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Cell Apr 2024Microbial communities are resident to multiple niches of the human body and are important modulators of the host immune system and responses to anticancer therapies....
Microbial communities are resident to multiple niches of the human body and are important modulators of the host immune system and responses to anticancer therapies. Recent studies have shown that complex microbial communities are present within primary tumors. To investigate the presence and relevance of the microbiome in metastases, we integrated mapping and assembly-based metagenomics, genomics, transcriptomics, and clinical data of 4,160 metastatic tumor biopsies. We identified organ-specific tropisms of microbes, enrichments of anaerobic bacteria in hypoxic tumors, associations between microbial diversity and tumor-infiltrating neutrophils, and the association of Fusobacterium with resistance to immune checkpoint blockade (ICB) in lung cancer. Furthermore, longitudinal tumor sampling revealed temporal evolution of the microbial communities and identified bacteria depleted upon ICB. Together, we generated a pan-cancer resource of the metastatic tumor microbiome that may contribute to advancing treatment strategies.
Topics: Humans; Microbiota; Neoplasm Metastasis; Neoplasms; Metagenomics; Lung Neoplasms; Immune Checkpoint Inhibitors; Neutrophils; Tumor Microenvironment; Bacteria
PubMed: 38599211
DOI: 10.1016/j.cell.2024.03.021 -
Nature Aug 2023Epithelial-to-mesenchymal transition (EMT) regulates tumour initiation, progression, metastasis and resistance to anti-cancer therapy. Although great progress has been...
Epithelial-to-mesenchymal transition (EMT) regulates tumour initiation, progression, metastasis and resistance to anti-cancer therapy. Although great progress has been made in understanding the role of EMT and its regulatory mechanisms in cancer, no therapeutic strategy to pharmacologically target EMT has been identified. Here we found that netrin-1 is upregulated in a primary mouse model of skin squamous cell carcinoma (SCC) exhibiting spontaneous EMT. Pharmacological inhibition of netrin-1 by administration of NP137, a netrin-1-blocking monoclonal antibody currently used in clinical trials in human cancer (ClinicalTrials.gov identifier NCT02977195 ), decreased the proportion of EMT tumour cells in skin SCC, decreased the number of metastases and increased the sensitivity of tumour cells to chemotherapy. Single-cell RNA sequencing revealed the presence of different EMT states, including epithelial, early and late hybrid EMT, and full EMT states, in control SCC. By contrast, administration of NP137 prevented the progression of cancer cells towards a late EMT state and sustained tumour epithelial states. Short hairpin RNA knockdown of netrin-1 and its receptor UNC5B in EPCAM tumour cells inhibited EMT in vitro in the absence of stromal cells and regulated a common gene signature that promotes tumour epithelial state and restricts EMT. To assess the relevance of these findings to human cancers, we treated mice transplanted with the A549 human cancer cell line-which undergoes EMT following TGFβ1 administration-with NP137. Netrin-1 inhibition decreased EMT in these transplanted A549 cells. Together, our results identify a pharmacological strategy for targeting EMT in cancer, opening up novel therapeutic interventions for anti-cancer therapy.
Topics: Animals; Humans; Mice; A549 Cells; Carcinoma, Squamous Cell; Cell Line, Tumor; Epithelial-Mesenchymal Transition; Netrin Receptors; Netrin-1; RNA, Small Interfering; Disease Models, Animal; Skin Neoplasms; Antibodies, Monoclonal; Neoplasm Metastasis; Single-Cell Gene Expression Analysis; RNA-Seq; Epithelial Cell Adhesion Molecule; Xenograft Model Antitumor Assays; Transforming Growth Factor beta1
PubMed: 37532929
DOI: 10.1038/s41586-023-06372-2 -
The Journal of Clinical Investigation Nov 2023The metastasis of cancer cells is the main cause of death in patients with gastric cancer (GC). Mounting evidence has demonstrated the vital importance of...
