Metastatic Cell Research Articles

Huaier inhibits cholangiocarcinoma cells through the twist1/FBP1/Wnt/β-catenin axis.

Although Huaier granules can be used as prospective anti-cholangiocarcinoma drugs, the mechanism of action of Huaier granules in cholangiocarcinoma is not clear. The anti-cholangiocarcinoma effect of Huaier granules was validated in cell line research. In vitro experiments were conducted to investigate the signalling pathways affected by Huaier in CCA cells. Real-time quantitative PCR (RT‒qPCR) and Western blot analysis were performed to analyse gene expression in CCA cells. MTT assays, scratch tests, and Transwell assays were used to explore the effects on the proliferation and metastasis of CCA cells. Chromatin immunoprecipitation assays were performed to reveal the potential underlying mechanisms involved. Twist1 was upregulated in human CCA tissues. In addition, its expression levels were negatively related to FBP1 expression levels. Mechanistically, Twist1 can bind to the region of the FBP1 promoter to reduce its expression. Huaier plays an indispensable role in suppressing Twist1 expression to inhibit the Twist1/FBP1/Wnt/β-catenin axis. Then, we verified the effect of Huaier in vitro. These findings suggested that Huaier granules were capable of inhibiting CCA development through regulating the Twist1/FBP1/Wnt/β-catenin signalling axis and provided a novel orientation for the development of novel anti-CCA drugs.

Effectiveness and safety of pembrolizumab as first-line treatment for non-small cell lung cancer in real clinical practice.

Pembrolizumab is currently the drug for the first-line treatment of stage-IV non-small cell lung cancer. The objective of this study is to measure the effectiveness of pembrolizumab as a first-line treatment and to analyze its safety in real clinical practice. This was a retrospective study that included patients with metastatic non-small cell lung cancer who had received pembrolizumab as a first-line treatment between 1 June 2018 and 31 January 2021. Variables related to the patients, treatment, and drug's efficacy and safety were collected. A total of 50 patients were analyzed. The median real-world progression-free survival and real-world overall survival of those who received pembrolizumab in monotherapy were 10.5 months (95% CI: 2.3-18.6) and 18.9 months (95% CI: 16.9-20.8), respectively. The median real-world progression-free survival and real-world overall survival of those who received the drug with chemotherapy was 7.9 months (95% CI: 4.1-11.7) and 13.3 months (95% CI: 0.0-27), respectively. Mostly digestive (48.3%) and endocrine (41.4%) immune-related adverse events were detected among the patients who received pembrolizumab in monotherapy, whereas mostly digestive immune-related adverse events (85.7%) and hematological toxicities (71.5%) were observed in those treated with pembrolizumab plus chemotherapy. Pembrolizumab has proven its effectiveness in terms of increasing real-world progression-free survival and real-world overall survival in real clinical practice. The main adverse events were digestive toxicities with pembrolizumab in monotherapy and with chemotherapy.

Concise review: breast cancer stems cells and their role in metastases

Background: Breast cancer stem cells (BCSCs) have been suggested to be responsible for the development of Breast cancer (BC). The aim of this study was to evaluate BCSCs and the target organs microenvironment immunophenotyping markers in common BC metastases, and therapeutic targets regarding to the mentioned criteria. Material and Methods: This narrative review involved searching international databases; PubMed, Google Scholar using predetermined keywords including breast cancer, breast cancer stem cells, breast cancer metastases, immunophenotyping, immunohistochemistry and metastases. The search results were assessed based on the title, abstract, and full text of the articles, and relevant findings were included in the review. Results: BCSCs express high amount of aldehyde dehydrogenase 1 (ALDH1), Ganglioside 2 (GD2), CD44 and CD133 but are negative for CD24 marker. CXCR4 and OPN have high expression in the cells and may contribute in BC metastasis to the bone. Nestin, CK5, prominin-1 (CD133) markers in BCSCs have been reported to correlate with brain metastasis. High expression of CD44 in BCSCs and CXCL12 expression in the liver microenvironment may contribute to BC metastasis to the liver. Aberrantly expressed vascular cell adhesion molecule-1 (VCAM-1) that binds to collagen and elastin fibers on pulmonary parenchyma, and CXCR4 of BCSCs and CXCL12 in lung microenvironment may promote the cells homing and metastasis to lung. Conclusion: As in various types of BC metastases different markers that expressed by the cells and target organ microenvironment are responsible, BCSCs immunophenotyping can be used as target markers to predict the disease prognosis and treatment.

