Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment.

Primary tumors are drivers of pre-metastatic niche formation, but the coordination by the secondary organ toward metastatic dissemination is underappreciated. Here, by single-cell RNA sequencing and immunofluorescence, we identified a population of cyclooxygenase 2 (COX-2)-expressing adventitial fibroblasts that remodeled the lung immune microenvironment. At steady state, fibroblasts in the lungs produced prostaglandin E2 (PGE2), which drove dysfunctional dendritic cells (DCs) and suppressive monocytes. This lung-intrinsic stromal program was propagated by tumor-associated inflammation, particularly the pro-inflammatory cytokine interleukin-1ß, supporting a pre-metastatic niche. Genetic ablation of Ptgs2 (encoding COX-2) in fibroblasts was sufficient to reverse the immune-suppressive phenotypes of lung-resident myeloid cells, resulting in heightened immune activation and diminished lung metastasis in multiple breast cancer models. Moreover, the anti-metastatic activity of DC-based therapy and PD-1 blockade was improved by fibroblast-specific Ptgs2 deletion or dual inhibition of PGE2 receptors EP2 and EP4. Collectively, lung-resident fibroblasts reshape the local immune landscape to facilitate breast cancer metastasis.

A second-generation eIF4A RNA helicase inhibitor exploits translational reprogramming as a vulnerability in triple-negative breast cancer.

In this study, we aimed to address the current limitations of therapies for macro-metastatic triple-negative breast cancer (TNBC) and provide a therapeutic lead that overcomes the high degree of heterogeneity associated with this disease. Specifically, we focused on well-documented but clinically underexploited cancer-fueling perturbations in mRNA translation as a potential therapeutic vulnerability. We therefore developed an orally bioavailable rocaglate-based molecule, MG-002, which hinders ribosome recruitment and scanning via unscheduled and non-productive RNA clamping by the eukaryotic translation initiation factor (eIF) 4A RNA helicase. We demonstrate that MG-002 potently inhibits mRNA translation and primary TNBC tumor growth without causing overt toxicity in mice. Importantly, given that metastatic spread is a major cause of mortality in TNBC, we show that MG-002 attenuates metastasis in pre-clinical models. We report on MG-002, a rocaglate that shows superior properties relative to existing eIF4A inhibitors in pre-clinical models. Our study also paves the way for future clinical trials exploring the potential of MG-002 in TNBC and other oncological indications.

Afadin cooperates with Claudin-2 to promote breast cancer metastasis.

Claudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that the PDZ-binding motif of Claudin-2 is necessary for anchorage-independent growth of cancer cells and is required for liver metastasis. Several PDZ domain-containing proteins were identified that interact with the PDZ-binding motif of Claudin-2 in liver metastatic breast cancer cells, including Afadin, Arhgap21, Pdlim2, Pdlim7, Rims2, Scrib, and ZO-1. We specifically examined the role of Afadin as a potential Claudin-2-interacting partner that promotes breast cancer liver metastasis. Afadin associates with Claudin-2, an interaction that requires the PDZ-binding motif of Claudin-2. Loss of Afadin also impairs the ability of breast cancer cells to form colonies in soft agar and metastasize to the lungs or liver. Immunohistochemical analysis of Claudin-2 and/or Afadin expression in 206 metastatic breast cancer tumors revealed that high levels of both Claudin-2 and Afadin in primary tumors were associated with poor disease-specific survival, relapse-free survival, lung-specific relapse, and liver-specific relapse. Our findings indicate that signaling downstream from a Claudin-2/Afadin complex enables the efficient formation of breast cancer metastases. Moreover, combining Claudin-2 and Afadin as prognostic markers better predicts the potential of breast cancer to metastasize to soft tissues.

RANK/RANKL axis promotes migration, invasion, and metastasis of osteosarcoma via activating NF-κB pathway.

