Lung Metastasis Research Articles

Metabolic shifts in lipid utilization and reciprocal interactions within the lung metastatic niche of triple-negative breast cancer revealed by spatial multi-omics

The Triple-Negative Breast Cancer (TNBC) subtype constitutes 15-20% of breast cancer cases and is associated with the poorest clinical outcomes. Distant metastasis, particularly to the lungs, is a major contributor to the high mortality rates in breast cancer patients. Despite this, there has been a lack of comprehensive insights into the heterogeneity of metastatic tumors and their surrounding ecosystem in the lungs. In this study, we utilized spatial RNA sequencing technology to investigate the heterogeneity of lung metastatic tumors and their microenvironment in two spontaneous lung metastatic mouse models. Our findings revealed an increase in metabolic-related genes within the cancer cells, with the hub gene Dlat (Dihydrolipoamide S-Acetyltransferase) showing a significant association with the development of lung metastatic tumors. Upregulation of Dlat led to the reprogramming of fatty acid utilization, markedly enhancing the bioenergetic capacity of cancer cells. This finding was corroborated by the increased dependence on fatty acid utilization in lung metastatic cancer cells, and inhibition of Dlat in breast cancer cells exhibited a reduced oxygen consumption rate. Consequently, inhibition of Dlat resulted in decreased survival capacity of breast cancer by reducing cancer stem cell properties and cell adhesion in the lung in vivo. The three cell components within the lung metastatic niche, including CD163+ macrophages, neutrophils, and endothelial cells, expressed elevated levels of ApoE, leading to the secretion of various protumorigenic molecules that promote cancer cell growth in the lung. These molecules include galectin-1, S100A10, S100A4, and S100A6. Collectively, our findings highlight the lipid metabolism reprogramming of cancer and components of the tumor microenvironment that support lung metastasis of TNBC breast cancer.

Durable and deep response to CVD chemotherapy in SDHB-mutated metastatic paraganglioma: case report

IntroductionSuccinate dehydrogenase subunit B (SDHB)-mutated paragangliomas (PGLs) are rare neuroendocrine tumors characterized by increased malignancy, readily metastasizing, and poorer prognosis. Here we report a case of SDHB-mutated metastatic PGL, wherein the patient showed significant tumor shrinkage and complete symptom remission following chemotherapy. We aim to contribute additional evidence to the existing knowledge associated with SDHB-mutated PGLs.Case reportA 40-year-old male patient presented with recurrent hypoglycemia and hypertension crisis. Imaging revealed a huge left retroperitoneal tumor and multiple diffuse metastases in lungs. Catecholamine was also elevated, aligning with a diagnosis of metastatic PGL. Pathology also confirmed this diagnosis. Additionally, the immunohistochemistry indicated negative expression of SDHB and gene test showed somatic SDHB mutation. Given the SDHB mutation, cyclophosphamide-vincristine-dacarbazine (CVD) chemotherapy was initiated in critical conditions. Subsequently, a significant tumor shrinkage and complete biochemical response were observed after two treatment cycles. In September 2024, CT scan revealed new pulmonary lesions. The progression-free survival (PFS) with CVD chemotherapy was 24 months.ConclusionThis report reviews the distinct clinical and biochemical characteristics and treatment approaches of SDHB-mutated paragangliomas, emphasizing that the significance of incorporating both genetic testing and immunohistochemical analysis in clinical practice.

Macrophages promote pre-metastatic niche formation of breast cancer through aryl hydrocarbon receptor activity