Adaptor protein CEMIP reduces the chemosensitivity of small cell lung cancer via activation of an SRC-YAP oncogenic module.

Small cell lung cancer (SCLC) is a recalcitrant malignancy with dismal prognosis due to rapid relapse after an initial treatment response. More effective treatments for SCLC are desperately needed. Our previous studies showed that cell migration-inducing hyaluronan binding protein (CEMIP) functionally promotes SCLC cell proliferation and metastasis. In this study, we investigated whether and how CEMIP regulates the chemosensitivity of SCLC. Through the GDSC database, we found that CEMIP expression levels were positively correlated with the IC50 values of several commonly used chemotherapeutic drugs in SCLC cells (cisplatin, gemcitabine, 5-fluorouracil and cyclophosphamide). We demonstrated that overexpression or knockdown of CEMIP in SCLC cells resulted in a notable increase or reduction in the IC50 value of cisplatin or etoposide, respectively. We further revealed that CEMIP functions as an adaptor protein in SCLC cells to interact with SRC and YAP through the 1-177 aa domain and 820-1361 aa domain, respectively, allowing the autophosphorylation of Y416 and activation of SRC, thus facilitating the interaction between YAP and activated SRC, and resulting in increased phosphorylation of Y357, protein stability, nuclear accumulation and transcriptional activation of YAP. Overexpressing SRC or YAP counteracted the CEMIP knockdown-mediated increase in the sensitivity of SCLC cells to cisplatin and etoposide. The combination of the SRC inhibitor dasatinib or the YAP inhibitor verteporfin and cisplatin/etoposide (EP regimen) displayed excellent synergistic antitumor effects on SCLC both in vitro and in vivo. This study demonstrated that targeted therapy against the CEMIP/SRC/YAP complex is a potential strategy for SCLC and provides a rationale for the development of future clinical trials with translational prospects.

A novel dual-recognition fluorescent biosensor for sialyl-Lewisx sensitive detection.

Sialyl-Lewisx (SLex) is a tetrasugar, which plays an important role in initial inflammation and cancer cell metastasis, and can be used as a marker for cancer diagnosis and prognosis or a therapeutic target. Detecting SLex from complex biological media remains a significant challenge. Herein, a single-stranded DNA aptamer of SLex was screened based on the double-stranded DNA library-modified magnetic bead (MB)-SELEX technology. After 14 rounds of screening, 12,639 sequences were obtained and divided into nine families. Three representative sequences were selected based on the number of sequence repeats and Gibbs binding free energy, and the aptamer SLex-Apt2 with 80 nt length (Kd = 23.01nM) had the best affinity and relatively high specificity for targeting SLex. Then, a novel dual-recognition fluorescent biosensor for SLex-sensitive detection based on aptamer SLex-Apt2 bio-dots and 3-aminobenzoboric acid-modified MB was developed. This method can detect SLex as low as 32 μM and has a good linear response in the range 100 μM to 2 mM. It has the advantages of low preparation cost, good targeting, and avoiding the occurrence of false-positive and false-negative detection results, which makes the biosensor more valuable in biological detection and clinical diagnosis.