Osteosarcoma (OS) is one of the most prevalent primary bone tumors with a high degree of metastasis and poor prognosis. Epithelial-to-mesenchymal transition (EMT) is a cellular mechanism that contributes to the invasion and metastasis of cancer cells, and OS cells have been reported to exhibit EMT-like characteristics. Our previous studies have shown that the interaction between tumor necrosis factor superfamily member 11 (TNFRSF11A; also known as RANK) and its ligand TNFSF11 (also known as RANKL) promotes the EMT process in breast cancer cells. However, whether the interaction between RANK and RANKL enhances aggressive behavior by inducing EMT in OS cells has not yet been elucidated. In this study, we showed that the interaction between RANK and RANKL increased the migration, invasion, and metastasis of OS cells by promoting EMT. Importantly, we clarified that the RANK/RANKL axis induces EMT by activating the nuclear factor-kappa B (NF-κB) pathway. Furthermore, the NF-κB inhibitor dimethyl fumarate (DMF) suppressed migration, invasion, and EMT in OS cells. Our results suggest that the RANK/RANKL axis may serve as a potential tumor marker and promising therapeutic target for OS metastasis. Furthermore, DMF may have clinical applications in the treatment of lung metastasis in patients with OS.

Tumor-polarized GPX3+ AT2 lung epithelial cells promote premetastatic niche formation.

The cellular and molecular components required for the formation of premetastatic niche (PMN) to promote lung metastasis need to be further investigated. Lung epithelial cells have been reported to exhibit immunomodulatory roles in lung homeostasis and also to mediate immunosuppressive PMN formation in lung metastasis. Here, by single-cell sequencing, we identified a tumor-polarized subpopulation of alveolar type 2 (AT2) epithelial cells with increased expression of glutathione peroxidase 3 (GPX3) and high production of interleukin (IL)-10 in the PMN. IL-10-producing GPX3+ AT2 cells inhibited CD4+ T cell proliferation but enhanced regulatory T cell generation. Mechanistically, tumor exosome-inducing GPX3 expression is required for GPX3+ AT2 cells to preferentially produce IL-10 by stabilizing hypoxia-inducible factor 1 (HIF-1α) and promoting HIF-1α-induced IL-10 production. Accordingly, conditional knockout of GPX3 in AT2 cells suppressed lung metastasis in spontaneous metastatic models. Together, our findings reveal a role of tumor-polarized GPX3+ AT2 cells in promoting lung PMN formation, adding insights into immune evasion in lung metastasis and providing potential targets for the intervention of tumor metastasis.

Identification of Nidogen 1 as a lung metastasis protein through secretome analysis.

Secreted proteins play crucial roles in mediating tumor-stroma interactions during metastasis of cancer to different target organs. To comprehensively profile secreted proteins involved in lung metastasis, we applied quantitative mass spectrometry-based proteomics and identified 392 breast cancer-derived and 302 melanoma-derived proteins secreted from highly lung metastatic cells. The cancer-specific lung metastasis secretome signatures (LMSSs) displayed significant prognostic value in multiple cancer clinical data sets. Moreover, we observed a significant overlap of enriched pathways between the LMSSs of breast cancer and melanoma despite an overall small overlap of specific proteins, suggesting that common biological processes are executed by different proteins to enable the two cancer types to metastasize to the lung. Among the novel candidate lung metastasis proteins, Nidogen 1 (NID1) was confirmed to promote lung metastasis of breast cancer and melanoma, and its expression is correlated with poor clinical outcomes. In vitro functional analysis further revealed multiple prometastatic functions of NID1, including enhancing cancer cell migration and invasion, promoting adhesion to the endothelium and disrupting its integrity, and improving vascular tube formation capacity. As a secreted prometastatic protein, NID1 may be developed as a new biomarker for disease progression and therapeutic target in breast cancer and melanoma.

FeSA­Ir/Metallene Nanozymes Induce Sequential Ferroptosis­Pyroptosis for Multi­Immunogenic Responses Against Lung Metastasis.

