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: 10520030
• 负责人: Naoki Oshimori
• 金额: $ 41.2万
• 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/10520030
• 关键词: ATAC-seq; Acceleration; Address; Antioxidants; Cancer Patient; Cell Survival; Cell physiology; Cells; Critical Pathways; Cues; Cytoprotection; Data; Development; Disease; Distant; Drug resistance; Epigenetic Process; Exhibits; Genes; Goals; Growth; Homeostasis; IgE; Immune; Immunohistochemistry; Label; Life; Macrophage; 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; Recurrent tumor; 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 Promotion; Tumor Tissue; cancer therapy; cancer type; chemotherapy; combat; cytokine; epigenetic regulation; improved; in vivo; malignant phenotype; meter; mouse model; neoplastic cell; novel; paracrine; programs; recruit; refractory cancer; response; single-cell RNA sequencing; stem; stem cell function; stem cell niche; stem cells; targeted treatment; therapy resistant; transcription factor; transcriptome sequencing; treatment strategy; tumor; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis; ATAC-seq; Acceleration; Address; Antioxidants; Cancer Patient; Cell Survival; Cell physiology; Cells; Critical Pathways; Cues; Cytoprotection; Data; Development; Disease; Distant; Drug resistance; Epigenetic Process; Exhibits; Genes; Goals; Growth; Homeostasis; IgE; Immune; Immunohistochemistry; Label; Life; Macrophage; 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; Recurrent tumor; 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 Promotion; Tumor Tissue; cancer therapy; cancer type; chemotherapy; combat; cytokine; epigenetic regulation; improved; in vivo; malignant phenotype; meter; mouse model; neoplastic cell; novel; paracrine; programs; recruit; refractory cancer; response; single-cell RNA sequencing; stem; stem cell function; stem cell niche; stem cells; targeted treatment; therapy resistant; transcription factor; transcriptome sequencing; treatment strategy; tumor; tumor initiation; 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 多种类型的癌症避免疾病的肿瘤细胞或肿瘤发射细胞（TICS），它们发挥了关键性 在癌症发展中的作用。在耐药性和肿瘤复发中暗示了抽动，使其成为 治疗干预的合理目标。但是，破坏抽动稳定的方法并不是证据 正如最初希望的那样。我的研究计划的长期目标是识别细胞串扰和分子 在组织稳态和癌症发育中调节干细胞调节的途径。就像 正常干细胞由源自专门微环境或干细胞的外部提示调节 TIC的壁ni，类似茎状的状态和恶性特性受到各种因素的控制 TIC相关的微环境，即所谓的TIC利基市场。因此，针对抽动之间的串扰 利基市场是耐用癌症治疗的有吸引力的途径。虽然已知实体瘤可以招募 基质中的免疫细胞并为其生长和生存创造了有利的条件，对 抽动如何调节其空间近端中肿瘤支持性免疫小球的定位和功能。我们的 对利基的复杂性和抽动的可塑性的不完全理解是对 提高治疗效率。侵入性鳞状细胞癌（SCC）表现出较高的复发率 受肿瘤疾病界面耐药性抽动的驱动，使其成为研究串扰的合理模型 在抽动和潜在的小众细胞之间。我们以前设计了一个从头scc鼠标模型，该模型允许我们 标记和谱系痕迹TGF-反应肿瘤细胞。通过这种方法，我们证明了 对旁分泌TGF-信号传导反应的肿瘤细胞促进侵入性肿瘤进展。而且，TGF-- 通过激活NRF2介导的抗氧化剂，反应肿瘤细胞充当抗药性抽动 代谢并驱动肿瘤复发。因此，导致“ TGF-富集”肿瘤的机制 微环境可能是在挑战相互作用的发展之前，这可能是 被利用为破坏抽动的新目标。最近，我们发现抽动通过TIC-发行IL-33 固有的耐应力活性，诱导巨噬细胞子集的积累 抽动的接近。这些IL-33响应巨噬细胞替代激活，并发送相互的TGF- 信号传导在抽动中诱导侵入性和抗药性特性。根据我们的初步数据，我们的中心 假设是IL-33 – TGF-旁分泌信号循环构成了一种前馈机制 促进稳健的TIC生态位的形成，其中巨噬细胞的肿瘤功能和 诱导抽动的恶性特性。在这里，我们将确定促进肿瘤的利基机理 抽动的形成和恶性转化，这可以帮助确定抽动与战斗的脆弱性 耐治疗的癌症。