Tumor-initiating cells establish an IL-33–TGF-β niche signaling loop to promote cancer progression

doi:10.1126/science.aay1813

GSTDTAP > 气候变化

DOI	10.1126/science.aay1813
	Tumor-initiating cells establish an IL-33–TGF-β niche signaling loop to promote cancer progression
	Sachiko Taniguchi; Ajit Elhance; Avery Van Duzer; Sushil Kumar; Justin J. Leitenberger; Naoki Oshimori
	2020-07-17
发表期刊	Science
出版年	2020
英文摘要	Cancer cells that give rise to solid tumors reside in a specialized microenvironment containing growth factors that support tumor growth and progression. The mechanisms by which tumor cells within this so-called “niche” attract and sustain these growth factors are poorly understood. Studying a mouse model of squamous cell carcinoma, Taniguchi et al. identified a signaling loop initiated by certain tumor cells within the niche that become more invasive on exposure to transforming growth factor β (TGF-β). They show that the tumor cells release the cytokine interleukin-33, which induces the differentiation of nearby myeloid cells into macrophages. These macrophages in turn release TGF-β, which feeds back to the tumor cells, promoting their malignant progression. Science this issue p. [eaay1813][1] ### INTRODUCTION A small subset of tumor cells with long-term tumorigenic capacity, known as tumor-initiating cells (TICs), play a pivotal role in cancer development and therapy resistance. However, the development of effective TIC-targeted therapies is moving at a restricted pace due to the lack of identification of TIC vulnerabilities. Just as normal stem cells are regulated by external cues derived from specialized microenvironments, or stem cell niches, the stem-like state of TICs and the malignant phenotypes of their progeny are controlled by various factors emanating from the TIC-associated tumor microenvironment, the so-called TIC niche. Therefore, a mechanistic understanding of the cross-talk between TICs and the niche could accelerate the development of durable cancer therapeutics. Although the TIC niche is thought to evolve through reciprocal interactions with TICs, the mechanism by which the TIC–niche interaction emerges in the course of tumor development is poorly understood. Solid tumors are known to recruit immune cells in the stroma and create favorable conditions for their growth and survival. However, not much is known about how TICs regulate the localization and function of TIC-supportive immune cells in their spatial proximity. ### RATIONALE Using a mouse model of squamous cell carcinoma (SCC), we previously showed that transforming growth factor β (TGF-β) induces a subset of drug-resistant TICs that give rise to invasive, poorly differentiated progeny. We observed that these TGF-β–responding tumor cells are spatially associated with localized TGF-β expression in the adjacent stroma. Therefore, the mechanisms that lead to “TGF-β–rich” tumor microenvironments may underlie the development of TIC–niche interactions and potentially be exploited as a new target for destabilizing TICs. Because normal stem cells coordinate their niches by sending short-distance signals, we hypothesized that TICs might send a specific signaling molecule to the adjacent stroma to induce a TIC-supporting niche. ### RESULTS Focusing on the cytokine milieu and immune cells in the proximity of TGF-β–responding TICs, here, we address how TICs generate a spatially distinct niche microenvironment that is required for invasive progression and drug resistance of SCC. In a search for potential paracrine regulators of the neighboring tumor microenvironment, we identified interleukin-33 (IL-33) as the most highly up-regulated cytokine in TGF-β–responding TICs. Whereas IL-33 is stored in the nucleus under normal conditions, we found that it is released into the extracellular space in response to the NRF2-mediated antioxidant response, a hallmark of TGF-β–responding TICs. This TIC-derived IL-33 was required for invasive progression and drug resistance of SCC. Mechanistically, IL-33 induces the accumulation of a subset of tumor-associated macrophages expressing the IL-33 receptor ST2 and the high-affinity IgE receptor (FcεRIα) in close proximity to TICs (i.e., within a 50-μm radius). These previously unappreciated FcεRIα+ macrophages were differentiated and alternatively activated from bone marrow–derived cells and created a TGF-β–rich niche microenvironment through the IL-33–ST2–NF-κB pathway, inducing paracrine TGF-β signaling to TICs and further upregulating IL-33 expression. The abrogation of the pathway or the depletion of FcεRIα+ macrophages reduced the number of TGF-β–responding TICs, the rate of invasive tumor progression, and chemotherapy resistance. ### CONCLUSION Therapy-resistant TICs are considered to be major culprits in cancer treatment failure. Studying a mouse model, we unveil the cellular and molecular basis for the formation of a TIC niche that promotes malignant progression and drug resistance of SCC. The discovery of the IL-33–TGF-β niche signaling loop between TICs and FcεRIα+ macrophages provides mechanistic insights into self-reinforcing TIC–niche interactions, which could be a potential target for destabilizing TICs to improve cancer treatment efficacy. ![Figure][2] Signaling loop in the TIC niche that promotes cancer progression in mice. TGF-β–responding TICs release IL-33 via the NRF2-mediated antioxidant response. This induces differentiation of immature myeloid cells into FcεRIα+ macrophages in close proximity to the TICs. In turn, FcεRIα+ macrophages send reciprocal paracrine TGF-β signals to TICs to promote invasive progression and drug resistance of SCC and further induce the release of IL-33, thereby establishing a self-reinforcing signaling loop. Targeting the cross-talk between tumor-initiating cells (TICs) and the niche microenvironment is an attractive avenue for cancer therapy. We show here, using a mouse model of squamous cell carcinoma, that TICs play a crucial role in creating a niche microenvironment that is required for tumor progression and drug resistance. Antioxidant activity in TICs, mediated by the transcription factor NRF2, facilitates the release of a nuclear cytokine, interleukin-33 (IL-33). This cytokine promotes differentiation of macrophages that express the high-affinity immunoglobulin E receptor FcεRIα and are in close proximity to TICs. In turn, these IL-33–responding FcεRIα+ macrophages send paracrine transforming growth factor β (TGF-β) signals to TICs, inducing invasive and drug-resistant properties and further upregulating IL-33 expression. This TIC-driven, IL-33–TGF-β feedforward loop could potentially be exploited for cancer treatment. [1]: /lookup/doi/10.1126/science.aay1813 [2]: pending:yes
领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/284341
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Sachiko Taniguchi,Ajit Elhance,Avery Van Duzer,等. Tumor-initiating cells establish an IL-33–TGF-β niche signaling loop to promote cancer progression[J]. Science,2020.
APA	Sachiko Taniguchi,Ajit Elhance,Avery Van Duzer,Sushil Kumar,Justin J. Leitenberger,&Naoki Oshimori.(2020).Tumor-initiating cells establish an IL-33–TGF-β niche signaling loop to promote cancer progression.Science.
MLA	Sachiko Taniguchi,et al."Tumor-initiating cells establish an IL-33–TGF-β niche signaling loop to promote cancer progression".Science (2020).