For cancer metastasis inhibition, the combining of nanozymes with immune checkpoint blockade (ICB) therapy remains the major challenge in controllable reactive oxygen species (ROS) generation for creating effective immunogenicity. Herein, new nanozymes with light-controlled ROS production in terms of quantity and variety are developed by conjugating supramolecular-wrapped Fe single atom on iridium metallene with lattice-strained nanoislands (FeSA-Ir@PF NSs). The Fenton-like catalysis of FeSA-Ir@PF NSs effectively produced •OH radicals in dark, which induced ferroptosis and apoptosis of cancer cells. While under second near-infrared (NIR-II) light irradiation, FeSA-Ir@PF NSs showed ultrahigh photothermal conversion efficiency (𝜂, 75.29%), cooperative robust •OH generation, photocatalytic O2 and 1O2 generation, and caused significant pyroptosis of cancer cells. The controllable ROS generation, sequential cancer cells ferroptosis and pyroptosis, led 99.1% primary tumor inhibition and multi-immunogenic responses in vivo. Most importantly, the inhibition of cancer lung metastasis is completely achieved by FeSA-Ir@PF NSs with immune checkpoint inhibitors, as demonstrated in different mice lung metastasis models, including circulating tumor cells (CTCs) model. This work provided new inspiration for developing nanozymes for cancer treatments and metastasis inhibition.

Prognostic and predictive value of super-enhancer-derived signatures for survival and lung metastasis in osteosarcoma.

BACKGROUND: Risk stratification and personalized care are crucial in managing osteosarcoma due to its complexity and heterogeneity. However, current prognostic prediction using clinical variables has limited accuracy. Thus, this study aimed to explore potential molecular biomarkers to improve prognostic assessment. METHODS: High-throughput inhibitor screening of 150 compounds with broad targeting properties was performed and indicated a direction towards super-enhancers (SEs). Bulk RNA-seq, scRNA-seq, and immunohistochemistry (IHC) were used to investigate SE-associated gene expression profiles in osteosarcoma cells and patient tissue specimens. Data of 212 osteosarcoma patients who received standard treatment were collected and randomized into training and validation groups for retrospective analysis. Prognostic signatures and nomograms for overall survival (OS) and lung metastasis-free survival (LMFS) were developed using Cox regression analyses. The discriminatory power, calibration, and clinical value of nomograms were evaluated. RESULTS: High-throughput inhibitor screening showed that SEs significantly contribute to the oncogenic transcriptional output in osteosarcoma. Based on this finding, focus was given to 10 SE-associated genes with distinct characteristics and potential oncogenic function. With multi-omics approaches, the hyperexpression of these genes was observed in tumor cell subclusters of patient specimens, which were consistently correlated with poor outcomes and rapid metastasis, and the majority of these identified SE-associated genes were confirmed as independent risk factors for poor outcomes. Two molecular signatures were then developed to predict survival and occurrence of lung metastasis: the SE-derived OS-signature (comprising LACTB, CEP55, SRSF3, TCF7L2, and FOXP1) and the SE-derived LMFS-signature (comprising SRSF3, TCF7L2, FOXP1, and APOLD1). Both signatures significantly improved prognostic accuracy beyond conventional clinical factors. CONCLUSIONS: Oncogenic transcription driven by SEs exhibit strong associations with osteosarcoma outcomes. The SE-derived signatures developed in this study hold promise as prognostic biomarkers for predicting OS and LMFS in patients undergoing standard treatments. Integrative prognostic models that combine conventional clinical factors with these SE-derived signatures demonstrate substantially improved accuracy, and have the potential to facilitate patient counseling and individualized management.

The sEVs miR-487a/Notch2/GATA3 axis promotes osteosarcoma lung metastasis by inducing macrophage polarization toward the M2-subtype.

Small extracellular vesicles (sEVs) are important mediators of intercellular communication between tumor cells and their surrounding environment. Furthermore, the mechanisms by which miRNAs carried in tumor sEVs regulate macrophage polarization remain largely unknown. To concentrate sEVs, we used the traditional ultracentrifugation method. Western blot, NanoSight, and transmission electron microscopy were used to identify sEVs. To determine the function of sEVs-miR-487a, we conducted in vivo and in vitro investigations. The intercellular communication mechanism between osteosarcoma cells and M2 macrophages, mediated by sEVs carrying miR-487a, was validated using luciferase reporter assays, transwell assays, and Western blot analysis. In vitro, sEVs enriched in miR-487a and delivered miR-487a to macrophages, promoting macrophage polarization toward an M2-like type, which promotes proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of osteosarcoma cells. In vivo, sEVs enriched in miR-487a facilitate lung metastasis of osteosarcoma. Moreover, plasma miR-487a in sEVs was shown to be a potential biomarker applicable for osteosarcoma diagnosis. In summary, miR-487a derived from osteosarcoma cells can be transferred to macrophages via sEVs, then promote macrophage polarization towards an M2-like type by targeting Notch2 and activating the GATA3 pathway. In a feedback loop, the activation of macrophages accelerates epithelial-mesenchymal transition (EMT), which in turn promotes the migration, invasion, and lung metastasis of osteosarcoma cells. This reciprocal interaction between activated macrophages and osteosarcoma cells contributes to the progression of the disease. Our data demonstrate a new mechanism that osteosarcoma tumor cells derived exosomal-miR-487a which is involved in osteosarcoma development by regulating macrophage polarization in tumor microenvironment (TME).