The metastasis of cancer cells is the main cause of death in patients with gastric cancer (GC). Mounting evidence has demonstrated the vital importance of tumor-associated macrophages in promoting tumor invasion and metastasis; however, the interaction between tumor cells and macrophages in GC is largely unknown. In this study, we demonstrated that cyclase-associated protein 2 (CAP2) was upregulated in GC, especially in cases with lymph node metastasis, and was correlated with a poorer prognosis. The transcription factor JUN directly bound to the promoter region of CAP2 and activated CAP2 transcription. The N-terminal domain of CAP2 bound to the WD5 to WD7 domains of receptor for activated C kinase 1 (RACK1) and induced M2 macrophage polarization by activating the SRC/focal adhesion kinase (FAK)/ERK signaling pathway, which resulted in IL-4 and IL-10 secretion. Polarized M2 macrophages induced premetastatic niche formation and promoted GC metastasis by secreting TGFB1, which created a TGFB1/JUN/CAP2 positive-feedback loop to activate CAP2 expression continuously. Furthermore, we identified salvianolic acid B as an inhibitor of CAP2, which effectively inhibited GC cell invasion capabilities by suppressing the SRC/FAK/ERK signaling pathway. Our data suggest that CAP2, a key molecule mediating the interaction between GC cells and tumor-associated macrophages, may be a promising therapeutic target for suppressing tumor metastasis in GC.
Topics: Humans; Tumor-Associated Macrophages; Stomach Neoplasms; Signal Transduction; Lymphatic Metastasis; MAP Kinase Signaling System; Cell Line, Tumor; Neoplasm Metastasis; Membrane Proteins; Adaptor Proteins, Signal Transducing
PubMed: 37707957
DOI: 10.1172/JCI166224 -
Nature Reviews. Clinical Oncology Jul 2023Given that cancer mortality is usually a result of late diagnosis, efforts in the field of early detection are paramount to reducing cancer-related deaths and improving... (Review)
Review
Given that cancer mortality is usually a result of late diagnosis, efforts in the field of early detection are paramount to reducing cancer-related deaths and improving patient outcomes. Increasing evidence indicates that metastasis is an early event in patients with aggressive cancers, often occurring even before primary lesions are clinically detectable. Metastases are usually formed from cancer cells that spread to distant non-malignant tissues via the blood circulation, termed circulating tumour cells (CTCs). CTCs have been detected in patients with early stage cancers and, owing to their association with metastasis, might indicate the presence of aggressive disease, thus providing a possible means to expedite diagnosis and treatment initiation for such patients while avoiding overdiagnosis and overtreatment of those with slow-growing, indolent tumours. The utility of CTCs as an early diagnostic tool has been investigated, although further improvements in the efficiency of CTC detection are required. In this Perspective, we discuss the clinical significance of early haematogenous dissemination of cancer cells, the potential of CTCs to facilitate early detection of clinically relevant cancers, and the technological advances that might improve CTC capture and, thus, diagnostic performance in this setting.
Topics: Humans; Neoplastic Cells, Circulating; Neoplasms
PubMed: 37268719
DOI: 10.1038/s41571-023-00781-y -
Nature Sep 2023Vertebral bone is subject to a distinct set of disease processes from long bones, including a much higher rate of solid tumour metastases. The basis for this distinct...
Vertebral bone is subject to a distinct set of disease processes from long bones, including a much higher rate of solid tumour metastases. The basis for this distinct biology of vertebral bone has so far remained unknown. Here we identify a vertebral skeletal stem cell (vSSC) that co-expresses ZIC1 and PAX1 together with additional cell surface markers. vSSCs display formal evidence of stemness, including self-renewal, label retention and sitting at the apex of their differentiation hierarchy. vSSCs are physiologic mediators of vertebral bone formation, as genetic blockade of the ability of vSSCs to generate osteoblasts results in defects in the vertebral neural arch and body. Human counterparts of vSSCs can be identified in vertebral endplate specimens and display a conserved differentiation hierarchy and stemness features. Multiple lines of evidence indicate that vSSCs contribute to the high rates of vertebral metastatic tropism observed in breast cancer, owing in part to increased secretion of the novel metastatic trophic factor MFGE8. Together, our results indicate that vSSCs are distinct from other skeletal stem cells and mediate the unique physiology and pathology of vertebrae, including contributing to the high rate of vertebral metastasis.
Topics: Humans; Breast Neoplasms; Cell Differentiation; Cell Lineage; Cell Self Renewal; Neoplasm Metastasis; Osteoblasts; Spine; Stem Cells; Biomarkers
PubMed: 37704733
DOI: 10.1038/s41586-023-06519-1 -
Nature Communications Oct 2023Metastasis is the leading cause of cancer-related death, where TGFβ-induced epithelial-mesenchymal transition (EMT) process confers on cancer cells increased metastatic...