Macrophages that acquire an immunosuppressive phenotype play a crucial role in establishing the pre-metastatic niche (PMN), which is essential for facilitating breast cancer metastasis to distant organs. Our study showed that increased activity of the aryl hydrocarbon receptor (AHR) in lung macrophages plays a crucial role in establishing the immunosuppressive PMN in breast cancer. Specifically, AHR activation led to high expression of PD-L1 on macrophages by directly binding to the promoter of Pdl1. This upregulation of PD-L1 promoted the differentiation of regulatory T cells (Tregs) within the PMN, further enhancing immunosuppressive conditions. Mice with Ahr conditional deletion in macrophages had reduced lung metastasis of breast cancer. The elevated AHR levels in PMN macrophages were induced by GM-CSF, which was secreted by breast cancer cells. Mechanistically, the activated STAT5 signaling pathway induced by GM-CSF prevented AHR from being ubiquitinated, thereby sustaining its activity in macrophages. In breast cancer patients, the expression of AHR and PD-L1 was correlated with increased Treg cell infiltration, and higher levels of AHR were associated with a poor prognosis. These findings reveal that the crosstalk of breast cancer cells, lung macrophages, and Treg cells via the GM-CSF-STAT5-AHR-PD-L1 cascade modulates the lung pre-metastatic niche during breast cancer progression.

Deciphering the synergistic role of tyrosyl-tRNA synthetase 1 and yes-associated protein 1: Catalysts of malignant progression in hepatocellular carcinoma

Objective: Hepatocellular carcinoma (HCC) represents a severe and aggressive malignancy with a poor prognosis, characterized by high incidences of illness and death, making it a critical issue for global health. Tyrosyl-tRNA synthetase 1 (YARS1) is known to be upregulated across various cancers and is considerably linked to tumorigenesis. However, the detailed functions and molecular mechanisms of YARS1 in HCC remain unclear. This research explores the expression of YARS1 in HCC and its role in promoting tumor progression through the yes-associated protein 1 (YAP1) pathway. Material and Methods: The potential role and diagnostic significance of YARS1 and YAP1 in HCC were analyzed using relevant datasets. Subsequently, we constructed HCC cell lines with stable knockdown or overexpression of YARS1. In vitro, we used Cell Counting Kit-8 and colony formation assays to examine cell proliferation, terminal deoxynucleotidyl transferase dUTP nick end labeling assays to detect apoptosis, and Transwell migration and invasion assays to assess cell metastasis. Western blotting was employed to analyze the molecular mechanisms. Finally, we developed a lung metastasis model for HCC to assess the impact of YARS1 and YAP1 on tumor spread in a living organism, as well as their interrelationship. Results: The findings revealed a notable increase in YARS1 expression in HCC tumors, associated with a worse prognosis. In vitro, YARS1 overexpression significantly increased HCC cell proliferation and metastasis when reducing apoptosis (P < 0.001). In addition, YARS1 overexpression accelerated HCC growth in vivo. Further experiments demonstrated that silencing YAP1 effectively reversed the effects of YARS1 on HCC cell invasion (P < 0.01), apoptosis inhibition (P < 0.01), and metastasis (P < 0.001). Conclusion: In summary, this research reveals that YARS1 enhances the malignant progression of HCC through the activation of the YAP1 signaling pathway. Elevated levels of YARS1 in HCC are strongly linked to poor prognosis, indicating that YARS1 might serve as a new therapeutic target for HCC. Future studies should investigate additional mechanisms of YARS1 in HCC and create targeted therapies to improve outcomes for HCC patients.

Epoxy metabolites of linoleic acid promote the development of breast cancer via orchestrating PLEC/NFκB1/CXCL9-mediated tumor growth and metastasis