5-Methoxytryptophan enhances the sensitivity of sorafenib on the inhibition of proliferation and metastasis for lung cancer cells.

BACKGROUND: Lung cancer is a leading cause of cancer-related mortality worldwide, and effective therapies are limited. Lung cancer is a leading cause of cancer-related mortality worldwide with limited effective therapy. Sorafenib is a multi-tyrosine kinase inhibitor frequently used to treat numerous types of malignant tumors. However, it has been demonstrated that sorafenib showed moderate antitumor activity and is associated with several side effects in lung cancer, which restricted its clinical application. This study aimed to examine the antitumor effect of the combination treatment of sorafenib and 5-methoxytryptophan (5-MTP) on cell growth and metastasis of Lewis lung carcinoma (LLC) cells. METHOD: The anticancer effect of the combination treatment of sorafenib and 5-MTP was determined through cytotoxicity assay and colony forming assays. The mechanism was elucidated using flow cytometry and western blotting. Wound healing and Transwell assays were conducted to evaluate the impact of the combination treatment on migration and invasion abilities. An in vivo model was employed to analyze the effect of the combination treatment on the tumorigenic ability of LLC cells. RESULT: Our results demonstrated that the sorafenib and 5-MTP combination synergistically reduced viability and proliferation compared to sorafenib or 5-MTP treatment alone. Reduction of cyclin D1 expression was observed in the sorafenib alone or combination treatments, leading to cell cycle arrest. Furthermore, the sorafenib-5-MTP combination significantly increased the inhibitory effect on migration and invasion of LLC cells compared to the single treatments. The combination also significantly downregulated vimentin and MMP9 levels, contributing to the inhibition of metastasis. The reduction of phosphorylated Akt and STAT3 expression may further contribute to the inhibitory effect on proliferation and metastasis. In vivo, the sorafenib-5-MTP combination further reduced tumor growth and metastasis compared to the treatment of sorafenib alone. CONCLUSIONS: In conclusion, our data indicate that 5-MTP sensitizes the antitumor activity of sorafenib in LLC cells in vitro and in vivo, suggesting that sorafenib-5-MTP has the potential to serve as a therapeutic option for patients with lung cancer.

Sialic Acid Conjugate-Modified Cationic Liposomal Paclitaxel for Targeted Therapy of Lung Metastasis in Breast Cancer: What a Difference the Cation Content Makes.

Cationic lipids play a pivotal role in developing novel drug delivery systems for diverse biomedical applications, owing to the success of mRNA vaccines against COVID-19 and the Phase III antitumor agent EndoTAG-1. However, the therapeutic potential of these positively charged liposomes is limited by dose-dependent toxicity. While an increased content of cationic lipids in the formulation can enhance the uptake and cytotoxicity toward tumor-associated cells, it is crucial to balance these advantages with the associated toxic side effects. In this work, we synthesized the cationic lipid HC-Y-2 and incorporated it into sialic acid (SA)-modified cationic liposomes loaded with paclitaxel to target tumor-associated immune cells efficiently. The SA-modified cationic liposomes exhibited enhanced binding affinity toward both RAW264.7 cells and 4T1 tumor cells in vitro due to the increased ratios of cationic HC-Y-2 content while effectively inhibiting 4T1 cell lung metastasis in vivo. By leveraging electrostatic forces and ligand-receptor interactions, the SA-modified cationic liposomes specifically target malignant tumor-associated immune cells such as tumor-associated macrophages (TAMs), reduce the proportion of cationic lipids in the formulation, and achieve dual objectives: high cellular uptake and potent antitumor efficacy. These findings highlight the potential advantages of this innovative approach utilizing cationic liposomes.