Modulation of the Antimelanoma Activity Imparted to Artemisinin Hybrids by the Monoterpene Counterpart

Molecular hybridization is a widely used strategy in drug discovery and development processes that consists of the combination of two bioactive compounds toward a novel entity. In the current study, two libraries of hybrid derivatives coming from the linkage of sesquiterpene counterparts dihydroartemisinin and artesunic acid, with a series of monoterpenes, were synthesized and evaluated by cell viability assay on primary and metastatic melanoma cell lines. Almost all the obtained compounds showed micromolar antimelanoma activity and selectivity toward the metastatic form of this cancer. Four hybrid derivatives containing perillyl alcohol, citronellol, and nerol as monoterpene counterpart emerged as the best compounds of the series, with nerol being active in combination with both sesquiterpenes, dihydroartemisinin and artesunic acid. Preliminary studies on the mechanism of action have shown the dependence of the pharmacological activity of newly synthesized hybrids on the formation of carbon- and oxygen-centered radical species. This study demonstrated the positive modulation of the pharmacodynamic effect of artemisinin semisynthetic derivatives dihydroartemisinin and artesunic acid due to the hybridization with monoterpene counterparts.

Epigenetic modification of PHLDA2 is associated with tumor microenvironment and unfavorable outcome of immune checkpoint inhibitor-based therapies in clear cell renal cell carcinoma

BackgroundA substantial proportion of patients with metastatic clear cell renal cell carcinoma (ccRCC) cannot derive benefit from immune checkpoint inhibitor (ICI) plus anti-angiogenic agent combination therapy, making identification of predictive biomarkers an urgent need. The members of pleckstrin homology-like domain family A (PHLDA) play critical roles in multiple cancers, whereas their roles in ccRCC remain unknown.MethodsTranscriptomic, clinical, genetic alteration and DNA methylation data were obtained for integrated analyses from TCGA database. RNA sequencing was performed on 117 primary tumors and 79 normal kidney tissues from our center. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis, gene set enrichment analysis were performed to explore transcriptomic features. Data from three randomized controlled trials (RCT), including CheckMate025, IMmotion151, JAVELIN101, were obtained for validation.ResultsMembers of PHLDA family were dysregulated in pan-cancer. Elevated PHLDA2 expression was associated with adverse clinicopathologic parameters and worse prognosis in ccRCC. Aberrant DNA hypomethylation contributed to up-regulation of PHLDA2. An immunosuppressive microenvironment featured by high infiltrates of Tregs and cancer-associated fibroblasts, was observed in ccRCC with higher PHLDA2 expression. Utilizing data from three RCTs, the association of elevated PHLDA2 expression with poor therapeutic efficacy of ICI plus anti-angiogenic combination therapy was confirmed.ConclusionsOur study revealed that elevated PHLDA2 expression regulated by DNA hypomethylation was correlated with poor prognosis and immunosuppressive microenvironment, and highlighted the role of PHLDA2 as a robust biomarker for predicting therapeutic efficacy of ICI plus anti-angiogenic agent combination therapy in ccRCC, which expand the dimension of precision medicine.

Socioeconomic and Demographic Disparities in Immunotherapy Utilization for Advanced Kidney and Bladder Cancer

ObjectivesImmunotherapy (IO) drugs have been increasingly utilized in locally advanced or metastatic clear cell renal cell carcinoma (ccRCC) and urothelial carcinoma of the bladder (UC). Multiple trials have demonstrated clear survival benefit, however, there are often barriers to access for these advanced therapies which has been demonstrated in other non-urologic malignancies. The goal of this study was to assess socioeconomic and demographic factors associated with the receipt of IO for advanced ccRCC and UC. Materials and methodsWe queried the National Cancer Database (NCDB) for patients with stage IV ccRCC and UC. The study period was 2015 to 2020 for ccRCC (FDA approval date of IO) and 2017 to 2020 for UC (FDA approval date of broadened indication for IO, initial limited approval in 2016). The primary outcome of interest was receipt of IO therapy using multivariable logistic regression, adjusting for relevant socioeconomic and demographic variables. ResultsWe identified 15,926 patients with stage IV ccRCC and 10,380 patients with stage IV UC of which 5,419 (34.0%) and 2,231 (21.5%) received IO therapy, respectively. IO utilization increased with each successive year. In both malignancies, treatment at a non-academic facility, education level, income, and insurance were independently associated with IO utilization. For ccRCC, black (OR = 0.77, 95% CI, 0.64–0.93, P = 0.009) and Hispanic race (OR = 0.73, 95% CI, 0.61–0.86, P = 0.006) were each associated with decreased IO utilization but there were no independent associations between race and receipt of IO in patients with UC. ConclusionsIn the era of FDA-approved IO therapy for advanced ccRCC and UC, this national cohort analysis suggests that IO utilization is increasing over time, but significant disparities exist based on income, education, and insurance status in both malignancies. Additionally, patients treated at non-academic facilities were less likely to receive IO therapy for these specific genitourinary malignancies. In ccRCC, additional disparities were seen black and Hispanic races which each were associated with lower odds of IO receipt. Identifying strategies to mitigate these differences and provide equitable access to IO therapy is of imperative need.

