A real-world clinicopathological model for predicting pathological complete response to neoadjuvant chemotherapy in breast cancer.

Purpose: This study aimed to develop and validate a clinicopathological model to predict pathological complete response (pCR) to neoadjuvant chemotherapy (NAC) in breast cancer patients and identify key prognostic factors. Methods: This retrospective study analyzed data from 279 breast cancer patients who received NAC at Zhejiang Provincial People's Hospital from 2011 to 2021. Additionally, an external validation dataset, comprising 50 patients from Lanxi People's Hospital and Second Affiliated Hospital, Zhejiang University School of Medicine from 2022 to 2023 was utilized for model verification. A multivariate logistic regression model was established incorporating clinical, ultrasound features, circulating tumor cells (CTCs), and pathology variables at baseline and post-NAC. Model performance for predicting pCR was evaluated. Prognostic factors were identified using survival analysis. Results: In the 279 patients enrolled, a pathologic complete response (pCR) rate of 27.96% (78 out of 279) was achieved. The predictive model incorporated independent predictors such as stromal tumor-infiltrating lymphocyte (sTIL) levels, Ki-67 expression, molecular subtype, and ultrasound echo features. The model demonstrated strong predictive accuracy for pCR (C-statistics/AUC 0.874), especially in human epidermal growth factor receptor 2 (HER2)-enriched (C-statistics/AUC 0.878) and triple-negative (C-statistics/AUC 0.870) subtypes, and the model performed well in external validation data set (C-statistics/AUC 0.836). Incorporating circulating tumor cell (CTC) changes post-NAC and tumor size changes further improved predictive performance (C-statistics/AUC 0.945) in the CTC detection subgroup. Key prognostic factors included tumor size >5cm, lymph node metastasis, sTIL levels, estrogen receptor (ER) status and pCR. Despite varied pCR rates, overall prognosis after standard systemic therapy was consistent across molecular subtypes. Conclusion: The developed predictive model showcases robust performance in forecasting pCR in NAC-treated breast cancer patients, marking a step toward more personalized therapeutic strategies in breast cancer.

Neoadjuvant chemotherapy-induced remodeling of human hormonal receptor-positive breast cancer revealed by single-cell RNA sequencing.

Hormone receptor-positive breast cancer (HR+ BC) is known to be relatively insensitive to chemotherapy, and since chemotherapy has remained the major neoadjuvant therapy for HR+ BC, the undetermined mechanism of chemoresistance and how chemotherapy reshapes the immune microenvironment need to be explored by high-throughput technology. By using single-cell RNA sequencing and multiplexed immunofluorescence staining analysis of HR+ BC samples (paired pre- and post-neoadjuvant chemotherapy (NAC)), the levels of previously unrecognized immune cell subsets, including CD8+ T cells with pronounced expression of T-cell development (LMNA) and cytotoxicity (FGFBP2) markers, CD4+ T cells characterized by proliferation marker (ATP1B3) expression and macrophages characterized by CD52 expression, were found to be increased post-NAC, which were predictive of chemosensitivity and their antitumor function was also validated with in vitro experiments. In terms of immune checkpoint expression of CD8+ T cells, we found their changes were inconsistent post-NAC, that LAG3, VSIR were decreased, and PDCD1, HAVCR2, CTLA4, KLRC1 and BTLA were increased. In addition, we have identified novel genomic and transcriptional patterns of chemoresistant cancer cells, both innate and acquired, and have confirmed their prognostic value with TCGA cohorts. By shedding light on the ecosystem of HR+ BC reshaped by chemotherapy, our results uncover valuable candidates for predicting chemosensitivity and overcoming chemoresistance in HR+ BC.

Integrated transcriptomics, proteomics, and functional analysis to characterize the tissue-specific small extracellular vesicle network of breast cancer.