Breast cancer (BC) is a common malignant tumor in women and requires a comprehensive understanding of its pathogenesis for the development of new therapeutic strategies. Polyunsaturated fatty acids (PUFAs) metabolism-driven inflammation is a causative factor in cancer development. However, the function of PUFAs′ metabolism in BC remains largely unknown. Here we report the role and underlying mechanism of epoxyoctadecenoic acids (EpOMEs), the metabolites of linoleic acid mediated by cytochrome P450 (CYP) monooxygenases, in promoting the development of BC, particularly triple-negative BC (TNBC). A metabolomics study identified that EpOMEs were significantly increased in the plasma of BC patients and MMTV-PyMT mice, which accounted for the upregulation of CYP2J2 in BC tumor tissues and tumor cells. Decreased EpOMEs by treatment of CYP monooxygenase inhibitors significantly alleviated tumor development in MMTV-PyMT mice. Treatment with EpOMEs and overexpression of CYP2J2 to increase EpOMEs in TNBC cells significantly promoted cellular proliferation, migration, tumor growth, and metastasis. Whereas knockdown of CYP2J2 to decrease EpOMEs inhibited tumorigenesis and lung metastasis of TNBC, which was reversed by EpOME administration. Transcriptomics and proteomics analyses revealed CXCL9 and PLEC were critical for EpOME-mediated promotion of TNBC. Knockdown of CXCL9 and PLEC inhibited TNBC progression and EpOME-mediated promotion of TNBC. Both overexpression of CYP2J2 and EpOME treatment upregulate PLEC, while PLEC upregulates NFκB1, which is a transcription regulator of CXCL9. This study extends the understanding of the function of PUFAs metabolism in BC development, providing potential therapeutic targets and dietary guidelines for patients with TNBC and other BCs.The illustration of the hypothetical mechanism CYP2J2/EpOMEs promotes the tumorigenesis and metastasis of TNBC via PLEC/NFKB1/CXCL9 signaling pathway.

EXPRESS: Investigation of the synergic effect of mocetinostat and capecitabine in a triple-negative breast neoplasms mouse model.

Combined administration of two or more drugs is emerging as a new strategy in triple negative breast neoplasms. This is the first study to investigate the combination of the histone deacetylase inhibitor (HDACi) mocetinostat and the antimetabolite drug capecitabine in triple-negative mammary neoplasms in a preclinical mouse model. 35 female mice were grouped into the control group, capecitabine group, mocetinostat group, and combine drugs group. At the end of experimental period, body weight, tumor weight were measured and tumor tissue and lung tissue were histologically examined. The results showed that the body weight of mice in the drug-treated groups was reduced by about 18%. Tumor weights were also reduced by 21% in the mosetinostat group, 27.5% in the capecitabine group and 45% in the combined group. The combination of mocetinostat and capecitabine decreased the formation of tumors and metastases in lung tissue.In summary, the combination of mocetinostat and capecitabine was more effective than either drug alone in reducing the size of triple-negative breast neoplasms in a mouse model.

Colonization of stenotrophomonas and its associated microbiome between paired primary colorectal cancers and their lung metastatic tumors. (experimental studies).

The role of gut microbiome in CRC lung metastases is still unclear. Herein, we collected primary colorectal tumors, matched lung metastasis, and adjacent normal colon from 7 patients for 16S rRNA sequencing to evaluate microbiome signature in distant site metastasis and analyze prognosis. Fecal samples from 19 non-metastases CRC patients and 11 CRC lung metastases patients were analyzed for validation. Our efforts led to a discovery of comprehensive microbiome in CRC lung metastatic tumors, characterized by a decreased microbial diversity and an increase bacterial interaction between gram-negative bacteria Stenotrophomonas and Brevundimonas. The primary-metastatic tumor pairs harbored highly similar microbial composition in both genus and species level, especially the high level of Stenotrophomonas maltophilia. Correspondingly, the S.maltophilia levels were positively associated with poor prognosis and cancer progression. Our work highlights the great potential of S.maltophilia and its associated microbiome as biomarkers in pathogenesis and prognosis of CRC lung metastases.

Mesenchymal Stem Cells-Derived Small Extracellular Vesicles and Their Validation as a Promising Treatment for Chondrosarcoma in a 3D Model in Vitro.

