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 胰腺癌诱导纤维微环境，结缔组织增生，其跨越大部分肿瘤块， 含有癌症相关成纤维细胞（CAF）。CAF通过产生 细胞外基质（ECM）和分泌炎症因子。CAF产生的ECM提示正常 成纤维细胞经历活化并转变成CAF，从而在一个细胞周期中传播促结缔组织增生性扩张。 正反馈回路虽然正常的微环境抑制肿瘤的发生，但结缔组织增生可以 支持或避免胰腺癌。更好地理解促结缔组织增生性扩张和ECM因素， 控制它可以使我们有利于它的抗癌功能。事实上，一些临床试验， 在福克斯大通，旨在“正常化结缔组织增生”的目标是利用CAF的抗肿瘤作用。 值得注意的是，我们已经定义了依赖于CAF-ECM的信号传导轴，包括其主要受体，整合素， 和一些肌动蛋白束，特别是内吞调节蛋白，以及一个细胞外系连的突触前 蛋白质称为NetrinG 1。值得注意的是，NetrinG 1需要顺式和反式的共受体来发出信号， 揭示了响应于ECM，NetrinG 1驱动促肿瘤CAF功能。我们还报道了ECM诱导 促肿瘤CAF活化包括重要ECM的活性构象的内吞定位 受体，激活的α5β1-整合素（α-α5），我们研究了它调节两种独特的细胞外 囊泡最后，我们看到NetrinG 1的反式共受体在CAFs中表达，并且需要有效的 当胰腺癌细胞被注射到免疫系统完整的小鼠的胰腺中时，肿瘤的形成。 我们的中心前提是，CAF的促肿瘤功能向抗肿瘤功能的转变可以通过阻断来实现 ECM依赖性NetrinG 1信号轴，这是实现功能性“促纤维增生”所必需的。 “正常化”可以在血液中检测到。 我们计划在三个具体目标中检验这一假设： 1-询问CAF-ECM如何调节NetrinG 1表达和内吞a-α5调节，以及 负责NetrinG 1表达和CAF的促肿瘤功能的特定ECM组分。 2-研究是否可以追踪表达CAF的NetrinG 1产生的独特细胞外囊泡 患者血液中的全身性（包括存档样本和正在进行的试验样本），并询问这些样本是否 指示肿瘤相关促结缔组织增生性促胰腺癌与抗胰腺癌状态。 3-询问NetrinG 1的反式受体，在促肿瘤功能CAFs中表达，是否可以作为新的靶点。 该研究的最终目标是利用CAFs的天然肿瘤抑制功能和特征， 阻断促癌因子，并系统诱导和检测促-抗胰腺癌CAF 过渡，这可能是局部促结缔组织增生状态的指示，用于潜在的未来临床用途。