Small extracellular vesicles (sEVs) are essential mediators of intercellular communication within the tumor microenvironment (TME). Although the biological features of sEVs have been characterized based on in vitro culture models, recent evidence indicates significant differences between sEVs derived from tissue and those derived from in vitro models in terms of both content and biological function. However, comprehensive comparisons and functional analyses are still limited. Here, we collected sEVs from breast cancer tissues (T-sEVs), paired normal tissues (N-sEVs), corresponding plasma (B-sEVs), and tumor organoids (O-sEVs) to characterize their transcriptomic and proteomic profiles. We identified the actual cancer-specific sEV signatures characterized by enriched cell adhesion and immunomodulatory molecules. Furthermore, we revealed the significant contribution of cancer-associated fibroblasts in the sEV network within the TME. In vitro model-derived sEVs did not entirely inherit the extracellular matrix- and immunity regulation-related features of T-sEVs. Also, we demonstrated the greater immunostimulatory ability of T-sEVs on macrophages and CD8+ T cells compared to O-sEVs. Moreover, certain sEV biomarkers derived from noncancer cells in the circulation exhibited promising diagnostic potential. This study provides valuable insights into the functional characteristics of tumor tissue-derived sEVs, highlighting their potential as diagnostic markers and therapeutic agents for breast cancer.

CD24hiCD27+ Bregs within Metastatic Lymph Nodes Promote Multidrug Resistance in Breast Cancer.

PURPOSE: Axillary lymph nodes (LN) are the primary and dominant metastatic sites in breast cancer. However, the interaction between tumor cells and immune cells within metastatic LNs (mLN) remains poorly understood. In our study, we explored the effect of CD24hiCD27+ regulatory B cells (Breg) within mLNs on orchestrating drug resistance of breast cancer cells. EXPERIMENTAL DESIGN: We collected mLN samples from patients with breast cancer who had received standard neoadjuvant therapy (NAT) and analyzed the spatial features of CD24hiCD27+ Bregs through multicolor immunofluorescence staining. The effect of CD24hiCD27+ Bregs on drug resistance of breast cancer cells was evaluated via in vitro experiments. A mouse model with mLNs was used to evaluate the strategies with blocking the interactions between Bregs and breast cancer for improving tumor regression within mLNs. RESULTS: In patients with breast cancer who had received NAT, there is a close spatial correlation between activated CD24hiCD27+ Bregs and residual tumor cells within mLNs. Mechanistically, CD24hiCD27+ Bregs greatly enhance the acquisition of multidrug resistance and stem-like features of breast cancer cells by secreting IL6 and TNFα. More importantly, breast cancer cells further promote the activation of CD24hiCD27+ Bregs via CD40L-dependent and PD-L1-dependent proximal signals, forming a positive feedback pattern. PD-L1 blockade significantly attenuates the drug resistance of breast cancer cells induced by CD24hiCD27+ Bregs, and addition of anti-PD-L1 antibody to chemotherapy improves tumor cell remission in mLNs. CONCLUSIONS: Our study reveals the pivotal role of CD24hiCD27+ Bregs in promoting drug resistance by interacting with breast cancer cells in mLNs, providing novel evidence for an improved strategy of chemoimmunotherapy combination for patients with breast cancer with mLNs.

Chemotherapy-induced exosomal circBACH1 promotes breast cancer resistance and stemness via miR-217/G3BP2 signaling pathway.

BACKGROUND: Chemoresistance involves metastasis and aggressiveness of breast cancer (BC). Chemotherapy-elicited exosomes have been reported to be associated with drug resistance and pro-metastatic capacity of BC cells. Non-coding RNAs (ncRNAs) are enriched in exosomes, which participated in generation, progression, and resistance of BC. However, the mechanism underlying the chemoresistance and metastasis in BC cells mediated by the BC-derived exosomal ncRNAs remained to be elucidated. METHODS: The effects of PTX-induced exosomal circBACH1 on BC cell function were assessed using RNA Binding Protein Immunoprecipitation (RIP), dual luciferase reporter gene, tube formation, CCK-8, and Western Blot assays. The circBACH1 and miR-217 expression levels were detected using quantitative real-time PCR (RT-qPCR) and Immunohistochemistry (IHC) assays in BC tissues and precancerous tissues of BC patients. RESULTS: CircBACH1 expression was increased in paclitaxel-treated BC-derived exosomes (PTX-EXO) and BC tissue. PTX-EXO was shown to promote PTX-resistance and angiogenesis through upregulation circBACH1. Downregulation of circBACH1 improved PTX-sensitiveness by suppressing the cell viability, stemness, migration, and angiogenesis of BC cells. Moreover, we found that miR-217 interacted with circBACH1 and targeted GTPase-activating SH3 domain-binding protein 2 (G3BP2) in BC cells. CircBACH1 combined miR-217 cotransfection suppressed the expression of G3BP2 proteins compared with circBACH1 treatment in MCF-7 cells. In addition, downregulation of G3BP2 suppressed BC cell migration. CONCLUSIONS: These results demonstrated that PTX-induced exosomal circBACH1 promoted stemness and migration of BC cells by sponging miR-217 to upregulate the expression of G3BP2, which provided a new therapeutic target for PTX-resistance and progression of BC via circBACH1/miR-217/G3BP2 axis.