Metastasis is the leading cause of cancer-related death, where TGFβ-induced epithelial-mesenchymal transition (EMT) process confers on cancer cells increased metastatic potential. However, the involvement of circRNAs in this process is still obscure. Here, we identify a TGFβ-induced circRNA called circITGB6 as an indispensable factor during the TGFβ-mediated EMT process. circITGB6 is significantly upregulated in metastatic cancer samples and its higher abundance is closely correlated to worse prognosis of colorectal cancer (CRC) patients. Through gain- and loss-of-function assays, circITGB6 is found to potently promote EMT process and tumor metastasis in various models in vitro and in vivo. Mechanistically, circITGB6 enhances the mRNA stability of PDPN, an EMT-promoting gene, by directly interacting with IGF2BP3. Notably, interfering circITGB6 with PEI-coated specific siRNA effectively represses liver metastasis. Therefore, our study reveals the function of a TGFβ-regulated circRNA in tumor metastasis and suggests that targeting circITGB6 is a promising strategy for cancer therapy.
Topics: Humans; RNA, Circular; Transforming Growth Factor beta; Epithelial-Mesenchymal Transition; Cell Line, Tumor; Colorectal Neoplasms; Cell Movement; Gene Expression Regulation, Neoplastic; Neoplasm Metastasis; Membrane Glycoproteins
PubMed: 37898647
DOI: 10.1038/s41467-023-42571-1 -
Journal of Experimental & Clinical... Sep 2023Fusobacterium nucleatum (Fn) acts as a procarcinogenic bacterium in colorectal carcinoma (CRC) by regulating the inflammatory tumor microenvironment (TME). Neutrophil...
BACKGROUND
Fusobacterium nucleatum (Fn) acts as a procarcinogenic bacterium in colorectal carcinoma (CRC) by regulating the inflammatory tumor microenvironment (TME). Neutrophil extracellular traps (NETs), which can be generated by persistent inflammation, have been recently considered to be significant contributors in promoting cancer progression. However, whether NETs are implicated in Fn-related carcinogenesis is still poorly characterized. Here, we explored the role of NETs in Fn-related CRC as well as their potential clinical significance.
METHODS
Fn was measured in tissue specimens and feces samples from CRC patients. The expression of NET markers were also detected in tissue specimens, freshly isolated neutrophils and blood serum from CRC patients, and the correlation of circulating NETs levels with Fn was evaluated. Cell-based experiments were conducted to investigate the mechanism by which Fn modulates NETs formation. In addition, we clarified the functional mechanism of Fn-induced NETs on the growth and metastasis of CRC in vitro and in vivo experiments.
RESULTS
Tissue and blood samples from CRC patients, particularly those from Fn-infected CRC patients, exhibited greater neutrophil infiltration and higher NETs levels. Fn infection induced abundant NETs production in in vitro studies. Subsequently, we demonstrated that Fn-induced NETs indirectly accelerated malignant tumor growth through angiopoiesis, and facilitated tumor metastasis, as manifested by epithelial-mesenchymal transition (EMT)-related cell migration, matrix metalloproteinase (MMP)-mediated basement membrane protein degradation, and trapping of CRC cells. Mechanistically, the Toll-like receptor (TLR4)-reactive oxygen species (ROS) signaling pathway and NOD-like receptor (NOD1/2)-dependent signaling were responsible for Fn-stimulated NETs formation. More importantly, circulating NETs combined with carcinoembryonic antigen (CEA) could predict CRC occurrence and metastasis, with areas under the ROC curves (AUCs) of 0.92 and 0.85, respectively.
CONCLUSIONS
Our findings indicated that Fn-induced NETs abundance by activating TLR4-ROS and NOD1/2 signalings in neutrophils facilitated CRC progression. The combination of circulating NETs and CEA was identified as a novel screening strategy for predicting CRC occurrence and metastasis.