Chondrosarcomas (CHS) constitute approximately 20% of all primary malignant bone tumors, characterized by a slow growth rate with initial manifestation of few signs and symptoms. These malignant cartilaginous neoplasms, particularly those with dedifferentiated histological subtypes, pose significant therapeutic challenges, as they exhibit high resistance to both radiation and chemotherapy. Ranging from relatively benign, low-grade tumors (grade I) to aggressive high-grade tumors with the potential for lung metastases and a grim prognosis, there is a critical need for innovative diagnostic and therapeutic approaches, particularly for patients with more aggressive forms. Herein, small extracellular vesicles (sEVs) derived from mesenchymal stem cells are presented as an efficient nanodelivery tool to enhance drug penetration in an in vitro 3D model of CHS. Employing high-pressure homogenization (HPH), we achieved unprecedented encapsulation efficiency of doxorubicin (DXR) in sEVs derived from mesenchymal stem cells (MSC-EVs). Subsequently, a comparative analysis between free DXR and MSC-EVs encapsulated with DXR (DXR-MSC-EVs) was conducted to assess their penetration and uptake efficacy in the 3D model. The results unveiled a higher incidence of necrotic cells and a more pronounced toxic effect with DXR-MSC-EVs compared to DXR alone. This underscores the remarkable ability of MSC-EVs to deliver drugs in complex environments, highlighting their potential application in the treatment of aggressive CHS.

Foxp3 + Treg-derived IL-10 promotes colorectal cancer-derived lung metastasis

The lung is one of the most frequently metastasized organs from various cancer entities, especially colorectal cancer (CRC). The occurrence of lung metastasis correlates with worse prognosis in CRC patients. Here, we aimed to investigate the role of IL-10 in lung metastasis development and identify the cellular source and target cells of IL-10 during lung metastatic establishment. To induce lung metastasis in mice, we injected MC38 murine colon cancer cells intravenously. Mice with Il10-deficiency were used to test the role of IL-10. The lung metastatic burden was assessed both macroscopically and histologically. IL-10- and Foxp3-reporter mice were employed to identify the cellular source and target cells of IL-10 in lung metastasis using flow cytometry. These findings were further confirmed using mice with cell-specific deletion of Il10- and IL-10 receptor (Il10ra). Interestingly, Il10 ablation led to reduced lung metastasis formation, suggesting a pathogenic role of IL-10 in lung metastasis. Moreover, using reporter mice, we identified Foxp3 + regulatory T cells (Tregs) as the predominant cellular source of IL-10 in lung metastasis. Accordingly, Foxp3 + Treg-specific deletion of Il10 resulted in decreased lung metastasis formation. In terms of target cells, myeloid cells and Foxp3 + Tregs expressed high IL-10Ra levels. Indeed, IL-10 signaling blockade in these two immune cell populations resulted in reduced lung metastatic burden. In conclusion, Foxp3 + Treg-derived IL-10 was found to act on Foxp3 + Tregs and myeloid cells, thereby promoting lung metastasis formation. These findings provide insights into lung metastasis-related immunity and establish the groundwork for optimizing metastasis-targeting immunotherapies through targeting of IL-10 as a novel therapeutic strategy.

Activatable Sulfur Dioxide Nanosonosensitizer Enables Precisely Controllable Sono-Gaseous Checkpoint Trimodal Therapy for Orthotopic Hepatocellular Carcinoma.

Immune checkpoint blockade (ICB) is combined with sonodynamic therapy (SDT) to increase response rates and enhance anticancer efficacy. However, the "always on" property of most sonosensitizers in reducing tumor microenvironment (TME) compromises the therapeutic outcome of sonoimmunotherapy and exacerbates adverse side effects. Precisely controllable strategies combining sulfur dioxide (SO2) gas therapy with cancer immunotherapy can address these issues but remain lacking. Herein an "activatable SO2 nanosonosensitizer" for precise sono-gaseous checkpoint trimodal therapy of orthotopic hepatocellular carcinoma (HCC) is reported, whose full activity is initiated by ultrasound (US) irradiation in the reducing TME. This "activatable SO2 nanosonosensitizer," Aza-DNBS nanoparticles (NPs), are established by self-assembling Aza-boron-dipyrromethene based sonosensitizer molecules and 2,4-dinitrobenzenesulfonate (DNBS)-caged SO2 prodrug. The activity of Aza-DNBS NPs is initially silenced, and the sonodynamic, gaseous, and immunosuppressive TME reprogramming activities are precisely awakened under US irradiation. Due to the glutathione-responsiveness of Aza-DNBS NPs, Aza-DNBS NPs can generate large amounts of SO2 for gas therapy-enhanced SDT, which triggers robust immunogenic cell death activation and reprogramming of the immunosuppressive TME, thereby significantly suppressing orthotopic tumor growth and delaying lung metastasis. Thus, this study represents a strategy for designing a generic nanoplatform for precisely combined immunotherapy of orthotopic HCC.

