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: 10418178
• 负责人: Edna Cukierman
• 金额: $ 51.71万
• 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/10418178
• 关键词: 3-Dimensional; Actin-Binding Protein; Actins; Animal Model; Archives; Binding; Biochemical; Biogenesis; Biological Markers; Blood; Bundling; Cartoons; Cells; Clinical; Clinical Trials; Data; Data Set; Desmoplastic; Detection; Development; ECM receptor; Endocytosis; Equilibrium; Exhibits; Extracellular Matrix; Feedback; Fibroblasts; Foxes; Future; Goals; Growth; Harvest; 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; Molecular; Molecular Conformation; Monitor; Mus; Nutritional; Outcome; PTK2 gene; Pancreatic Ductal Adenocarcinoma; Pathologic; Patients; Peptides; Plasma; Polarization Microscopy; Process; Production; Proteins; Regulation; Reporting; Role; Route; Sampling; Series; Signal Transduction; Stress; Stromal Cells; Structure; Supporting Cell; System; Testing; Tissues; Transforming Growth Factor beta; Work; anti-cancer; antitumor effect; base; cancer type; design; effective therapy; extracellular; extracellular vesicles; 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; response; 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.

项目摘要/摘要 胰腺癌诱导了纤维微环境，脱木质，该环境涵盖了大多数肿瘤质量和 包含与癌症相关的成纤维细胞（CAF）。 CAF通过产生癌症稳态平衡 细胞外矩阵（ECM）和分泌炎症因素。 CAF生产的ECM提示正常 成纤维细胞会激活并过渡到CAF，从而在A 积极的反馈循环。正常的微环境抑制肿瘤的发作，而脱木质可以 支持或避免胰腺癌。更好地理解脱糖扩展和ECM因素 控制它可以使我们能够偏爱其抗癌功能。实际上，一些临床试验在内 在福克斯·蔡斯（Fox Chase），旨在“使脱木质”归一化，目的是利用CAF的抗肿瘤效应。 值得注意的是，我们定义了一个取决于CAF-ECM的信号轴，并包括其主要受体，整联蛋白， 还有一些肌动蛋白束，特定的内吞调节蛋白和细胞外束缚前突触 蛋白质称为Netring1。值得注意的是，netring1需要顺式和转换中的共受体，我们 揭示了对ECM Netring1的响应，驱动了亲肿瘤CAF的功能。我们还报告了ECM诱导的 亲肿瘤CAF激活包括重要ECM的主动构象的内吞定位 受体，激活的α5β1-整合蛋白（A-α5），我们可以调节两个独特的细胞外产生 囊泡。最后，我们看到netring1的反式共振动器在CAF中表达，需要有效 当将胰腺癌细胞注入免疫系统独立小鼠的胰腺时，肿瘤的形成。 我们的中心前提提出的CAF Pro-Ati肿瘤功能过渡可以通过阻塞附加 依赖ECM的Netring1信号轴的轴，这是实现功能性“脱塑料”所需的 可以在血液中检测到的归一化”。 我们计划以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调控以及什么是 负责Netring1表达和CAF的促肿瘤功能的特定ECM组件。 2-调查是否可以追溯到由Netring1表达CAF产生的独特细胞外蔬菜 系统地在患者的血液中（包括正在进行的试验中的存档样本和样本），并询问这些是否是否 指示与肿瘤相关的脱肿瘤疾病与抗胰腺癌统计。 3-询问Netring1的trans接收器是否在肿瘤功能CAF中表示，是否可以作为新目标。 该研究的最终目标是利用CAFS的自然肿瘤抑制功能和特征 阻止促进肿瘤的肿瘤，并系统地诱导和检测pro-to-anti胰腺癌CAF 对于潜在的未来临床用途，过渡可能表明局部去肿瘤状态。