ELOVL1 is upregulated and promotes tumor growth in hepatocellular carcinoma through regulating PI3K-AKT-mTOR signaling

BackgroundThe functions of the ELOVLs are mainly involved in the elongation of saturated and polyunsaturated fatty acids, thus influencing the metabolism of fatty acids. Abnormal lipid metabolism may result in NAFLD and NASH, which may lead to cirrhosis and liver cancer. These results suggest that ELOVLs-mediated metabolism might be involved in the development of HCC. The purpose of this study was to study the expression and function of ELOVL1 in human liver cancer. MethodUsing TCGA, GEPIA and other databases, we analyzed the relationship between the expression of ELOVL1 and liver cancer. The expression of ELOVL1 was detected by immunohistochemical method and Western blot method in hepatic carcinoma and hepatic carcinoma cells. Then, the effects of ELOVL1 on proliferation, apoptosis and invasion in vitro and in vivo were investigated by means of different methods. ResultOur results indicate that ELOVL1 is more highly expressed in liver cancer than in normal tissues. Survival analysis showed that OS and DSS were shorter in patients with high ELOVL1 expression than in those with low expression. Multivariate Cox analysis further demonstrated that over-expression of ELOVL1 was an independent risk factor for overall survival in HCC. The results of ROC also confirmed the value of ELOVL1 in the diagnosis of liver cancer. The results of KEGG enrichment and GSEA indicate that ELOVL1 is associated with lipid metabolism and NAFLD, as well as PPAR, PI3K-AKT-mTOR. Compared with the control group, it was found that silencing ELOVL1 in Huh7 and HepG2 cells could inhibit the growth of cells, promote the apoptosis and decrease the metastasis and invasion. Changes in ELOVL1 induced cell proliferation and metastasis may be related to PI3K/AKT/mTOR. Low expression of ELOVL1 inhibited the growth of xenograft tumors in hepatocellular carcinoma xenograft model. ConclusionOur data indicate that the activation of PI3K/AKT/mTOR pathway in HCC may contribute to the promotion of cancer. Thus, ELOVL1 may be a promising therapeutic target for HCC.

Identification of ASMTL-AS1 and LINC02604 lncRNAs as novel biomarkers for diagnosis of colorectal cancer