MFAP2 upregulation promotes ESCC metastasis via FAK-AKT signaling pathway.

Metastasis is the leading cause of mortality from esophageal squamous cell carcinoma (ESCC). By the time of diagnosis, most ESCC tumors have already invaded the lymph nodes or distant organs; however, it has been challenging to identify and confirm genes with a crucial role in ESCC metastasis. The microfibrillar-associated protein 2 (MFAP2) is upregulated in human ESCC, and its expression level was positively associated with poor overall and disease-free survival. Consistently, upregulation of MFAP2 promoted the metastasis and invasion of ESCC cells invitro and invivo. Conversely, these processes were reduced by MFAP2 knockdown. Mechanistically, MFAP2 was shown to bind to the FERM domain of focal adhesion kinase (FAK) and to alleviate FAK intramolecular inhibition, resulting in the enhanced binding affinity between FAK and integrin beta 4 (ITGB4) and activation of the FAK-AKT signaling pathway. Treatment of ESCC cells with the FAK inhibitor PND-1186 reduced MFAP2, induced the activation of the FAK-AKT pathway invitro, and suppressed lung metastasis in a mouse model of ESCC. These findings support a major role for MFAP2 in promoting ESCC metastasis, in part via the activation of FAK-AKT signaling, and highlight the potential of MFAP2 as a promising therapeutic target for ESCC.

PHAX enhanced LIN28B-mediated PBX3 mRNA stability to promote esophageal cancer development.

The abnormal expression of PHAX was observed in esophageal cancer, however, its specific function and mechanism remain to be further elucidated. We demonstrated that PHAX, LIN28B, and PBX3 were upregulated in esophageal cancer, while TET2 was downregulated. Elevated PHAX correlated with adverse outcomes among esophageal cancer patients. PHAX or PBX3 knockdown not only inhibited esophageal cancer cell proliferation, and promoted apoptosis and autophagy invitro, but it also repressed tumor growth and lung metastasis in mice. Mechanically, PHAX stabilized PBX3 mRNA through interacting with LIN28B. PBX3 directly bound to the TET2 promoter region and inhibited its expression. In conclusion, PHAX directly bound to LIN28B and enhanced LIN28B-mediated stabilization of PBX3 mRNA, leading to upregulation of PBX3. PBX3 then transcriptionally repressed TET2 expression to promote esophageal cancer cell proliferation, and suppress apoptosis and autophagy. Targeting this signaling cascade could represent a promising therapeutic strategy for esophageal cancer.

The Role of Radiotherapy to the Primary Site in Oropharyngeal Cancer with Limited Metastases—An Analysis of a Hospital-Based Registry

Background/Objectives: Limited metastatic squamous cell carcinoma of the oropharynx (OPC) lacks clear management guidelines, especially for HPV-associated disease. The objective of this study was to investigate if primary site radiotherapy (RT) benefits overall survival in limited metastatic OPC. Methods: Utilizing the National Cancer Database (NCDB), patients aged 18–90 with OPC presenting as cM1 with limited metastatic disease to one distant site were identified. Propensity score matching, Cox-proportional hazards models, and Kaplan–Meier estimates were employed to assess factors associated with overall survival. Results: In this study, 1056 patients were included with metastases involving bone (19.0%), brain (0.8%), lung (52.9%), liver (10.1%), and lymph nodes (20.4%). Treatment modalities included 54.6% receiving primary site RT, 45.4% receiving no RT, and 69.9% undergoing systemic therapy. For HPV-positive patients, RT (HR 0.64, p = 0.0026) and receipt of chemotherapy (HR = 0.57, p = 0.0057) were associated with improved overall survival, while bone and lung metastases were associated with decreased survival (HR = 1.75 and 1.39, p = 0.0041 and 0.041, respectively). In HPV-negative cases, survival also correlated with RT (HR = 0.65, p = 0.0047), receipt of chemotherapy (HR = 0.45, p < 0.001), clinical T4 disease (HR = 1.99, p = 0.012), presence of bone metastases (HR = 2.52, p < 0.001), lung metastases (HR = 1.49, p = 0.035), and lymphovascular invasion (HR = 1.10, p < 0.001). Overall, patients who received RT showed increased median overall survival from 9.9 to 16.1 months (p < 0.001) compared to those who did not. When stratified by RT and HPV status, there was higher median survival for both HPV-positive (from 17.1 to 24.9 months, p < 0.001) and HPV-negative patients (from 8.4 to 12.9 months, p = 0.0016) who received RT compared to those who did not. Conclusions: Primary-site radiotherapy may positively impact overall survival in limited metastatic OPC, irrespective of HPV status.