Exploration of prognosis and immunometabolism landscapes in ER+ breast cancer based on a novel lipid metabolism-related signature.

Introduction: Lipid metabolic reprogramming is gaining attention as a hallmark of cancers. Recent mounting evidence indicates that the malignant behavior of breast cancer (BC) is closely related to lipid metabolism. Here, we focus on the estrogen receptor-positive (ER+) subtype, the most common subgroup of BC, to explore immunometabolism landscapes and prognostic significance according to lipid metabolism-related genes (LMRGs). Methods: Samples from The Cancer Genome Atlas (TCGA) database were used as training cohort, and samples from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), Gene Expression Omnibus (GEO) datasets and our cohort were applied for external validation. The survival-related LMRG molecular pattern and signature were constructed by unsupervised consensus clustering and least absolute shrinkage and selection operator (LASSO) analysis. A lipid metabolism-related clinicopathologic nomogram was established. Gene enrichment and pathway analysis were performed to explore the underlying mechanism. Immune landscapes, immunotherapy and chemotherapy response were further explored. Moreover, the relationship between gene expression and clinicopathological features was assessed by immunohistochemistry. Results: Two LMRG molecular patterns were identified and associated with distinct prognoses and immune cell infiltration. Next, a prognostic signature based on nine survival-related LMRGs was established and validated. The signature was confirmed to be an independent prognostic factor and an optimal nomogram incorporating age and T stage (AUC of 5-year overall survival: 0.778). Pathway enrichment analysis revealed differences in immune activities, lipid biosynthesis and drug metabolism by comparing groups with low- and high-risk scores. Further exploration verified different immune microenvironment profiles, immune checkpoint expression, and sensitivity to immunotherapy and chemotherapy between the two groups. Finally, arachidonate 15-lipoxygenase (ALOX15) was selected as the most prominent differentially expressed gene between the two groups. Its expression was positively related to larger tumor size, more advanced tumor stage and vascular invasion in our cohort (n = 149). Discussion: This is the first lipid metabolism-based signature with value for prognosis prediction and immunotherapy or chemotherapy guidance for ER+ BC.

Case report: Individualized treatment of advanced breast cancer with the use of the patient-derived tumor-like cell cluster model.

Breast cancer is one of the most common tumors in women. Despite various treatments, the survival of patients with advanced breast cancer is still disappointing. Furthermore, finding an effective individualized treatment for different kinds of patients is a thorny problem. Patient-derived tumor-like cell clusters were reported to be used for personalized drug testing in cancer therapy and had a prediction accuracy of 93%. However, there is still a lack of case reports about its application in the individualized treatment of breast cancer patients. Here, we described four cases of individualized treatment for advanced breast cancer using the patient-derived tumor-like cell cluster model (PTC model). In these four cases, the PTC model showed a good predictive effect. The tumor size was reduced significantly or even disappeared completely through clinical, radiological, or pathological evaluation with the help of the PTC model for selecting an individualized therapy regimen. Furthermore, the drug sensitivity test results of the PTC model were consistent with pathological molecular typing and the actual clinical drug resistance of the patients. In summary, our case report first evaluated the application value of the PTC model in advanced breast cancer, and the PTC model might be used as an efficient tool for drug resistance screening and for selecting a better personalized treatment, although further study is needed to prove the validity and stability of the PTC model in drug screening.