Interleukin-25 as a Potential Biomarker in Lung Metastasis of Hepatocellular Carcinoma with HBV History in Chinese Patients: A Single Center, Case-control Study.

Background: Interleukin-25 (IL-25) has been proved to play a role in the pathogenesis and metastasis of Hepatocellular carcinoma (HCC), but the relationship between the level of IL-25 and the metastasis and prognosis of HCC is still not clear. This study aimed to investigate the expression of IL-25 and other potential biochemical indicators among healthy people, HBV-associated HCC patients without lung metastasis and HBV-associated HCC patients with lung metastasis. Methods: From September 2019 to November 2021, 33 HCC patients without lung metastasis, 37 HCC patients with lung metastasis and 29 healthy controls were included in the study. IL-25 and other commonly used biochemical markers were measured to establish predictors of overall survival (OS) and progression-free survival (PFS) after treatment. Results: The serum level of IL-25 was increased in HCC patients than healthy controls (p < 0.001) and HCC patients with lung metastasis had higher IL-25 level than HCC patients without metastasis (p = 0.035). Lung metastasis also indicated higher death rate (p < 0.001) by chi-square test, higher GGT level (p = 0.024) and higher AFP level (p = 0.049) by non-parametric test. Kaplan-Meier analysis demonstrated that IL-25 was negatively associated with PFS (p = 0.024). Multivariate Cox-regression analysis indicated IL-25 (p = 0.030) and GGT (p = 0.020) to be independent predictors of poorer PFS, while IL-25 showed no significant association with OS. Conclusion: The level of IL-25 was significantly associated with disease progression and lung metastasis of HBV-associated HCC. The high expression of IL-25 predicted high recurrence rate and death probability of HCC patients after treatment. Therefore, IL-25 may be an effective predictor of prognosis in HCC.

Effect of lung metastasis on the treatment and prognosis of patients with gestational trophoblastic neoplasia: A systematic review and meta-analysis.

INTRODUCTION: Gestational trophoblastic neoplasia (GTN) is a highly invasive tumor, mainly spreading to the lungs. However, lung metastasis in GTN is usually not considered as an adverse prognostic factor. Therefore, the aim of this study was to summarize the results of previous studies and evaluate the effects of lung metastasis on the treatment and prognosis of GTN. MATERIAL AND METHODS: The study was prospectively registered in PROSPERO (CRD42023372371). Electronic databases including PubMed, Embase, the Cochrane Library, Chinese National Knowledge Infrastructure, Wanfang, and China Biomedical Literature Database were used for a systematical search of relevant studies published up to November 21, 2022. The observational studies reporting the clinical outcomes of GTN patients with and without lung metastasis were selected. The incidences of resistance, relapse, and mortality of GTN patients were extracted and successively grouped based on the presence of lung metastasis. The pooled relative risks (RRs) and 95% confidence interval (95% CI) of the eligible studies were calculated. The qualities of included studies were assessed with the Newcastle-Ottawa Scale and the certainty of evidence was graded based on the GRADE. The meta-analysis was performed using Stata 12.0 and GradePro software. RESULTS: Five publications with 3629 GTN patients were included. The meta-analysis revealed that the GTN with lung metastasis was strongly correlated with first-line chemoresistance (pooled RR = 1.40, 95% CI: 1.22 to 1.61, p < 0.001), recurrence (pooled RR = 3.03, 95% CI: 1.21 to 7.62, p = 0.018), and disease-specific death (pooled RR = 22.11, 95% CI: 3.37 to 145.08, p = 0.001). Ethnicity was also an important factor and Caucasian GTN patients with lung metastasis showed a higher risk of recurrence as revealed by the subgroup analysis (pooled RR = 5.10, 95% CI: 2.38 to 10.94, p < 0.001). CONCLUSIONS: GTN patients with lung metastasis exhibited a higher risk of chemoresistance, relapse, and disease-specific death. Patients with lung metastasis among the Caucasian population had a higher risk of recurrence than Asian populations. Therefore, the presence of lung metastases might be considered as a high-risk factor for prognosis of GTN and deserves more attention in the choice of first-line chemotherapy regimens and follow-up.