Tumor-Targeted Metal-Organic Framework for Improved Photodynamic Therapy and Inhibited Tumor Metastasis in Melanoma.

Tumor hypoxia and elevated intracellular glutathione (GSH) levels significantly compromise the effectiveness of photodynamic therapy (PDT) in treating melanoma. In this study, we synthesized positively charged nanoparticles through a self-assembly method, incorporating photosensitizer verteporfin (VER), mitochondrial respiratory inhibitor atovaquone (ATO), and Fe3+. Subsequently, the nanoparticles were modified with sodium hyaluronate (HA) to obtain HA-ATO-Fe3+-VER nanoparticles (HAFV NPs). The fabricated HAFV NPs demonstrated excellent stability and in vitro Fenton reaction activity. HA facilitated the cellular internalization of HAFV NPs by targeting CD44 receptors, hence relieving tumor hypoxia through the disruption of the mitochondrial respiratory chain and involvement in the Fenton reaction. Simultaneously, ATO directly impeded the biosynthesis of GSH by diminishing ATP levels, while Fe3+ was supposed to oxidate GSH to GSSG, thereby doubly depleting GSH. The integration of these multiple mechanisms markedly enhanced the PDT efficacy of VER. Following intravenous administration, HAFV NPs preferentially accumulated in tumor tissues with minimal accumulation in the skin, demonstrating favorable biocompatibility in vivo. Furthermore, HAFV NPs effectively inhibited tumor growth and lung metastasis, which presents a promising strategy for melanoma treatment.

Abstract A009: Genetic disruption of CAPNS1 impedes triple-negative breast cancer metastasis: A case for selective calpain-1/2 inhibitors

Abstract Calpains are a family of 15 calcium-activated cysteine proteases that have emerged as potential therapeutic targets in triple negative breast cancer (TNBC). They regulate the function of their substrates via limited proteolytic processing and are involved in both pro- and anti-apoptotic signaling pathways, as well as membrane-cytoskeletal remodeling events associated with cell migration and invasion. The most well-understood members of the calpain family are the classical calpain-1 and calpain-2 isoforms, which are ubiquitously expressed heterodimers each consisting of a large catalytic subunit, encoded by the capn1 and capn2 genes, respectively, and a common small regulatory subunit encoded by capns1. Overexpression of calpain-1 and calpain-2 has been associated with shorter survival in HER2+ breast cancer and TNBC, respectively. We hypothesize that inhibition of calpain-1 and calpain-2 may be exploited to improve tumor response to cytotoxic chemotherapy and suppress metastasis. CRISPR-Cas9 mediated knockout of capns1 in AC2M2 mouse mammary carcinoma cells, which results in a loss of both calpain-1 and calpain-2 activity, disrupts migration and invasion in vitro and impedes lung metastasis in tail vein and orthotopic engraftment mouse models. Calpain knockout also sensitizes AC2M2 cells to the microtubule stabilizing drug paclitaxel, and preliminary results suggest that cancer cell intrinsic calpain depletion may prevent neoadjuvant chemotherapy-induced metastasis. To explore potential off-target effects associated with systemic calpain inhibition, we have established a novel transgenic mouse with conditional deletion of capns1 in its hematopoietic stem cell lineage. By comparing the immune profiles of wild-type and capns1 knockout mice, we aim to better understand how calpain inhibitors will affect various immune cell populations and their respective functions. We plan to extend this understanding to anticancer immunity by conducting tumor immunophenotyping experiments in syngeneic orthotopic engraftment models using wild-type and capns1 knockout mice. At present, no clinically relevant calpain inhibitors are available. However, using genetic approaches, we have validated calpain-1 and calpain-2 as relevant therapeutic targets in TNBC, providing rationale for the development of selective calpain inhibitors. Citation Format: Danielle Harper, Ivan Shapovalov, Samantha Cockburn, Jenny Min, Yan Gao, Peter A. Greer. Genetic disruption of CAPNS1 impedes triple-negative breast cancer metastasis: A case for selective calpain-1/2 inhibitors [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr A009.