Crosstalk between the peripheral nervous system and breast cancer influences tumor progression.

Recent studies have shown that peripheral nerves play an important role in the progression of breast cancer. Breast cancer cells (BCCs) promote local peripheral nerve growth and branching by secreting neuroactive molecules, including neurotrophins and axon guidance molecules (AGMs). Sympathetic nerves promote breast cancer progression, while parasympathetic and sensory nerves mainly have anti-tumor effects in the progression of breast cancer. Specifically, peripheral nerves can influence the progression of breast cancer by secreting neurotransmitters not only directly binding to the corresponding receptors of BCCs, but also indirectly acting on immune cells to modulate anti-tumor immunity. In this review, we summarize the crosstalk between breast cancer and peripheral nerves and the roles of important neuroactive molecules in the progression of breast cancer. In addition, we summarize indicators, including nerve fiber density and perineural invasion (PNI), that may help determine the prognosis of breast cancer based on current research results, as well as potential therapeutic approaches, such as ß-blockers and retroviral-mediated genetic neuroengineering techniques, that may enhance the prognosis of breast cancer. In addition, we propose suggestions for future research priorities based on a current lack of knowledge in this area.

A comprehensive comparison of circulating tumor cells and breast imaging modalities as screening tools for breast cancer in Chinese women.

Background: Circulating tumor cells (CTCs) have been recognized as a sensitive biomarker for breast cancer (BC). This study aimed to comprehensively compare CTC with imaging modalities, including ultrasonography, mammography, and contrast-enhanced magnetic resonance imaging (MRI) in screening for BC in Chinese women. Methods: Three hundred forty-three participants were enrolled in this study, including 102 treatment-naive BC patients, 177 with breast benign diseases (BBD) and 64 healthy female patients. All participants underwent CTC testing and at least one of the following examinations, ultrasonography, mammography, and MRI at the Second Affiliated Hospital of Zhejiang University between December 2017 and November 2020. CTCs were quantitatively assessed using cell counting (CTC detection rate/counts) and categorically examined using a cutoff value (CTC classification). The diagnostic power of CTC tests and imaging modalities, including accuracy and capability to predict clinicopathological characteristics of BC, were evaluated and compared. Results: CTC classification with a cutoff value of 2 showed a "good" diagnostic accuracy of 0.889 for early- to mid-stage BC comparable to breast imaging modalities using Breast Imaging-Reporting and Data System (BI-RADS). MRI demonstrated the highest sensitivity of 0.872 for BC, and CTC classification had the highest specificity of 0.938. A relatively low sensitivity was found for mammography in this cohort of patients. Successful detection of BC by CTC detection rate/counts, but not CTC classification, correlated with two important clinicopathological features, American Joint Committee on Cancer (AJCC) stage and tumor-node-metastasis (TNM) stage. The detection power of certain imaging modalities was also associated with AJCC stage (ultrasonography, p = 0.0438 and MRI, p = 0.0422) and lymph node metastasis (ultrasonography, 0.0157). There were clear correlations between CTC tests (counts or classification) and imaging BI-RADS scoring system in detecting positive BC cases (p < 0.05). Further correlation analysis suggested that CTC quantity, but not CTC classification, had the capability to predict clinicopathological traits of BC that were identified by ultrasonography. Conclusions: CTC tests have a diagnostic potency comparable to breast imaging modalities, and may be used as an alternative screening tool for BC.

High PANX1 Expression Leads to Neutrophil Recruitment and the Formation of a High Adenosine Immunosuppressive Tumor Microenvironment in Basal-like Breast Cancer.

