Pancreatic cancer-associated fibroblasts: function, detection, and regulation

胰腺癌相关成纤维细胞：功能、检测和调节

• 批准号: 10625325
• 负责人: Edna Cukierman
• 金额: $ 50.89万
• 依托单位: RESEARCH INST OF FOX CHASE CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625325
• 关键词: 3-Dimensional; Actin-Binding Protein; Actins; Animal Model; Archives; Biochemical; Biogenesis; Biological Markers; Blood; Bundling; Cartoons; Cell secretion; Cells; Clinical; Clinical Trials; Data; Data Set; Desmoplastic; Detection; Development; ECM receptor; Endocytosis; Equilibrium; Exhibits; Extracellular Matrix; Feedback; Fibroblasts; Future; Goals; Growth; Harvest; Homeostasis; Human; Immune system; In Vitro; Inflammatory; Integrin alpha5beta1; Integrins; Knock-out; Link; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Measures; Metabolic; Metabolism; Methods; Modeling; Molecular; Molecular Conformation; Monitor; Multivesicular Body; Mus; Nutritional; Outcome; PTK2 gene; Pancreatic Ductal Adenocarcinoma; Pathologic; Patients; Peptide Receptor; Plasma; Polarization Microscopy; Population; Process; Production; Proteins; Regulation; Reporting; Role; Route; Sampling; Series; Signal Transduction; Stress; Stromal Cells; Structure; Supporting Cell; System; Testing; Tissues; Transforming Growth Factor beta; Tumor Immunity; Tumor Promotion; Work; anti-cancer; antitumor effect; cancer type; carcinogenesis; design; effective therapy; extracellular; extracellular vesicles; gain of function; genetic regulatory protein; immunoregulation; improved; in vivo; inhibitor; interstitial; loss of function; mimetics; minimally invasive; mouse model; netrin-G1; novel; pancreatic cancer cells; pancreatic ductal adenocarcinoma cell; pancreatic ductal adenocarcinoma model; pancreatic neoplasm; postsynaptic; presynaptic; prevent; proteomic signature; receptor; receptor binding; receptor function; response; restraint; sample archive; three dimensional cell culture; transcriptome sequencing; tumor

PROJECT SUMMARY/ABSTRACT Pancreatic cancer induces a fibrous microenvironment, desmoplasia, which spans most of the tumor mass and contains cancer-associated fibroblasts (CAFs). CAFs sustain a cancer homeostatic equilibrium by producing extracellular matrices (ECMs) and secreting inflammatory factors. The ECM produced by CAFs prompts normal fibroblasts to undergo activation and transition into CAFs, thereby propagating desmoplastic expansion in a positive feedback loop. While the normal microenvironment suppresses tumor onset, desmoplasia can either support or avert pancreatic cancer. A better understanding of desmoplastic expansion and the ECM factors that control it could enable us to favor its anti-cancer functions. In fact, several clinical trials including some conducted at Fox Chase, aim at “normalizing desmoplasia” with the goal of harnessing CAF’s anti-tumor effects. Of note, we have defined a signaling axis that depends on CAF-ECM and includes its main receptors, integrins, and some actin bundling, particular endocytic regulatory proteins, and an extracellularly tethered presynaptic protein known as NetrinG1. Of note, NetrinG1 necessities co-receptors in cis and in trans to signal and we revealed that in response to ECM NetrinG1 drives pro-tumor CAF function. We also reported that ECM induced pro-tumor CAF activation includes the endocytic localization of the active conformation of an important ECM receptor, activated α5β1-integrin (a-α5), which we posit regulates the production of two unique extracellular vesicles. Finally, we saw that the trans co-receptor of NetrinG1 is expressed in CAFs and needed for effective formation of tumors when pancreatic cancer cells are injected into the pancreata of immune system-intact mice. Our central premise proposes that CAF pro-to-anti tumor function transition can be attained via blockage of the ECM-dependent NetrinG1 signaling axis, which is needed to achieve the functional “desmoplastic normalization” that can be detected in blood. We plan to test this hypothesis in three specific aims: 1- Ask how CAF-ECM regulates NetrinG1 expression and endocytic a-α5 regulation as well as what are the specific ECM components that are responsible for NetrinG1 expression and CAF’s pro-tumor function. 2- Investigate if the unique extracellular vesicles generated by NetrinG1 expressing CAFs could be traced systemically in patients’ blood (including archived samples and samples from the ongoing trial) and ask if these are indicative of the tumor associated desmoplastic pro vs anti-pancreatic cancer statuses. 3- Inquire if NetrinG1’s trans receptor, expressed in pro-tumoral functioning CAFs, could serve as a new target. The study’s ultimate goal is to capitalize on the natural tumor suppressive function and features of CAFs and block the tumor promoting ones as well as to systemically induce and detect a pro-to-anti pancreatic cancer CAF transition, which could be indicative of local desmoplastic status, for potential future clinical uses.

项目概要/摘要 胰腺癌会诱发纤维微环境，即结缔组织形成，它跨越大部分肿瘤块并 含有癌症相关成纤维细胞（CAF），通过产生维持癌症稳态平衡。 细胞外基质（ECM）和分泌炎症因子 CAF 产生的 ECM 提示正常。 成纤维细胞经历激活并转变为 CAF，从而在 虽然正常的微环境抑制肿瘤的发生，但结缔组织增生也可以。 支持或避免胰腺癌。更好地了解促纤维增生扩张和 ECM 因素。 事实上，控制它可以使我们支持其抗癌功能，其中包括一些临床试验。 Fox Chase 的目标是“使结缔组织形成正常化”，以利用 CAF 的抗肿瘤作用。 值得注意的是，我们定义了一个依赖于 CAF-ECM 的信号轴，包括其主要受体、整合素、 和一些肌动蛋白捆绑，特别是内吞调节蛋白，以及细胞外束缚的突触前蛋白 值得注意的是，NetrinG1 需要顺式和反式的辅助受体才能发出信号。 揭示了 NetrinG1 响应 ECM 驱动促肿瘤 CAF 功能，我们还报道了 ECM 诱导。 促肿瘤 CAF 激活包括重要 ECM 活性构象的内吞定位 受体，激活的α5β1-整合素（a-α5），我们认为它调节两种独特的细胞外蛋白的产生 最后，我们发现 NetrinG1 的反式辅助受体在 CAF 中表达，并且是有效发挥作用所必需的。 当胰腺癌细胞被注射到免疫系统完整的小鼠的胰腺中时，就会形成肿瘤。 我们的中心前提提出，CAF 的促肿瘤功能向抗肿瘤功能转变可以通过阻断来实现 ECM 依赖的 NetrinG1 信号轴，这是实现功能性“促纤维塑性”所必需的 正常化”可以在血液中检测到。 我们计划通过三个具体目标来检验这一假设： 1-询问CAF-ECM如何调节NetrinG1表达和内吞a-α5调节以及什么是 负责 NetrinG1 表达和 CAF 促肿瘤功能的特定 ECM 组件。 2- 研究是否可以追踪表达 NetrinG1 的 CAF 产生的独特细胞外囊泡 系统地检测患者的血液（包括存档样本和正在进行的试验的样本），并询问这些是否 指示肿瘤相关促纤维增生性促胰腺癌与抗胰腺癌的状态。 3- 询问在促肿瘤功能 CAF 中表达的 NetrinG1 反式受体是否可以作为新靶点。 该研究的最终目标是利用 CAF 的天然肿瘤抑制功能和特征， 阻断肿瘤促进因子，并系统诱导和检测抗胰腺癌 CAF 转变，这可能表明局部促纤维增生状态，用于未来潜在的临床用途。