PurposeColorectal cancer is one of the major leading causes of death worldwide, and available treatments for advanced colorectal cancer are not successful. Therefore, early detection of colorectal cancer is essential to improve patient survival, and biomarkers are potential tools to achieve this goal. Considering the key role of lncRNAs in cancers, the aim of this study is to identify lncRNAs involved in colorectal cancer as new potential prognosis biomarkers for CRC.MethodsIn this observational study, gene expression data obtained from the TCGA database were analyzed, Identification of differentially expressed mRNAs, miRNAs, and lncRNAs was performed, and ceRNA network was drawn. Also, survival analysis of patients was performed in order to identify potential biomarkers related to the diagnosis and prognosis of colon cancer. After confirming the results using the GSE39582 dataset, the expression of target lncRNAs in colorectal tumor tissues was also investigated to confirm the bioinformatic data.ResultsAnalysis of the TCGA data showed that the expression of three lncRNAs—SNHG7, ASMTL-AS1, and LINC02604—that had the highest interaction with other miRNAs and mRNAs identified based on the ceRNA network was increased in colorectal cancer. Also, based on the ceRNA network, three microRNAs, hsa-let-7d-5p, hsa-mir-92a-3p, and hsa-mir-423-5p, and eight mRNAs, including CPA4, MSI2, RRM2, IGF2BP1, ONECUT2, HMGA1, SOX4, and SRM, were associated with all three mentioned lncRNAs, the expression of microRNAs was decreased and the expression of mRNAs was increased. By enrichment analysis, it was found that the target lncRNAs are involved in the processes of cell proliferation, apoptosis, and metastasis, indicating their importance in the development and malignancy of colorectal cancer. Furthermore, Kaplan–Meier analysis showed a significant increase in mortality in patients with higher expression levels of these lncRNAs. Analysis of the GSE39582 dataset, and real-time RT-PCR analysis, confirmed our bioinformatic results. Also, ROC analysis showed that SNHG7 was a relatively good promising biomarker (AUC = 0.73, p value = 0.02), while ASMTL-AS1 (AUC = 0.92, p value < 0.0001) and LINC02604 (AUC = 1.00, p value < 0.0001) emerged as excellent diagnostic biomarkers in colorectal cancer.ConclusionIt seems that increased expression of lncRNAs ASMTL-AS1 and LINC02604 can serve as molecular biomarkers for CRC, possibly through the sponge hsa-let-7d-5p, hsa-mir-92a-3p, and hsa-mir-423 5p, which increases target mRNAs, which are effective in the carcinogenesis process.

Do tunneling nanotubes drive chemoresistance in solid tumors and other malignancies?

Intercellular communication within the tumor microenvironment (TME) is essential for establishing, mediating, and synchronizing cancer cell invasion and metastasis. Cancer cells, individually and collectively, react at the cellular and molecular levels to insults from standard-of-care treatments used to treat patients with cancer. One form of cell communication that serves as a prime example of cellular phenotypic stress response is a type of cellular protrusion called tunneling nanotubes (TNTs). TNTs are ultrafine, actin-enriched contact-dependent forms of membrane protrusions that facilitate long distance cell communication through transfer of various cargo, including genetic materials, mitochondria, proteins, ions, and various other molecules. In the past 5-10 years, there has been a growing body of evidence that implicates TNTs as a novel mechanism of cell-cell communication in cancer that facilitates and propagates factors that drive or enhance chemotherapeutic resistance in a variety of cancer cell types. Notably, recent literature has highlighted the potential of TNTs to serve as cellular conduits and mediators of drug and nanoparticle delivery. Given that TNTs have also been shown to form in vivo in a variety of tumor types, disrupting TNT communication within the TME provides a novel strategy for enhancing the cytotoxic effect of existing chemotherapies while suppressing this form of cellular stress response. In this review, we examine current understanding of interplay between cancer cells occurring via TNTs, and even further, the implications of TNT-mediated tumor-stromal cross-talk and the potential to enhance chemoresistance. We then examine tumor microtubes, an analogous cell protrusion heavily implicated in mediating treatment resistance in glioblastoma multiforme, and end with a brief discussion of the effects of radiation and other emerging treatment modalities on TNT formation.

Metastatic colorectal cancer cells upregulate SMLR1 that interacts with tumor-associated macrophages in the liver

Metastatic colorectal cancer cells upregulate SMLR1 that interacts with tumor-associated macrophages in the liver

Cyclic tachyplesin I kills proliferative, non-proliferative and drug-resistant melanoma cells without inducing resistance

Acquired drug resistance is the major cause for disease recurrence in cancer patients, and this is particularly true for patients with metastatic melanoma that carry a BRAF V600E mutation. To address this problem, we investigated cyclic membrane-active peptides as an alternative therapeutic modality to kill drug-tolerant and resistant melanoma cells to avoid acquired drug resistance. We selected two stable cyclic peptides (cTI and cGm), previously shown to have anti-melanoma properties, and compared them with dabrafenib, a drug used to treat cancer patients with the BRAF V600E mutation. The peptides act via a fast membrane-permeabilizing mechanism and kill metastatic melanoma cells that are sensitive, tolerant, or resistant to dabrafenib. Melanoma cells do not become resistant to long-term treatment with cTI, nor do they evolve their lipid membrane composition, as measured by lipidomic and proteomic studies. In vivo studies in mice demonstrated that the combination treatment of cTI and dabrafenib resulted in fewer metastases and improved overall survival. Such cyclic membrane-active peptides are thus well suited as templates to design new anticancer therapeutic strategies.