A pH-responsive nanoplatform with dual-modality imaging for enhanced cancer phototherapy and diagnosis of lung metastasis.

To address the limitations of traditional photothermal therapy (PTT)/ photodynamic therapy (PDT) and real-time cancer metastasis detection, a pH-responsive nanoplatform (NP) with dual-modality imaging capability was rationally designed. Herein, 1 H,1 H-undecafluorohexylamine (PFC), served as both an oxygen carrier and a 19F magnetic resonance imaging (MRI) probe, and photosensitizer indocyanine green (ICG) were grafted onto the pH-responsive peptide hexahistidine (H6) to form H6-PFC-ICG (HPI). Subsequently, the heat shock protein 90 inhibitor, gambogic acid (GA), was incorporated into hyaluronic acid (HA) modified HPI (HHPI), yielding the ultimate HHPI@GA NPs. Upon self-assembly, HHPI@GA NPs passively accumulated in tumor tissues, facilitating oxygen release and HA-mediated cell uptake. Once phagocytosed by lysosomes, protonation of H6 was triggered due to the low pH, resulting in the release of GA. With near-infrared laser irradiation, GA-mediated decreased HSP90 expression and PFC-mediated increased ROS generation amplified the PTT/PDT effect of HHPI@GA, leading to excellent in vitro and in vivo anticancer efficacies. Additionally, the fluorescence and 19F MRI dual-imaging capabilities of HHPI@GA NPs enabled effective real-time primary cancer and lung metastasis monitoring. This work offers a novel approach for enhanced cancer phototherapy, as well as precise cancer diagnosis.

Risk factors for mediastinal lymph node metastasis and lung metastasis in papillary thyroid carcinoma patients: who benefits from preoperative computed tomography?

In papillary thyroid carcinoma (PTC) patients with mediastinal lymph nodes (LN) and lung metastases, adding preoperative computed tomography (CT) to ultrasound is useful for planning surgery. We identified risk factors (RFs) for mediastinal lymph node metastasis (MLNM) and lung metastasis in PTC patients. Frequencies of MLNM and lung metastases were compared in 478 patients. Relative risk (RR) was calculated based on RFs. MLNM and lung metastases were detected in 1.2% and 3.3% of patients, respectively. cT3-4, cN1, central LN metastasis, and lateral LN metastasis were RFs for MLNM in all patients (p < 0.05, p < 0.05, p < 0.05, p < 0.01) and older patients (age: ≥55 years) (p < 0.01, p < 0.05, p < 0.05, p < 0.05). cT3-4, cN1, gross extrathyroidal extension, central LN metastasis, and lateral LN metastasis were RFs for lung metastasis in all patients (p < 0.01, p < 0.05, p < 0.01, p < 0.01, p < 0.01, respectively). cN1 and gross extrathyroidal extension, central LN metastasis, and lateral LN metastasis were RFs in older patients (p < 0.01, p < 0.01, p < 0.05, p < 0.01), while lateral LN metastasis was an RF for lung metastasis in those of <55 years of age (younger patients) (p < 0.05). No MLNM was observed in cT1-2cN0 PTC patients, who accounted for 50.5% of patients included in the MLNM analysis. No lung metastasis was present in cT1-2cN0 PTC patients, who accounted for 50.5% of the patients included in the lung metastasis analysis. PTC patients with cT3-4 and cN1 have an increased risk of MLNM and lung metastasis. RFs differed between older and younger patients. Preoperative neck and chest CT are not necessary for PTC patients with ultrasound-diagnosed as cT1-2cN0.

Impact of lateral cervical lymph node metastasis on lung metastasis in pediatric thyroid cancer: A correlation study.