Background: A high adenosine level is an important characteristic of the tumor microenvironment (TME) in breast cancer. Pannexin 1 (PANX1) can release intracellular ATP to the extracellular space and elevate extracellular ATP (exATP) levels under physiological conditions. Methods: We performed public database bioinformatics analysis, surgical specimen histological validation, RNA sequencing, and exATP/extracellular adenosine (exADO) assays to reveal the role of PANX1 in regulating the immune microenvironment of basal-like breast cancer. Results: Our results revealed that PANX1 acted as a poor prognostic factor for breast cancer and had high expression in basal-like breast cancer. PANX1 expression was positively correlated with exATP and exADO levels in basal-like breast cancer TME. PANX1 expression was also positively correlated with tumor-associated neutrophil (TAN) infiltration in breast cancer TME and TANs highly expressed ENTPD1 (CD39)/NT5E (CD73). Conclusions: This study suggests that high PANX1 expression is associated with high TAN infiltration and adenosine production to induce local immunosuppression in basal-like breast cancer TME.

Treatment patterns, effectiveness, and patient-reported outcomes of palbociclib therapy in Chinese patients with advanced breast cancer: A multicenter ambispective real-world study.

BACKGROUND: Palbociclib was the only available cyclin-dependent kinase 4/6 inhibitor in China until very recently, and its effect has not been systemically evaluated among Chinese patients. This study aims to assess the efficacy, safety and patient-reported outcomes (PROs) of palbociclib plus endocrine therapy (ET) in real-world China. METHODS: An ambispective cohort study was conducted on patients with advanced HR+HER2- breast cancer who received palbociclib between July 2018, and November 2020 and were enrolled from 12 hospitals. Treatment patterns, survival outcomes, and safety events were documented, and PROs (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 items [EORTC QLQ-C30] and EuroQoL 5 dimensions [EQ-5D]) were analyzed. The Kaplan-Meier method was used to visualize and estimate the median progression-free survival (mPFS). Log-rank tests, Cox regressions, t tests, and chi-square tests were performed for comparison. RESULTS: A total of 190 patients (median follow-up of 18.0 months) were enrolled. Palbociclib was mostly combined with aromatase inhibitors (66.3%), fulvestrant (32.6%), and tamoxifen (1.1%). The mPFS values were 21.0, 14.0, and 7.0 months with palbociclib administered in first- (n = 83), second- (n = 41) and subsequent-line settings (n = 66), respectively. Endocrine sensitivity was significantly associated with patient prognosis (mPFS: 23.0, 12.0, and 6.0 months for endocrine naïve, acquired, and primary resistant patients, respectively, p < 0.01). The outcome was worse for patients who failed to meet the inclusion criteria of PALOMA-3 than for those who met the criteria (later-line: 6.0 months vs. 9.0 months). The most common adverse events (AEs) were neutropenia (74.2%; grade 3/4: 30.0%), fatigue (48.4%), anemia (32.6%), and thrombocytopenia (22.1%). PRO data suggested that palbociclib plus ET significantly improved cognitive and emotional function, pain symptoms, and overall quality of life. CONCLUSIONS: Palbociclib is effective for front-line use and for treating endocrine-sensitive patients in real-world China and is generally well tolerated. The prevalence of AEs in the Chinese population is different from that reported in the PALOMA-2/3 trials.

Role of Intra- and Extracellular Lipid Signals in Cancer Stemness and Potential Therapeutic Strategy.

Accumulating evidence showed that cancer stem cells (CSCs) play significant roles in cancer initiation, resistance to therapy, recurrence and metastasis. Cancer stem cells possess the ability of self-renewal and can initiate tumor growth and avoid lethal factors through flexible metabolic reprogramming. Abnormal lipid metabolism has been reported to be involved in the cancer stemness and promote the development of cancer. Lipid metabolism includes lipid uptake, lipolysis, fatty acid oxidation, de novo lipogenesis, and lipid desaturation. Abnormal lipid metabolism leads to ferroptosis of CSCs. In this review, we comprehensively summarized the role of intra- and extracellular lipid signals in cancer stemness, and explored the feasibility of using lipid metabolism-related treatment strategies for future cancer.

Adjuvant ovarian suppression for premenopausal hormone receptor-positive breast cancer: A network meta-analysis.