Therapeutic Targeting of the GLS1-c-Myc Positive Feedback Loop Suppresses Glutaminolysis and Inhibits Progression of Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) is addicted to glutaminolysis. Targeting this metabolic dependency has emerged as a potential therapeutic approach for HNSCC. Here, we conducted a bioinformatic analysis of the TCGA HNSCC cohort that revealed a robust correlation between expression of c-Myc and GLS1, which catalyzes the first step in glutaminolysis. Intriguingly, disruption of GLS1 signaling in HNSCC cells by genetic depletion or CB-839 treatment resulted in a reduction in c-Myc protein stability via a USP1-dependent ubiquitin-proteasome pathway. On the other hand, c-Myc directly binds to the promoter region of GLS1 and upregulates its transcription. Notably, the GLS1-c-Myc pathway enhanced ACC-dependent SLUG acetylation, prompting cancer cell invasion and metastasis. Thus, the GLS1-c-Myc axis emerged as a positive feedback loop critical for driving the aggressiveness of HNSCC. Therapeutically, combining CB-839 with the c-Myc inhibitor MYCi975 strongly suppressed GLS1-c-Myc signaling, resulting in a superior antitumor effect compared to either single agent in an orthotopic mouse model of HNSCC. These findings hold promise for the development of effective therapies for HNSCC patients, addressing an urgent need arising from the significant incidence and high metastatic rate of the disease.

Netrin signaling mediates survival of dormant epithelial ovarian cancer cells.

Dormancy in cancer is a clinical state in which residual disease remains undetectable for a prolonged duration. At a cellular level, rare cancer cells cease proliferation and survive chemotherapy and disseminate disease. We created a suspension culture model of high-grade serous ovarian cancer (HGSOC) dormancy and devised a novel CRISPR screening approach to identify survival genes in this context. In combination with RNA-seq, we discovered the Netrin signaling pathway as critical to dormant HGSOC cell survival. We demonstrate that Netrin-1, -3, and its receptors are essential for low level ERK activation to promote survival, and that Netrin activation of ERK is unable to induce proliferation. Deletion of all UNC5 family receptors blocks Netrin signaling in HGSOC cells and compromises viability during the dormancy step of dissemination in xenograft assays. Furthermore, we demonstrate that Netrin-1 and -3 overexpression in HGSOC correlates with poor outcome. Specifically, our experiments reveal that Netrin overexpression elevates cell survival in dormant culture conditions and contributes to greater spread of disease in a xenograft model of abdominal dissemination. This study highlights Netrin signaling as a key mediator HGSOC cancer cell dormancy and metastasis.

GDNF-induced phosphorylation of MUC21 promotes pancreatic cancer perineural invasion and metastasis by activating RAC2 GTPase.

Perineural invasion (PNI) is an adverse prognostic feature of pancreatic ductal adenocarcinoma (PDAC). However, the understanding of the interactions between tumors and neural signaling within the tumor microenvironment is limited. In the present study, we found that MUC21 servers as an independent risk factor for poor prognosis in PDAC. Furthermore, we demonstrated that MUC21 promoted the metastasis and PNI of PDAC cells by activating JNK and inducing epithelial-mesenchymal transition (EMT). Mechanistically, glial cell-derived neurotrophic factor, secreted by Schwann cells, phosphorylates the intracellular domain S543 of MUC21 via CDK1 in PDAC cells, facilitating the interaction between MUC21 and RAC2. This interaction leads to membrane anchoring and activation of RAC2, which in turn activates the JNK/ZEB1/EMT axis, ultimately enhancing the metastasis and PNI of PDAC cells. Our results present a novel mechanism of PNI, suggesting that MUC21 is a potential prognostic marker and therapeutic target for PDAC.