Case report: A rare case of intragastric metastasis after liver transplantation for liver cancer

A 13-year-old boy was admitted to Xiang’an Hospital of Xiamen University due to HBV-related liver cancer. Intrahepatic metastasis was considered to occur by CT scan. A gastroscope revealed esophagogastric variceal bleeding, and later, the patient underwent a successful liver transplantation. Fourteen months posttransplant, chest CT indicated lung metastasis, and the patient underwent thoracoscopic radical resection of lung cancer. Twenty-one months posttransplant, gastroscopy revealed a gastric fundus tumor growing into the gastric cavity. Proximal gastrectomy was performed, and pathology indicated moderately to poorly differentiated carcinoma without invasion of serosa, suggesting the first study to report HCC metastasis to the stomach lumen without invasion of serosa after LT. Currently, the alpha-fetoprotein (AFP) level of the patient has dropped below normal.

Construction of a prognostic model based on cuproptosis-related genes and exploration of the value of DLAT and DLST in the metastasis for non-small cell lung cancer.

To reveal the clinical value of cuproptosis-related genes on prognosis and metastasis in non-small cell lung cancer. Gene expression profiles and clinical information of non-small cell lung cancer were downloaded from The Cancer Genome Atlas and Gene Expression Omnibus databases. The data were grouped into training set, internal testing set, and external testing set. A risk prognostic model was constructed by Lasso-Cox regression analysis. Hub genes were identified and evaluated using immunohistochemistry and the transwell migration assay in 50 clinical patients. A total of 17/19 cuproptosis-related genes were differentially expressed in tumors, 8 were significantly associated with prognosis, and 4 were markedly associated with metastasis. A risk model based on 2 cuproptosis-related genes was constructed and validated for predicting overall survival. The risk score was proven to be an independent risk factor for the prognosis of non-small cell lung cancer. Dihydrolipoamide S-acetyltransferase and dihydrolipoamide S-succinyltransferase, key genes in cuproptosis, were proven to be associated with non-small cell lung cancer prognosis and metastasis. Immunohistochemistry showed that their expression significantly predicted metastasis but failed to predict prognosis in non-small cell lung cancer patients. The transwell migration assay further increased the cellular reliability of our findings. The cuproptosis-related genes prognostic model effectively predicted the prognosis of non-small cell lung cancer. Dihydrolipoamide S-acetyltransferase and dihydrolipoamide S-succinyltransferase may serve as predictive markers for metastasis in non-small cell lung cancer.

Extracellular nicotinamide phosphoribosyltransferase visfatin activates JAK2-STAT3 pathway in cancer-associated fibroblasts to promote colorectal cancer metastasis.

