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

基本信息

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
项目类别：
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

项目摘要

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.

项目概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发挥着关键作用。 TIC 在癌症发展中的作用与耐药性和肿瘤复发有关，这使得它们成为可能。治疗干预的合理目标然而，破坏 TIC 稳定的方法尚不明确。正如最初所希望的那样，我的研究计划的长期目标是识别细胞串扰和分子。参与组织稳态和癌症发展中干细胞调节的途径。正常干细胞受到来自特殊微环境或干细胞的外部信号的调节在生态位中，TIC 的干状状态和恶性特性受多种因素控制 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。众所周知，实体瘤会招募新的肿瘤，而这一利基市场是持久癌症治疗的一个有吸引力的途径。间质中的免疫细胞并为其生长和生存创造有利条件，但人们对此知之甚少 TIC 如何调节肿瘤支持性免疫细胞在其空间邻近的定位和功能。对生态位的复杂性和 TIC 的可塑性的不完全了解是一个重大障碍提高侵袭性鳞状细胞癌（SCC）的复发率。由肿瘤-基质界面处的治疗抵抗性 TIC 驱动，使其成为研究串扰的合理模型我们之前设计了一种新的 SCC 小鼠模型，使我们能够在 TIC 和潜在的利基细胞之间进行研究。通过这种方法，我们已经证明了对 TGF-β 反应的肿瘤细胞进行标记和谱系追踪。肿瘤细胞对旁分泌 TGF-β 信号作出反应，促进侵袭性肿瘤进展。响应性肿瘤细胞通过激活 NRF2 介导的抗氧化剂发挥耐药 TIC 的作用因此，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，这可能是最近，我们发现 TIC 通过 TIC- 释放 IL-33。内在的抗应激活动，诱导巨噬细胞子集在近距离内积累这些 IL-33 反应巨噬细胞交替激活并发送相反的 TGF-β。根据我们的初步数据，我们的核心是诱导 TIC 的侵袭性和耐药性。假设 IL-33–TGF-β 旁分泌信号环路构成了一种前馈机制促进强大的 TIC 生态位的形成，其中巨噬细胞和 TIC 的恶性特性被诱导，在这里我们将确定肿瘤促进生态位的机制。 TIC 的形成和恶性转化，这有助于识别 TIC 的脆弱性治疗耐药的癌症。