Discordance of retroperitoneal and thoracic histologic findings in patients with metastatic germ cell tumors at postchemotherapy residual tumor resection

Introduction and objectivesPostchemotherapy residual tumor resection (PC-RTR) is an important part of the multimodal treatment for patients with metastatic germ cell tumors. Simultaneous retroperitoneal and thoracic metastases often require consecutive surgical procedures. This study analyzes the histologic findings after abdominal and thoracic surgery in order to tailor the sequence and intensity of surgery.Patients and methodsFrom a total of 671 PC-RTRs from 2008 to 2021 we analyzed 50 patients with stage III non-seminomatous germ cell tumor (NSGCT) who had undergone both retroperitoneal and thoracic postchemotherapy residual tumor resection after first-line and salvage chemotherapy.ResultsAll patients included had stage III NSGCT. 39 and 11 patients received first-line and salvage chemotherapy, respectively. 45 (90%) patients received retroperitoneal resection first, followed by thoracic surgery. Three patients (6%) underwent thoracic surgery before retroperitoneal surgery and two patients (4%) underwent simultaneous surgery. Overall, the histology of retroperitoneal and thoracic specimens was discordant in 23% of cases. After first-line chemotherapy, of fourteen patients with necrosis in retroperitoneal histology, four patients had vital carcinoma in lung histology. In patients with teratoma in the retroperitoneum, the thoracic findings were concordant in most cases (78%). When teratomatous elements were also present in the orchiectomy specimen, concordance was 100%. After salvage chemotherapy, the discordance rate was 55%.ConclusionThe data presented in this study underline that retroperitoneal residual masses with necrosis cannot reliably predict histologic findings of thoracic specimens. Patients with teratoma in the retroperitoneum have a high likelihood of teratoma in the thoracic specimen.

Cost-efficiency and budget-neutral expanded access modeling of pembrolizumab versus the novel PD-1 inhibitor toripalimab in locally advanced or metastatic nonsquamous non-small cell lung cancer

Aims To estimate in a panel of patients with locally advanced/metastatic nonsquamous non-small cell lung cancer (NSCLC) treated with a programmed death receptor-1 inhibitor in the US in 2024 (1) the cost-efficiency of toripalimab regimens compared to pembrolizumab regimens; and (2) the budget-neutral expanded access to additional toripalimab cycles and regimens from accrued savings. Methods Simulation modeling of toripalimab + pemetrexed + carboplatin in nonsquamous NSCLC to a similar pembrolizumab regimen in a panel of 49,647 patients; utilizing two cost inputs (wholesale acquisition cost (WAC) at market entry and an estimated ex ante toripalimab price point of 80% of pembrolizumab average sales price (ASP)) plus administration costs over one and two years of treatment with treatment rates from 1%-10%. Scenario analyses with treatment durations equivalent to toripalimab and pembrolizumab trials’ median PFS were also conducted. Results In the WAC-based models, toripalimab saves $2,223 per patient per cycle and $40,014 over 1 year of treatment ($77,805 over 2 years). Extrapolated to the 49,647-patient panel, estimated 1-year savings range from $19,865,840 (1% treatment rate) to $198,658,399 (10% rate). Reallocating these savings permits budget-neutral expanded access to an additional 1,753 (1% rate) to 17,533 (10% rate) toripalimab maintenance cycles or to an additional 97 (1% rate) to 972 (10%) full 1-year toripalimab regimens with all agents. Two-year savings range from $38,628,022 (1% rate) to $386,280,221 (10%). Reallocating these efficiencies provides expanded access ranging from 3,409 (1% rate) to 34,093 (10%) additional toripalimab cycles or to 97 to 973 full 2-year regimens. The ex ante ASP model showed similar results as did the scenario analyses but at a lower magnitude than the base case. Conclusion Toripalimab generates significant savings that enable budget-neutral funding for up to 17,533 [34,093] additional maintenance cycles over one year [two years] with toripalimab + pemetrexed in nonsquamous NSCLC, or 972 [973] full one-year [two-year] regimens.