Metastasis is one of the major challenges in the treatment of colorectal cancer (CRC), during which cancer-associated fibroblasts (CAFs) in the tumor microenvironment are critically involved. In this study, we aim to explore the regulatory role of extracellular nicotinamide phosphoribosyltransferase Visfatin and its impact on CRC metastasis. To examine the effect of visfatin on CAFs, human CRC tissue-derived CAFs were exposed to visfatin, and the expression of inflammatory factors, activation of JAK-STAT pathway and production of ROS in CAFs were assessed. To examine the effect of visfatin-treated CAFs on CRC metastasis, human CRC cell line SW480 or SW620 were cultured with the conditioned medium derived from visfatin-treated CAFs, and the invasion and migration ability of SW480 or SW620 cells were evaluated by transwell migration and matrigel invasion assays. Our previous study found that visfatin, a secreted form of nicotinamide phosphoribosyltransferase that governs the rate-limiting step of NAD synthesis, promoted CRC metastasis. However, little is known about the effect of visfatin on CAFs. The conditioned medium derived from visfatin- treated CAFs promotes the migratory and invasive capability of CRC cells, and enhance lung metastasis in mouse model. Visfatin treatment stimulated the expression of a couple of inflammatory factors in CAFs, which was mediated by visfatin-induced activation of JAK- STAT pathway and accumulation of ROS. Inhibition of JAK-STAT pathway or neutralization of cellular ROS attenuated visfatin-mediated migration and invasion of CRC cells. The present work highlights a critical role of visfatin in the crosstalk between CRC cells and CAFs, which moonlight as a non-metabolic extracellular signal molecule to hijacks JAK-STAT pathway in CAFs to promote CRC metastasis.

Ten-year survival and pattern of recurrence in patients with locally recurrent rectal or sigmoid cancer undergoing resection.

The aim of this work is to report actual overall survival (AOS) at 5 and 10 years after multimodal treatment for locally recurrent rectal or sigmoid cancer (LRRC) and the importance of local re-recurrence (reLRRC) and distant metastases for AOS. All patients resected for LRRC at a single centre between years 1990 and 2007 were included. Resections were based on images taken after neoadjuvant treatment. Patients were prospectively followed up for 5 years. After a minimum of 10 years, the records of referring hospitals were analysed. A total of 224 patients underwent resection. At 5 and 10 years 33% and 17%, respectively, had survived. Median survival was 38 months [interquartile range (IQR) 62 months]. Patients with complete resections had 5- and 10-year survival of 56% and 28%, respectively, versus 22% and 11% for those with microscopic remaining tumour; none with macroscopic remains survived beyond 4 years. Median survival was 71 months (IQR 106 months), 33 months (IQR 35 months) and 15 months (IQR 17 months), respectively. With a median survival of 123 months (IQR 80 months), the 54 patients without recurrence had 5- and 10-year survival of 69% and 59%, respectively. The independent predictor of survival was R-stage. Of the 197 patients who had radical resection, 83 developed reLRRC and 108 distant metastases. ReLRRC appeared at a median of 18 months (IQR 21 months) and distant metastases at 12 months (IQR 21 months). Lung metastases were the most common form of distant disease. More than 5 years postoperatively the mortality from cancer was substantial. Most metastases appeared not to be secondary to reLRRC. Planning surgery from pretreatment images might reduce reLRRC.

Heterogeneous immune landscapes and macrophage dynamics in primary and lung metastatic adenoid cystic carcinoma of the head and neck.

Recurrent or metastatic adenoid cystic carcinoma (ACC) of the head and neck is rare and highly aggressive. Due to the ineffectiveness of immune checkpoint therapies, this study aims to investigate the tumor immune microenvironment of primary tumor tissues and lung metastatic tissues and to comprehend the challenges of immunotherapy. We analyzed RNA sequencing data and constructed immune landscapes from 25 primary tumors and 34 lung metastases. The data were then validated by immunohistochemistry and single-cell sequencing analysis. Compared to adjacent normal tissues, both primary and lung metastatic ACC showed low immune infiltration. Lung metastases had higher immune infiltration levels and antigen presentation scores but also higher T cell exclusion and dysfunction scores. Single-cell sequencing data and immunohistochemistry revealed abundant immunosuppressive tumor-associated macrophages in lung metastases. Patients with high M2 macrophage infiltration had shorter lung metastasis-free survival. Primary and lung metastatic ACC exhibit heterogeneous tumor immune microenvironments. Higher immune cell infiltration in lung metastases is countered by the presence of suppressive tumor-associated macrophages, which may limit effective anti-tumor responses.