BACKGROUND: Ovarian function suppressor (OFS) plus either tamoxifen (TAM) or aromatase inhibitor (AI) could improve the survival outcome for premenopausal hormone receptor-positive (HR+) breast cancer. However, the optimal OFS-based regimen and medication duration remain uncertain. This article aims to systematically evaluate the OFS-based adjuvant endocrine therapy for premenopausal breast cancer. METHODS: We searched several public databases from January 1980 to November 2020. A random model was adopted in this meta-analysis. We used the hazard ratio (HR) with a 95% confidence interval (CI) for the statistical analysis of efficacy. The primary outcome measures included overall survival and disease-free survival. RESULTS: A total of 32 articles with 37,224 cases were included in this network meta-analysis. OFS+TAM improved 5-year disease-free survival (HR -0.09, 95% CI -0.16 to -0.01) and 5-year overall survival (HR -0.18, 95% CI -0.33 to -0.03) compared with TAM monotherapy. For OFS+AI, although the 5-year disease-free survival was improved (HR -0.18, 95% CI -0.29 to -0.08), the 5-year overall survival was not improved (HR -0.13, 95% CI -0.43 to 0.18). In subgroup analysis, both OFS+AI and OFS+TAM showed a protective effect in stage I-III patients compared with stage I-II patients. For the course of therapy, OFS+TAM for 2-years could achieve clinical benefit and the best course of therapy of OFS+AI still waits for further study. CONCLUSIONS: OFS+TAM might be a better option than OFS+AI for premenopausal intensive adjuvant endocrine therapy. Stage III patients are more suitable for the OFS-based therapy. For the medication duration, the 2-years course of OFS+TAM could be effective. This analysis provides helpful information for selecting therapeutic regimen in intensive adjuvant endocrine therapy and identifying the target population.

Antiangiogenic therapy reverses the immunosuppressive breast cancer microenvironment.

Tumor angiogenesis induces local hypoxia and recruits immunosuppressive cells, whereas hypoxia subsequently promotes tumor angiogenesis. Immunotherapy efficacy depends on the accumulation and activity of tumor-infiltrating immune cells (TIICs). Antangiogenic therapy could improve local perfusion, relieve tumor microenvironment (TME) hypoxia, and reverse the immunosuppressive state. Combining antiangiogenic therapy with immunotherapy might represent a promising option for the treatment of breast cancer. This article discusses the immunosuppressive characteristics of the breast cancer TME and outlines the interaction between the tumor vasculature and the immune system. Combining antiangiogenic therapy with immunotherapy could interrupt abnormal tumor vasculature-immunosuppression crosstalk, increase effector immune cell infiltration, improve immunotherapy effectiveness, and reduce the risk of immune-related adverse events. In addition, we summarize the preclinical research and ongoing clinical research related to the combination of antiangiogenic therapy with immunotherapy, discuss the underlying mechanisms, and provide a view for future developments. The combination of antiangiogenic therapy and immunotherapy could be a potential therapeutic strategy for treatment of breast cancer to promote tumor vasculature normalization and increase the efficiency of immunotherapy.

Crosstalk between Macrophages, T Cells, and Iron Metabolism in Tumor Microenvironment.

Leukocytes, including macrophages and T cells, represent key players in the human immune system, which plays a considerable role in the development and progression of tumors by immune surveillance or immune escape. Boosting the recruitment of leukocytes into the tumor microenvironment and promoting their antitumor responses have been hot areas of research in recent years. Although immunotherapy has manifested a certain level of success in some malignancies, the overall effectiveness is far from satisfactory. Iron is an essential trace element required in multiple, normal cellular processes, such as DNA synthesis and repair, cellular respiration, metabolism, and signaling, while dysregulated iron metabolism has been declared one of the metabolic hallmarks of malignant cancer cells. Furthermore, iron is implicated in the modulation of innate and adaptive immune responses, and elucidating the targeted regulation of iron metabolism may have the potential to benefit antitumor immunity and cancer treatment. In the present review, we briefly summarize the roles of leukocytes and iron metabolism in tumorigenesis, as well as their crosstalk in the tumor microenvironment. The combination of immunotherapy with targeted regulation of iron and iron-dependent regulated cell death (ferroptosis) may be a focus of future research.

Multi-Omics Profiling Suggesting Intratumoral Mast Cells as Predictive Index of Breast Cancer Lung Metastasis.

