A synthetic metastatic niche reveals antitumor neutrophils drive breast cancer metastatic dormancy in the lungs

Abstract

Biomaterial scaffolds mimicking the environment in metastatic organs can deconstruct complex signals and facilitate the study of cancer progression and metastasis. Here we report that a subcutaneous scaffold implant in mouse models of metastatic breast cancer in female mice recruits lung-tropic circulating tumor cells yet suppresses their growth through potent in situ antitumor immunity. In contrast, the lung, the endogenous metastatic organ for these models, develops lethal metastases in aggressive breast cancer, with less aggressive tumor models developing dormant lungs suppressing tumor growth. Our study reveals multifaceted roles of neutrophils in regulating metastasis. Breast cancer-educated neutrophils infiltrate the scaffold implants and lungs, secreting the same signal to attract lung-tropic circulating tumor cells. Second, antitumor and pro-tumor neutrophils are selectively recruited to the dormant scaffolds and lungs, respectively, responding to distinct groups of chemoattractants to establish activated or suppressive immune environments that direct different fates of cancer cells.

Neutrophils in the tumor microenvironment: role in tumor progression and potential targeted therapeutic strategy

“…By analyzing blood samples from 70 patients and 5 mouse models of breast cancer, Szczerba et al found that the majority of leukocytes escorting circulating breast cancer cells were neutrophils (85.5%-91.7%), and depleting the neutrophils with neutralizing antibodies leads to a delayed metastasis. They also found that the mouse injected with CTCs from CTC-neutrophil clusters developed metastasis much more quickly than those injected with CTCs alone, mirrored by a shorter overall survival (OS) [8] .…”

“…TANs were first identified as N1 and N2 by Fridlender in 2009, similar to tumor-associated macrophages (TAM) with heterogeneity and plasticity [3] . The N1 TANs are characterized by cytotoxic and pro-inflammatory properties due to their production of intercellular adhesion molecule-1 (ICAM-1), factor-related apoptosis (FAS), reactive oxygen species (ROS), and tumor necrosis factor-α (TNF-α), whereas N2 TANs have strong immunosuppressive properties induced by secreting cytokines, chemokines, chemokine ligands, and matrix metalloproteinase (MMPs), promoting angiogenesis to contribute to tumor metastasis [3,8] . Studies in mouse models of breast cancer have shown that the antitumor immunity in the metastatic niche (MN) is positively correlated with the proportion of N1/N2 TANs.…”

“…However, CTCs continuously suffer from the continuous impact of fluid shear force, oxidative stress, and immune cellkilling, so only a few CTCs can eventually reach the distal organs for colonization [28] . Neutrophils can interact with CTCs to form CTC-neutrophil clusters mediated by vascular cell adhesion molecule-1 (VCAM-1), aiding in CTC survival and even and even stimulating proliferation by promoting cell cycle progression in the blood vessels [8] . By analyzing blood samples from 70 patients and 5 mouse models of breast cancer, Szczerba et al found that the majority of leukocytes escorting circulating breast cancer cells were neutrophils (85.5%-91.7%), and depleting the neutrophils with neutralizing antibodies leads to a delayed metastasis.…”

Targets of tumor microenvironment for potential drug development

“…Besides PMN‐MDSCs, activity of other types of neutrophils can differ in protumor or antitumor states depending on their environment 107 . Neutrophils contribute to the formation of a premetastatic niche 108–111 . They are recruited by bone marrow‐derived myeloid cells, influenced by the primary tumor, which modulates secondary organ environments before tumor cell dissemination.…”

Rolling 2D Bioelectronic film into 1D: a Suturable Long-term Implantable Soft Microfiber

“…4g and 4h). This serve inflammatory may induce cancer later ( 42, 43 ). We attempted to analyze the reasons behind the above results.…”