BACKGROUND: Thyroid cancer (TC) frequently manifests with lung metastases in the pediatric population, occurring at a significant rate of 30 %. This study aims to evaluate the impact of regional patterns of cervical lymph node metastases on lung metastases in pediatric TC. METHODS: Retrospective analysis was conducted on data from pediatric TC patients spanning the years 2000 to 2018. We compared the rates of lymph node metastasis (LNR), the number of lymph node metastases, and the number of dissected lymph nodes in the central and lateral cervical regions between patients with and without lung metastases. Statistical methods were employed to adjust for confounders during hypothesis testing. RESULTS: A total of 227 pediatric patients, with a median age of 15.12 ± 2.84 years, were included in the study. Of these, 202 (89 %) exhibited LN metastasis, with 40(17.62 %) patients presenting with lung metastasis. Patients with lung metastases were found to be younger (13.40 ± 3.11 vs. 15.50 ± 2.64, p < 0.001), had larger primary tumor diameters (3.49 ± 1.98 vs. 2.31 ± 1.45, p < 0.001), and exhibited a higher number of lymph node metastases (23.40 ± 10.75 vs. 14.65 ± 13.16, p < 0.001). Notably, in patients with LN metastases, the presence of >12 lateral cervical lymph node metastases emerged as a significant risk factor for lung metastases. Among children with metachronous lung metastases, the median time to detection of lung metastases was 43 (12-132) months, and they appeared to receive a greater proportion of radioactive iodine (RAI) treatment compared to those with synchronous lung metastases. CONCLUSION: Lateral cervical lymph node metastasis independently predicts the likelihood of lung metastases in pediatric TC. Furthermore, our findings emphasize the importance of thorough examination of the lungs during follow-up, particularly when the number of metastatic lateral cervical lymph nodes exceeds 12.

Diagnostic and prognostic nomograms for laryngeal carcinoma patients with lung metastasis: a SEER-based study.

PURPOSE: To establish two nomograms to quantify the risk of lung metastasis (LM) in laryngeal carcinoma (LC) and predict the overall survival of LC patients with LM. METHODS: Totally 9515 LC patients diagnosed histologically from 2000 to 2019 were collected from the Surveillance, Epidemiology, and End Results database. The independent diagnostic factors for LM in LC patients and prognostic factors for LC patients with LM were identified by logistic and Cox regression analysis, respectively. Nomograms were established based on regression coefficients and evaluated by receiver operating characteristic curve, calibration curves, and decision curve analysis. RESULTS: Patients with supraglottis, higher pathological grade, higher N stage, and distant metastasis (bone, brain, or liver) were more likely to have LM (P < 0.05). Chemotherapy, surgery and radiotherapy were independent factors of the overall survival of LC patients with LM (P < 0.05). The area under curve of diagnostic nomogram were 0.834 and 0.816 in the training and validation cohort respectively. For the prognostic nomogram, the area under curves of 1-, 2-, and 3-years were 0.735, 0.734, and 0.709 in the training cohort and 0.705, 0.803, and 0.809 in the validation cohort. The calibration curves and decision curve analysis indicated good performance of the nomograms. CONCLUSION: Distant metastasis (bone, brain, or liver) and N stage should be considered for prediction of LM in LC patients. Chemotherapy is the most significant influencing prognostic factor improving the survival of LC patients with LM. Two nomograms may benefit for providing better precautionary measures and treatment decision.

RHAMM regulates MMTV-PyMT-induced lung metastasis by connecting STING-dependent DNA damage sensing to interferon/STAT1 pro-apoptosis signaling.