Topics: Fusobacterium nucleatum; Extracellular Traps; Colorectal Neoplasms; Disease Progression; Humans; Neutrophils; Tumor Microenvironment; Inflammation; Signal Transduction; Reactive Oxygen Species; Toll-Like Receptor 4; Nod1 Signaling Adaptor Protein; Nod2 Signaling Adaptor Protein; Carcinoembryonic Antigen; Male; Female; Middle Aged; Cell Line, Tumor; Mice, Inbred BALB C; Animals; Mice; Neoplasm Metastasis
PubMed: 37684625
DOI: 10.1186/s13046-023-02817-8 -
Signal Transduction and Targeted Therapy Sep 2023Lymph nodes (LNs) are important hubs for metastatic cell arrest and growth, immune modulation, and secondary dissemination to distant sites through a series of... (Review)
Review
Lymph nodes (LNs) are important hubs for metastatic cell arrest and growth, immune modulation, and secondary dissemination to distant sites through a series of mechanisms, and it has been proved that lymph node metastasis (LNM) is an essential prognostic indicator in many different types of cancer. Therefore, it is important for oncologists to understand the mechanisms of tumor cells to metastasize to LNs, as well as how LNM affects the prognosis and therapy of patients with cancer in order to provide patients with accurate disease assessment and effective treatment strategies. In recent years, with the updates in both basic and clinical studies on LNM and the application of advanced medical technologies, much progress has been made in the understanding of the mechanisms of LNM and the strategies for diagnosis and treatment of LNM. In this review, current knowledge of the anatomical and physiological characteristics of LNs, as well as the molecular mechanisms of LNM, are described. The clinical significance of LNM in different anatomical sites is summarized, including the roles of LNM playing in staging, prognostic prediction, and treatment selection for patients with various types of cancers. And the novel exploration and academic disputes of strategies for recognition, diagnosis, and therapeutic interventions of metastatic LNs are also discussed.
Topics: Humans; Lymphatic Metastasis; Clinical Relevance; Lymph Nodes
PubMed: 37752146
DOI: 10.1038/s41392-023-01576-4 -
Cell Reports. Medicine Sep 2023Upper tract urothelial carcinoma (UTUC) is often diagnosed late and exhibits poor prognosis. Limited data are available on potential non-invasive biomarkers for disease...
Upper tract urothelial carcinoma (UTUC) is often diagnosed late and exhibits poor prognosis. Limited data are available on potential non-invasive biomarkers for disease monitoring. Here, we investigate the proteomic profile of plasma in 362 UTUC patients and 239 healthy controls. We present an integrated tissue-plasma proteomic approach to infer the signature proteins for identifying patients with muscle-invasive UTUC. We discover a protein panel that reflects lymph node metastasis, which is of interest in identifying UTUC patients with high risk and poor prognosis. We also identify a ten-protein classifier and establish a progression clock predicting progression-free survival of UTUC patients. Finally, we further validate the signature proteins by parallel reaction monitoring assay in an independent cohort. Collectively, this study portrays the plasma proteomic landscape of a UTUC cohort and provides a valuable resource for further biological and diagnostic research in UTUC.
Topics: Humans; Carcinoma, Transitional Cell; Urinary Bladder Neoplasms; Proteomics; Lymphatic Metastasis; Muscles
PubMed: 37633276
DOI: 10.1016/j.xcrm.2023.101166 -
Journal of Extracellular Vesicles Aug 2023Lymph nodes (LNs) are frequently the first sites of metastasis. Currently, the only prognostic LN assessment is determining metastatic status. However, there is evidence...
Lymph nodes (LNs) are frequently the first sites of metastasis. Currently, the only prognostic LN assessment is determining metastatic status. However, there is evidence suggesting that LN metastasis is facilitated by the formation of a pre-metastatic niche induced by tumour derived extracellular vehicles (EVs). Therefore, it is important to detect and modify the LN environmental changes. Earlier work has demonstrated that neutrophil extracellular traps (NETs) can sequester and promote distant metastasis. Here, we first confirmed that LN NETs are associated with reduced patient survival. Next, we demonstrated that NETs deposition precedes LN metastasis and NETs inhibition diminishes LN metastases in animal models. Furthermore, we discovered that EVs are essential to the formation of LN NETs. Finally, we showed that lymphatic endothelial cells secrete CXCL8/2 in response to EVs inducing NETs formation and the promotion of LN metastasis. Our findings reveal the role of EV-induced NETs in LN metastasis and provide potential immunotherapeutic vulnerabilities that may occur early in the metastatic cascade.
Topics: Animals; Lymphatic Metastasis; Endothelial Cells; Extracellular Traps; Extracellular Vesicles; Lymph Nodes
PubMed: 37563798
DOI: 10.1002/jev2.12341