Mechanisms of cellular crosstalk in tumor-promoting niche formation

细胞串扰促进肿瘤微环境形成的机制

• 批准号: 10310520
• 负责人: Naoki Oshimori
• 金额: $ 42.04万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10310520
• 关键词: ATAC-seq; Address; Antioxidants; Cancer Patient; Cell physiology; Cells; Critical Pathways; Cues; Data; Development; Disease; Distant; Drug resistance; Epigenetic Process; Exhibits; Genes; Goals; Growth; Homeostasis; IgE; Immune; Immunohistochemistry; Label; Lead; Life; Malignant - descriptor; Malignant Neoplasms; Mediating; Metabolism; Methods; Modeling; Molecular; Molecular Profiling; Myeloid Cells; Oncogenic; Paracrine Communication; Pathway interactions; Phenotype; Play; Property; RAS genes; Radial; Recurrence; Regulation; Research; Research Project Grants; Resistance; Role; Signal Transduction; Signaling Molecule; Solid Neoplasm; Squamous cell carcinoma; Stress; Stromal Cells; Supporting Cell; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transcriptional Regulation; Treatment Efficacy; Treatment Failure; Tumor Tissue; base; cancer therapy; cancer type; chemotherapy; combat; cytokine; epigenetic regulation; improved; in vivo; macrophage; malignant phenotype; mouse model; neoplastic cell; novel; paracrine; programs; recruit; refractory cancer; response; single-cell RNA sequencing; stem; stem cell function; stem cells; targeted treatment; therapy resistant; transcription factor; transcriptome sequencing; treatment strategy; tumor; tumor microenvironment; tumor progression; tumorigenesis

Project Summary Many types of cancer harbor disease-sustaining tumor cells, or tumor-initiating cells (TICs), that play a pivotal role in cancer development. TICs have been implicated in drug resistance and tumor recurrence, making them a rational target for therapeutic intervention. However, methods for destabilizing TICs have not been as evident as was initially hoped. The long-term goal of my research program is to identify cellular crosstalk and molecular pathways involved in the regulation of stem cells in tissue homeostasis and cancer development. Just as normal stem cells are regulated by external cues derived from specialized microenvironments or stem cell niches, the stem-like state and malignant properties of TICs are controlled by various factors emanating from the TIC-associated microenvironment, the so-called TIC niche. Therefore, targeting the crosstalk between TICs and the niche is an attractive avenue for durable cancer therapy. While solid tumors are known to recruit immune cells in the stroma and create favorable conditions for their growth and survival, little is known about how TICs regulate the localization and function of tumor-supportive immune cells in their spatial proximity. Our incomplete understanding of the complexity of the niche and the plasticity of TICs is a significant barrier to improving therapeutic efficacy. Invasive squamous cell carcinoma (SCC) exhibits high rates of recurrence driven by therapy-resistant TICs at the tumor-stroma interface, making it a rational model to study the crosstalk between TICs and the potential niche cells. We previously devised a de novo SCC mouse model that allows us to label and lineage trace TGF--responding tumor cells. Through this approach, we have demonstrated that tumor cells responding to paracrine TGF- signaling promote invasive tumor progression. Moreover, TGF-- responding tumor cells function as drug-resistant TICs through activation of NRF2-mediated antioxidant metabolism and drive tumor recurrence. Therefore, the mechanisms that lead to “TGF--rich” tumor microenvironments may precede the development of TIC–niche interactions, which could potentially be exploited as a new target for destabilizing TICs. Recently, we found that TICs release IL-33 through TIC- intrinsic stress-resistant activities, which induces the accumulation of a subset of macrophages in close proximity of TICs. These IL-33-responding macrophages are alternatively-activated and send reciprocal TGF- signaling to induce invasive and drug-resistant properties in TICs. Based on our preliminary data, our central hypothesis is that the IL-33–TGF- paracrine signaling loop constitutes a feedforward mechanism that promotes the formation of a robust TIC niche, in which both tumor-promoting functions of macrophages and malignant properties of TICs are induced. Here we will determine the mechanism of tumor-promoting niche formation and malignant transformation of TICs, which could help identify the vulnerability of TICs to combat therapy-resistant cancers.

项目摘要 许多类型的癌症都含有维持疾病的肿瘤细胞，或肿瘤起始细胞（TIC），它们在癌症的发生中起着关键作用。 在癌症发展中的作用。TIC与耐药性和肿瘤复发有关， 治疗干预的合理目标。然而，使TIC不稳定的方法并不明显 正如最初所希望的那样。我的研究计划的长期目标是确定细胞串扰和分子 干细胞在组织稳态和癌症发展中的调节途径。正如 正常的干细胞受到来自特殊微环境或干细胞的外部信号的调节， 小生境、干样状态和恶性性质的TIC是由各种因素控制的， TIC相关的微环境，即所谓的TIC生态位。因此，针对TIC之间的串扰 这个利基市场是一个有吸引力的持久癌症治疗途径。虽然实体瘤是已知的招募 免疫细胞在基质中的作用，并为它们的生长和存活创造有利条件， TIC如何调节肿瘤支持性免疫细胞在其空间邻近性中的定位和功能。我们 对生态位的复杂性和CIC的可塑性的不完全理解是一个重大障碍， 提高治疗效果。浸润性鳞状细胞癌（SCC）的复发率很高 由肿瘤-间质界面处的治疗抗性TIC驱动，使其成为研究串扰的合理模型。 和潜在的小生境细胞之间的联系我们以前设计了一个从头SCC小鼠模型， 以标记和追踪TGF-β-应答肿瘤细胞。通过这种方法，我们已经证明， 肿瘤细胞对旁分泌TGF-β信号传导的应答促进侵袭性肿瘤进展。此外，TGF-β- 应答肿瘤细胞通过激活NRF 2介导的抗氧化剂发挥耐药TIC的功能 代谢和驱动肿瘤复发。因此，导致“富含TGF-β”肿瘤的机制 微环境可能先于TIC生态位相互作用的发展，这可能是潜在的 被用作破坏TIC稳定的新目标最近，我们发现TIC通过TIC释放IL-33， 内在的抗应激活动，诱导一个子集的巨噬细胞的积累，在关闭 TICs附近这些IL-33应答巨噬细胞被交替激活， 信号传导以诱导TIC中的侵袭性和耐药性。根据我们的初步数据， 假设IL-33-TGF-β旁分泌信号环构成前馈机制， 促进了一个强大的TIC生态位的形成，其中巨噬细胞和 诱导TIC的恶性性质。在这里，我们将确定肿瘤促进龛的机制 形成和恶性转化的TIC，这可以帮助确定脆弱性的TIC打击 治疗抵抗性癌症。