BACKGROUND: RHAMM is a multifunctional protein that is upregulated in breast tumors, and the presence of strongly RHAMM+ve cancer cell subsets associates with elevated risk of peripheral metastasis. Experimentally, RHAMM impacts cell cycle progression and cell migration. However, the RHAMM functions that contribute to breast cancer metastasis are poorly understood. METHODS: We interrogated the metastatic functions of RHAMM using a loss-of-function approach by crossing the MMTV-PyMT mouse model of breast cancer susceptibility with Rhamm-/- mice. In vitro analyses of known RHAMM functions were performed using primary tumor cell cultures and MMTV-PyMT cell lines. Somatic mutations were identified using a mouse genotyping array. RNA-seq was performed to identify transcriptome changes resulting from Rhamm-loss, and SiRNA and CRISPR/Cas9 gene editing was used to establish cause and effect of survival mechanisms in vitro. RESULTS: Rhamm-loss does not alter initiation or growth of MMTV-PyMT-induced primary tumors but unexpectedly increases lung metastasis. Increased metastatic propensity with Rhamm-loss is not associated with obvious alterations in proliferation, epithelial plasticity, migration, invasion or genomic stability. SNV analyses identify positive selection of Rhamm-/- primary tumor clones that are enriched in lung metastases. Rhamm-/- tumor clones are characterized by an increased ability to survive with ROS-mediated DNA damage, which associates with blunted expression of interferon pathway and target genes, particularly those implicated in DNA damage-resistance. Mechanistic analyses show that ablating RHAMM expression in breast tumor cells by siRNA knockdown or CRISPR-Cas9 gene editing blunts interferon signaling activation by STING agonists and reduces STING agonist-induced apoptosis. The metastasis-specific effect of RHAMM expression-loss is linked to microenvironmental factors unique to tumor-bearing lung tissue, notably high ROS and TGFB levels. These factors promote STING-induced apoptosis of RHAMM+ve tumor cells to a significantly greater extent than RHAMM-ve comparators. As predicted by these results, colony size of Wildtype lung metastases is inversely related to RHAMM expression. CONCLUSION: RHAMM expression-loss blunts STING-IFN signaling, which offers growth advantages under specific microenvironmental conditions of lung tissue. These results provide mechanistic insight into factors controlling clonal survival/expansion of metastatic colonies and has translational potential for RHAMM expression as a marker of sensitivity to interferon therapy.

KLF3 Transcription Activates WNT1 and Promotes the Growth and Metastasis of Gastric Cancer via Activation of the WNT/ß-Catenin Signaling Pathway.

The transcription factor Krüppel-like factor (KLF) 3 is one of the members of the KLF family, which plays an important role in tumor progression. Nevertheless, the role of KLF3 in the growth and metastasis of gastric cancer (GC) still needs to be elucidated. Bioinformatics analysis showed that KLF3 was overexpressed in patients with GC, and the high expression of KLF3 was correlated with poor survival. KLF3 was also overexpressed in GC clinical samples and cell lines. In vitro functional role of KLF3 in GC cells was explored by a gain-of-function and loss-of-function assay. Overexpressed KLF3 promoted the cell proliferation, migration, invasion, and epithelial-mesenchymal transition of GC cells, whereas suppressed KLF3 inhibited these biological behaviors. The clinical samples and bioinformatics analysis showed that WNT1 was also highly expressed in GC tumor tissues and positively correlated with KLF3 expression. The luciferase reporter assay and chromatin immunoprecipitation result confirmed that KLF3 could directly bind to the WNT1 promoter to increase the transcriptional activity of WNT1, thus regulating its expression. Overexpressed KLF3 enhanced the protein expression level of p-GSK3ß(Ser9) and ß-catenin, the key elements in the WNT/ß-catenin signaling pathway. Repression of KLF3 decreased the level of p-GSK3ß(Ser9) and ß-catenin. Immunofluorescence images showed that KLF3 promoted nuclear ß-catenin accumulation. Inhibition of WNT1 attenuated the proliferation, migration, and invasiveness of KLF3-overexpressing GC cells. Moreover, the xenograft mouse model confirmed that KLF3 promotes GC tumor growth and metastasis in vivo. Our results demonstrated that KLF3 activates the WNT/ß-catenin signaling pathway via WNT1 to promote GC tumor growth and metastasis, indicating that repression of KLF3 may act as a potential therapeutic target for patients with GC.

Glycosylation as a regulator of site-specific metastasis.

Metastasis is considered to be responsible for 90% of cancer-related deaths. Although it is clinically evident that metastatic patterns vary by primary tumor type, the molecular mechanisms underlying the site-specific nature of metastasis are an area of active investigation. One mechanism that has emerged as an important player in this process is glycosylation, or the addition of sugar moieties onto protein and lipid substrates. Glycosylation is the most common post-translational modification, occurring on more than 50% of translated proteins. Many of those proteins are either secreted or expressed on the cell membrane, thereby making glycosylation an important mediator of cell-cell interactions, including tumor-microenvironment interactions. It has been recently discovered that alteration of glycosylation patterns influences cancer metastasis, both globally and in a site-specific manner. This review will summarize the current knowledge regarding the role of glycosylation in the tropism of cancer cells for several common metastatic sites, including the bone, lung, brain, and lymph nodes.