Chondroitin sulfate proteoglycan 4 (CSPG4) increases invasion of recessive dystrophic epidermolysis bullosa-associated cutaneous squamous cell carcinoma by modifying TGFβ signaling.

Recessive dystrophic epidermolysis bullosa (RDEB) is a rare genetic skin-blistering disorder often progressing to metastatic cutaneous squamous cell carcinoma (cSCC) at chronic wound sites. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell-surface proteoglycan that is an oncoantigen in multiple malignancies, where it modulates oncogenic signaling, drives epithelial-to-mesenchymal transition (EMT), and enables cell motility. To evaluate CSPG4 expression and function in RDEB-cSCC. RDEB-cSCC cell lines were used to assess CSPG4-dependent changes in invasive potential, TGFβ1-stimulated signal activation, and clinically relevant cytopathology metrics in an in vitro full-thickness tumor model. CSPG4 expression in RDEB-cSCC and non-RDEB cSCC tumors was analyzed via immunohistochemistry and single-cell RNA sequencing (scRNA-seq), respectively. Inhibiting CSPG4 expression reduced invasive potential in multiple RDEB-cSCC cell lines and altered membrane-proximal TGFβ signal activation through changes in SMAD3 phosphorylation. CSPG4 expression was uniformly localized to basal-layer keratinocytes in fibrotic RDEB skin and tumor cells at the tumor/stroma interface at the invasive front in RDEB-cSCC tumors in vivo. Analysis of published scRNA-seq data revealed that CSPG4 expression was correlated with an enhanced EMT transcriptomic signature in cells at the tumor/stroma interface of non-RDEB cSCC tumors. Cytopathological metrics, like nucleus:cell area ratio, were influenced by CSPG4 expression in in vitro tumor models. We determined that CSPG4 expression in RDEB-cSCC cell lines enhanced invasive potential. Mechanistically, CSPG4 was found to enhance membrane-proximal TGFβ-stimulated signaling through SMAD3, which is a key mediator of EMT in RDEB-cSCC. The implication of these studies is that CSPG4 may represent a therapeutic target that can be leveraged for clinical management in patients with RDEB-cSCC.

Histone lactylation facilitates hepatocellular carcinoma progression by upregulating endothelial cell-specific molecule 1 expression.

Hepatocellular carcinoma (HCC) is a common malignant tumor. Histone lactylation, a novel epigenetic modification, plays a crucial role in various cancers. However, the functional role and underlying mechanism of histone lactylation in HCC progression have not yet been investigated. Histone lactylation levels in HCC tissues and cells were assessed using a densitometric kit and western blot analysis. The role of histone lactylation in cell malignant phenotypes was determined through functional assays in vitro, and a xenograft tumor model was established to verify the function of histone lactylation in vivo. ChIP assay was performed to explore the interaction between histone lactylation and endothelial cell-specific molecule 1 (ESM1). Additionally, gain-and-loss-of-function assays were conducted to investigate the regulatory role of ESM1 in HCC pathogenesis. Histone lactylation levels were increased in HCC tissues and cells, and H3K9 lactylation (H3K9la) and H3K56 lactylation (H3K56la) were identified as the histone modification sites. We observed that H3K9la and H3K56la caused abnormal histone lactylation and were associated with poor prognosis. Functionally, histone lactylation was found to promote HCC cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) process in vitro. However, histone lactylation inhibition with 2-deoxy-d-glucose (2-DG) reduced the malignant phenotypes of HCC cells. In vivo, 2-DG treatment reduced tumor growth and metastasis in the HCC mouse model. Mechanistically, it was revealed that histone lactylation activated ESM1 transcription in HCC cells. ESM1 was expressed at a high level in HCC and exerted a carcinogenic role. Histone lactylation facilitates cell malignant phenotypes, tumor growth, and metastasis by upregulating ESM1 expression in HCC, which reveals the downstream molecular mechanism of histone lactylation and might provide a novel therapeutic target for HCC therapy.