Reciprocal interactions between innate immune cells and astrocytes facilitate neuroinflammation and brain metastasis via lipocalin-2

Adler, Omer; Zait, Yael; Cohen, Noam; Blazquez, Raquel; Doron, Hila; Monteran, Lea; Scharff, Ye’ela; Shami, Tamar; Mundhe, Dhanashree; Glehr, Gunther; Kanner, Andrew A.; Horn, Suzana; Yahalom, Vered; Haferkamp, Sebastian; Hutchinson, James A.; Bleckmann, Annalen; Nahary, Limor; Benhar, Itai; Katz, Shlomit Yust; Pukrop, Tobias; Erez, Neta

doi:10.1038/s43018-023-00519-w

Cited by 26 publications

(11 citation statements)

References 53 publications

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“…In two other mouse models of E0771 breast cancer and B16F10 melanoma, the IroA- E. coli demonstrated improved anti-tumor ability as compared to WT bacteria ( Figure 3g–j , and Figure 3—figure supplement 1b–c ). It should be pointed out LCN2 expression has been shown to elevate the aggressiveness of breast ( Yang et al, 2009 ), melanoma ( Adler et al, 2023 ), and colon cancers ( Chaudhary et al, 2021 ), suggesting that WT bacteria may show reduced anticancer activity in more aggressive cancer types due to higher iron competition. Overall, we showed that the IroA cluster equips E. coli with an effective iron-scavenging capability, exerting a potent anti-tumor effect in the LCN2-rich tumor microenvironment.…”

Section: Resultsmentioning

confidence: 99%

Overcoming the nutritional immunity by engineering iron-scavenging bacteria for cancer therapy

Huang,

Lim,

et al. 2024

eLife

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Certain bacteria demonstrate the ability to target and colonize the tumor microenvironment, a characteristic that positions them as innovative carriers for delivering various therapeutic agents in cancer therapy. Nevertheless, our understanding of how bacteria adapt their physiological condition to the tumor microenvironment remains elusive. In this work, we employed liquid chromatography-tandem mass spectrometry to examine the proteome of E. coli colonized in murine tumors. Comparing to E. coli cultivated in the rich medium, we found that E. coli colonized in tumors notably upregulated the processes related to ferric ions, including the enterobactin biosynthesis and iron homeostasis. This finding indicated that the tumor is an iron-deficient environment to E. coli. We also found that the colonization of E. coli in the tumor led to an increased expression of lipocalin 2 (LCN2), a host’s protein that can sequester the enterobactin. We therefore engineered E. coli in order to evade the nutritional immunity provided by LCN2. By introducing the IroA cluster, the E. coli synthesizes the glycosylated enterobactin, which creates steric hindrance to avoid the LCN2 sequestration. The IroA-E. coli showed enhanced resistance to LCN2 and significantly improved the anti-tumor activity in mice. Moreover, the mice cured by the IroA-E. coli treatment became resistant to the tumor re-challenge, indicating the establishment of immunological memory. Overall, our study underscores the crucial role of bacteria’s ability to acquire ferric ions within the tumor microenvironment for effective cancer therapy.

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Section: Resultsmentioning

confidence: 99%

Overcoming the nutritional immunity by engineering iron-scavenging bacteria for cancer therapy

Huang,

Lim,

et al. 2024

eLife

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“…S5b-5c). It should be pointed out LCN2 expression has been shown to elevate the aggressiveness of breast (Yang et al 2009), melanoma (Adler et al 2023), and colon cancers (Chaudhary et al 2021), suggesting that WT bacteria may show reduced anticancer activity in more aggressive cancer types due to higher iron competition. Overall, we showed that the IroA cluster equips E. coli with an effective iron-scavenging capability, exerting a potent anti-tumor effect in the LCN2-rich tumor microenvironment.…”

Section: Resultsmentioning

confidence: 99%

Overcoming the nutritional immunity by engineering iron scavenging bacteria for cancer therapy

Huang

Lim

et al. 2023

Preprint

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Certain bacteria demonstrate the ability to target and colonize the tumor microenvironment, a characteristic that positions them as innovative carriers for delivering various therapeutic agents in cancer therapy. Nevertheless, our understanding of how bacteria adapt their physiological condition to the tumor microenvironment remains elusive. In this work, we employed liquid chromatography-tandem mass spectrometry to examine the proteome ofE. colicolonized in murine tumors. Comparing toE. colicultivated in the rich medium, we found thatE. colicolonized in tumors notably upregulated the processes related to ferric ions, including the enterobactin biosynthesis and iron homeostasis. This finding indicated that the tumor is an iron-deficient environment toE. coli. We also found that the colonization ofE. coliin the tumor led to an increased expression of lipocalin 2 (LCN2), a host’s protein that can sequester the enterobactin. We therefore engineeredE. coliin order to evade the nutritional immunity provided by LCN2. By introducing the IroA cluster, theE. colisynthesizes the glycosylated enterobactin, which creates steric hindrance to avoid the LCN2 sequestration. The IroA-E. colishowed enhanced resistance to LCN2 and significantly improved the anti-tumor activity in mice. Moreover, the mice cured by the IroA-E. colitreatment became resistant to the tumor re-challenge, indicating the establishment of immunological memory. Overall, our study underscores the crucial role of bacteria’s ability to acquire ferric ions within the tumor microenvironment for effective cancer therapy.

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“…3D). Neuroinflammation involving glia is known to be a feature of the micro-environment in the setting of brain metastases [31,32], explaining the presence of inflammatory pathways in the non-irradiated glial niches, but to decipher which mechanisms were preferentially activated after targeted radiotherapy, we next examined genes that were overexpressed specifically in the irradiated glial niche after calculating DEGs between clusters (Fig. 4A, C).…”

Section: Irradiated Glial Niches Have An Inflammatory and Angiogenic ...mentioning

confidence: 99%

The inflammatory micro-environment induced by targeted CNS radiotherapy is underpinned by disruption of DNA methylation

Millner,

Panday,

Xiao

et al. 2024

Preprint

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Although targeted radiotherapy (RT) is integral to the increasing survival of cancer patients, it has significant side-effects, the cellular and molecular mechanisms of which are not fully understood. During RT epigenetic changes occur in neoplastic tissue, but few studies have assessed these in non-neoplastic tissue and results are highly variable. Using bulk DNA methylation and RNA sequencing as well as spatial transcriptomics (ST) in a unique cohort of patient tissue samples, we show distinct differences in DNA methylation patterns in irradiated brain tissue, whilst ST characterisation identifies specific micro-environmental niches present after irradiation and highlights neuropeptides that could be propagating neuroinflammation. We also show that in a cerebral organoid (CO) model of early changes in neurons after irradiation there are similar DNA methylation alterations and disruption of the DNA methylation machinery, suggesting that early but persistent epigenetic dysregulation plays a role in neurotoxicity. We provide a link between radiotherapy induced neuroinflammation and disruption of DNA methylation for the first time and suggest possible driving mechanisms for this chronic neuroinflammation.

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Reciprocal interactions between innate immune cells and astrocytes facilitate neuroinflammation and brain metastasis via lipocalin-2

Cited by 26 publications

References 53 publications

Overcoming the nutritional immunity by engineering iron-scavenging bacteria for cancer therapy

Overcoming the nutritional immunity by engineering iron-scavenging bacteria for cancer therapy

Overcoming the nutritional immunity by engineering iron scavenging bacteria for cancer therapy

The inflammatory micro-environment induced by targeted CNS radiotherapy is underpinned by disruption of DNA methylation

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