Targeting S100A9–ALDH1A1–Retinoic Acid Signaling to Suppress Brain Relapse in<i>EGFR</i>-Mutant Lung Cancer

Biswas, Anup; Han, Sang Hoon; Tai, Yifan; Ma, Wanchao; Coker, Courtney; Quinn, S. Aidan; Shakri, Ahmad Rushdi; Zhong, Timothy James; Scholze, Hanna; Lagos, Galina G.; Mela, Angeliki; Manova-Todorova, Katia; Stanchina, Elisa de; Ferrando, Adolfo A.; Mendelsohn, Cathy; Canoll, Peter; Yu, Helena A.; Paik, Paul K.; Saqi, Anjali; Shu, Catherine A.; Kris, Mark G.; Massagué, Joan; Acharyya, Swarnali

doi:10.1158/2159-8290.cd-21-0910

Cited by 36 publications

(26 citation statements)

References 61 publications

(75 reference statements)

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“…Our results, together with recent data 52 , suggest that the acquisition of therapeutic resistance in brain metastasis might be linked to the induction of cellular plasticity mechanisms activated by the crosstalk with the microenvironment during colonization. The interface between the microenvironmental influence on cell plasticity and the pre-existing heterogeneity within cancer cells might promote the emergence of specific cellular and functional phenotypes (that is, cancer stem cells) that could be therapeutically relevant.…”

Section: Discussionsupporting

confidence: 73%

“…Cancer-related phenotypes ascribed to S100A9 include its involvement as an inducer of invasion 47 , 48 that has been linked to the premetastatic niche 49 , 50 as well as to chemoresistance driven by the recruitment of myeloid cells to lung metastases 51 or in a cell-autonomous manner 52 . Knockdown of S100A9 in H2030-BrM cells (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

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Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

Monteiro¹,

Miarka²,

Perea-García³

et al. 2022

Nat Med

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Whole-brain radiotherapy (WBRT) is the treatment backbone for many patients with brain metastasis; however, its efficacy in preventing disease progression and the associated toxicity have questioned the clinical impact of this approach and emphasized the need for alternative treatments. Given the limited therapeutic options available for these patients and the poor understanding of the molecular mechanisms underlying the resistance of metastatic lesions to WBRT, we sought to uncover actionable targets and biomarkers that could help to refine patient selection. Through an unbiased analysis of experimental in vivo models of brain metastasis resistant to WBRT, we identified activation of the S100A9–RAGE–NF-κB–JunB pathway in brain metastases as a potential mediator of resistance in this organ. Targeting this pathway genetically or pharmacologically was sufficient to revert the WBRT resistance and increase therapeutic benefits in vivo at lower doses of radiation. In patients with primary melanoma, lung or breast adenocarcinoma developing brain metastasis, endogenous S100A9 levels in brain lesions correlated with clinical response to WBRT and underscored the potential of S100A9 levels in the blood as a noninvasive biomarker. Collectively, we provide a molecular framework to personalize WBRT and improve its efficacy through combination with a radiosensitizer that balances therapeutic benefit and toxicity.

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Section: Discussionsupporting

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

Monteiro¹,

Miarka²,

Perea-García³

et al. 2022

Nat Med

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“…S100A9 overexpression in obesity impaired macrophage differentiation via TLR4-NFkB signaling, worsening inflammation and wound healing (Franz et al, 2022). S100A9-ALDH1A1-RA signaling pathway that drives lethal brain relapse and could be targeted by pan-RAR antagonists to prevent cancer progression (Biswas et al, 2022). A microRNA-21-mediated SATB1/S100A9/NF-κB axis has been reported to promote chronic obstructive pulmonary disease pathogenesis (Kim et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

Association Between Plasma Exosomes S100A9/C4BPA and Latent Tuberculosis Infection Treatment: Proteomic Analysis Based on a Randomized Controlled Study

Xin

Cao

et al. 2022

Front. Microbiol.