Breast cancer lung metastasis has a high mortality rate and lacks effective treatments, for the factors that determine breast cancer lung metastasis are not yet well understood. In this study, data from 1067 primary tumors in four public datasets revealed the distinct microenvironments and immune composition among patients with or without lung metastasis. We used multi-omics data of the TCGA cohort to emphasize the following characteristics that may lead to lung metastasis: more aggressive tumor malignant behaviors, severer genomic instability, higher immunogenicity but showed generalized inhibition of effector functions of immune cells. Furthermore, we found that mast cell fraction can be used as an index for individual lung metastasis status prediction and verified in the 20 human breast cancer samples. The lower mast cell infiltrations correlated with tumors that were more malignant and prone to have lung metastasis. This study is the first comprehensive analysis of the molecular and cellular characteristics and mutation profiles of breast cancer lung metastasis, which may be applicable for prognostic prediction and aid in choosing appropriate medical examinations and therapeutic regimens.

CD62Ldim Neutrophils Specifically Migrate to the Lung and Participate in the Formation of the Pre-Metastatic Niche of Breast Cancer.

Lung metastasis is one of the leading causes of death in patients with breast cancer. The mechanism of tumor metastasis remains controversial. Recently, the formation of a pre-metastatic niche has been considered a key factor contributing to breast cancer metastasis, which might also explain the tendency of organ metastasis. Our study initially re-examined the critical time of the niche formation and simultaneously detected a novel subset of neutrophils, CD62Ldim neutrophils, which had not previously been reported in tumor metastasis; the number of these cells progressively increased during breast cancer progression and was closely related to the formation of the pre-metastatic niche. Furthermore, we explored the mechanism of their aggregation in the pre-metastatic niche in the lung and found that they were specifically chemoattracted by the CXCL12-CXCR4 signaling pathway. Compared to the CD62Lhi neutrophils, CD62Ldim neutrophils exhibited stronger adhesion and increased survival. The results provide new insights into the subsequent targeted treatment of breast cancer metastasis.

A Rosetta Stone for Breast Cancer: Prognostic Value and Dynamic Regulation of Neutrophil in Tumor Microenvironment.

Increasing evidence has revealed that the initiation and progression of breast cancer are greatly affected by the immune environment. Neutrophils are the most abundant leucocytes in circulation and act as the spearhead in inflammation, including in breast cancer. Circulating neutrophils are closely related to the prognosis of breast cancer patients, and tumor-infiltrating neutrophils have varied functions at different stages of breast cancer, such as antitumor or tumor-promoting neutrophils, which are termed N1 and N2 neutrophils, respectively. In this review, we will discuss the utility of circulating neutrophils for predicting prognosis and therapeutic efficacy and the underlying mechanisms of their chemotaxis, the dynamic regulation of their antitumor or protumor functions and their different spatial distributions in tumor microenvironment. Finally, we also discuss the possibility of targeting neutrophils as a therapeutic strategy in breast cancer.

Epigenomic and genomic analysis of transcriptome modulation in skin cutaneous melanoma.

Skin cutaneous melanoma (SKCM) is characterized by both epigenetic DNA methylation (MET) abnormalities and genomic copy number variations (CNVs). The resulting transcriptome dysregulation promotes progression of many cancers. In this study, DNA copy numbers and MET, as well as mRNA expression, were examined in 466 SKCM samples from The Cancer Genome Atlas. Our results indicate that CNVs-correlated (CNVcor) genes and MET-correlated (METcor) genes are coregulated to a remarkable degree. In addition, integrative multi-omics analysis of both METcor and CNVcor genes revealed four SKCM subtypes with differing prognoses; these subtypes were validated with independent data. Immune cell scores were markedly elevated in the iC1 subtype, which had the best prognosis. Immune cell infiltration correlated with DNA MET or CNV level in SKCM. In the iC3 subtype, which was associated with the most aggressive SKCM cases, FAM135B gene mutation frequencies were increased, while CD8A, GBP5, KIAA0040, and SAMHD1 expression were downregulated, suggesting that these genes play important roles in cancer development and immune responses. Taken together, the results of our epigenetic and genomic transcriptome modulation analysis improve our understanding of SKCM pathobiology and may aid in the development of more effective therapies.