纤维细胞”（PAF）。的 我们的三州胰腺癌TBEL（Tri-PACT）中心的目标-合并UT MD安德森 癌症中心（UTMDACC），密歇根大学（UMich）和约翰霍普金斯大学（JHU）-是创造 一个合作和综合的U 54中心，在早期胰腺肿瘤中进行基础和转化研究。 Tri-PACT中心将由Anirban Maitra博士（UTMDACC）和Co-PI Marina Pasca di Magliano博士领导 （Umich）。我们的Tri-PACT中心提案的标题是“肿瘤微环境串扰驱动早期病变 我们提出了三个项目（两个基本项目，一个翻译项目），每个项目都将是 由多尺度计算肿瘤学研究核心（M-CORE）和管理核心（AC）支持。 项目1（基础）将研究一种关键细胞因子白细胞介素IL-33的功能需求， PanIN和IPMN的PAF和上皮区室响应KRAS和GNAS突变， 分别在疾病进展和PME的重编程中。项目2（基础）将研究一种独特的 代谢的“合成必要性”集中于在囊性前体中产生的线粒体质量控制， RNF 43是一种E3泛素连接酶，在约50%的IPMN中丢失。值得注意的是，Tri-PACT调查人员 开发了胰腺癌前病变的基因工程模型（GEM）， 人类病变，并将广泛利用在两个基本项目，与跨物种验证， 患者衍生的临床前模型。项目3（平移）将部署一个独特的3D重建工具（CODA） 与人类前驱病变的多区域测序配对，以绘制个体的进化轨迹， 前体在前所未有的分辨率，并关联亚克隆结构与高维分析 免疫和血小板活化因子的组成。这些项目累积起来将提高我们的 了解早期胰腺肿瘤的驱动因素，以及早期检测方法的温床。

OVERALL - ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is the 3rd most common cause of cancer-related mortality in the United States, with the overhwhelming majority of patients presenting advanced stage disease. Invasive neoplasia in the pancreas represents the culmination of a multistep progression that begins with non-invasive precursor lesions, which remain an untapped “window of opportunity” for early detection and cancer interception. Two major histological subtypes of precursor lesions are recognized - the more common non-cystic pathway, represented by pancreatic intarepithelial neoplasia or PanIN lesions, estimated to precede ~90% of PDAC, and the cystic pathway, most commonly represented by intraductal papillary mucinous neoplasms or IPMNs, accounting for the remaining 10%. While members of this team have played a seminal role in characterizing the histology and genetics of PanINs and IPMNs, much remains to be elucidated in terms of the molecular dependencies that sustain early pancreatic neoplasia, and how signaling cues from these early lesions reprogram the “precursor microenvironment” (PME), including “precursor-associated fibroblasts” (PAFs). The goal of our Tri-state Pancreatic Adenocarcinoma TBEL (Tri-PACT) Center - incorporating UT MD Anderson Cancer Center (UTMDACC), University of Michigan (UMich) and Johns Hopkins University (JHU) - is to create a collaborative and integrated U54 center to conduct basic and translational studies in early pancreatic neoplasia. The Tri-PACT Center will be led by Dr. Anirban Maitra (UTMDACC) and Co-PI Dr. Marina Pasca di Magliano (UMich). The title of our Tri-PACT Center proposal is “Tumor Microenvironment Crosstalk Drives Early Lesions in Pancreatic Cancer”, and we are proposing three projects (two basic, one translational), each of which will be supported by a Multiscale Computational Oncology Research Core (M-CORE) and an Administrative Core (AC). Project 1 (basic) will study the functional requirement of a pivotal cytokine, interleukin IL-33, which is induced in the PAF and epithelial compartments of PanINs and IPMNs in response to KRAS and GNAS mutations, respectively, in disease progression and reprogramming of the PME. Project 2 (basic) will study a unique metabolic “synthetic essentiality” centered on mitochondrial quality control created in cystic precursors that harbor loss of RNF43, a E3 ubiquitin ligase lost in ~50% of IPMNs. Notably, the Tri-PACT investigators have developed genetically engineered models (GEMs) of pancreatic preneoplasia that recapitulate the cognate human lesions, and will be extensively leveraged in the two basic projects, with cross-species validation in patient-derived preclinical models. Project 3 (translational) will deploy a unique 3D reconstruction tool (CODA) paired with multi-region sequencing of human precursor lesions to map the evolutionary trajectory of individual precursors at an unprecedented resolution, and correlate subclonal architecture with high dimensional analysis of the immune and PAF composition within the PME. Cumulatively, these projects will enhance our understanding of the drivers of early pancreatic neoplasia, and a seedbed for early detection approaches.