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BackgroundIdentifying host plasma exosome proteins associated with host response to latent tuberculosis infection (LTBI) treatment might promote our understanding of tuberculosis (TB) pathogenesis and provide useful tools for implementing the precise intervention.MethodsBased on an open-label randomized controlled trial (RCT) aiming to evaluate the short-course regimens for LTBI treatment, plasma exosomes from pre- and post-LTBI treatment were retrospectively detected by label-free quantitative protein mass spectrometry and validated by a parallel reaction monitoring method for participants with changed or not changed infection testing results after LTBI treatment. Eligible participants for both screening and verification sets were randomly selected from the based-RCT in a 1:1 ratio by age and gender. Reversion was defined as a decrease in IFN-γ levels from >0.70 IU/ml prior to treatment to 0.20 IU/ml within 1 week of treatment. The predictive ability of the candidate proteins was evaluated by receiver operating characteristic (ROC) analysis.ResultsTotally, two sample sets for screening (n = 40) and validation (n = 60) were included. Each of them included an equal number of subjects with persistent positive or reversed QuantiFERON-TB Gold In-Tube (QFT) results after LTBI. A total of 2,321 exosome proteins were detected and 102 differentially expressed proteins were identified to be associated with QFT reversion. Proteins with high confidence and original values intact were selected to be further verified. Totally, 9 downregulated proteins met the criteria and were validated. After verification, C4BPA and S100A9 were confirmed to be still significantly downregulated (fold change <0.67, p < 0.05). The respective areas under the ROC curve were 0.73 (95% CI: 0.57–0.89) and 0.69 (95% CI: 0.52–0.86) for C4BPA and S100A9, with a combined value of 0.78 (95% CI: 0.63–0.93). The positive and negative predictive values for combined markers were 70.10% (95% CI: 50.22–86.30%) and 55.63% (95% CI: 29.17–61.00%).ConclusionOur findings suggest that downregulated C4BPA and S100A9 in plasma exosomes might be associated with a host positive response to LTBI treatment. Further studies are warranted to verify the findings and potential underlying mechanisms in varied populations with a larger sample size.

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“…High expression of ALDH1 can be achieved by activating the MEK/ERK signaling pathway ( 59 ). S100A9 upregulates ALDH1A1 expression and activates the RA signaling pathway in lung cancer cells ( 60 ). Regulation and expression of ALDH1 in lung cancer are mainly related to TSPYL5 ( 61 ), STAT3 ( 62 ), SOX9 ( 63 ), β-catenin ( 64 ), MiR-34a/IL-629 ( 54 ), miR-326/GNB1 ( 65 ), RNAMACC1-AS143 ( 66 ), PFKFB346 ( 67 ) and other signals and pathways.…”

Section: Aldh1 and Various Solid Tumorsmentioning

confidence: 99%

“…The vitamin A/retinoic acid axis depletes ALDH1 positive CSCs and resensitizes drug resistant lung cancer cells to cisplatin ( 53 ). Targeting the s100A9-ALDH1A1-retinoic acid signaling pathway inhibits brain recurrence in EGFR-mutant lung cancer ( 60 ). Standard drugs for lung cancer treatment, cisplatin/gemcitabine,and menadione, reduced ALDH1 expression ( 68 ), while the elimination of ALDH1A1 significantly increased apoptosis and decreased resistance to cisplatin ( 69 ).…”

Section: Aldh1 and Various Solid Tumorsmentioning

confidence: 99%

ALDH1: A potential therapeutic target for cancer stem cells in solid tumors

Wei

Chen

et al. 2022

Front. Oncol.

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Solid tumors can be divided into benign solid tumors and solid malignant tumors in the academic community, among which malignant solid tumors are called cancers. Cancer is the second leading cause of death in the world, and the global incidence of cancer is increasing yearly New cancer patients in China are always the first. After the concept of stem cells was introduced in the tumor community, the CSC markers represented by ALDH1 have been widely studied due to their strong CSC cell characteristics and potential to be the driving force of tumor metastasis. In the research results in the past five years, it has been found that ALDH1 is highly expressed in various solid cancers such as breast cancer, lung cancer, colorectal cancer, liver cancer, gastric cancer, cervical cancer, esophageal cancer, ovarian cancer, head,and neck cancer. ALDH1 can activate and transform various pathways (such as the USP28/MYC signaling pathway, ALDH1A1/HIF-1α/VEGF axis, wnt/β-catenin signaling pathway), as well as change the intracellular pH value to promote formation and maintenance, resulting in drug resistance in tumors. By targeting and inhibiting ALDH1 in tumor stem cells, it can enhance the sensitivity of drugs and inhibit the proliferation, differentiation, and metastasis of solid tumor stem cells to some extent. This review discusses the relationship and pathway of ALDH1 with various solid tumors. It proposes that ALDH1 may serve as a diagnosis and therapeutic target for CSC, providing new insights and new strategies for reliable tumor treatment.

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Targeting S100A9–ALDH1A1–Retinoic Acid Signaling to Suppress Brain Relapse inEGFR-Mutant Lung Cancer

Cited by 36 publications

References 61 publications

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

Stratification of radiosensitive brain metastases based on an actionable S100A9/RAGE resistance mechanism

Association Between Plasma Exosomes S100A9/C4BPA and Latent Tuberculosis Infection Treatment: Proteomic Analysis Based on a Randomized Controlled Study

ALDH1: A potential therapeutic target for cancer stem cells in solid tumors

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