Sarcoma Research Articles

Background: The GINS complex, composed of GINS1/2/3/4 subunits, is an essential structure of Cdc45-MCM-GINS (CMG) helicase and plays a vital role in establishing the DNA replication fork and chromosome replication. Meanwhile, GINS genes have been associated with the poor prognosis of various malignancies. However, the abnormal expression of GINS genes and their diagnostic and prognostic value in sarcomas (SARC) remain unclear.Methods: Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), Kaplan-Meier Plotter, Cancer cell line encyclopedia (CCLE), The University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN), R studio, and Tumor Immune Estimation Resource (TIMER) were used to analyze the expression profiles, prognostic value, biological function, ceRNA, and immune infiltration associated with GINS genes in sarcomas.Results: We found that GINS1/2/3/4 genes exhibited significantly upregulated transcription levels in SARC samples compared to non-tumor tissues and exhibited high expression levels in sarcoma cell lines. In addition, SARC patients with increased expression levels of GINS1/2/3/4 showed poorer survival rates. Immune infiltration analysis showed that GINS subunits were closely associated with the infiltration of immune cells in sarcomas.Conclusion: Our research identified GINS subunits as potential diagnostic and prognostic biological targets in SARC and elucidated their underlying effects in the genesis and progression of SARC. These results may provide new opportunities and research directions for targeted sarcoma therapy.

Background: Previous studies have partly explored the role of B-cell CLL/lymphoma 7 protein family member B (BCL7B) in tumorigenesis and development. However, the prognosis and immunoregulatory value of BCL7B in pan-cancer patients remains unclear.Methods: Through The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, the distinct expression of BCL7B gene in 33 tumors and adjacent normal tissues was analyzed. The Kaplan–Meier method (univariate Cox regression analysis and Kaplan–Meier curve) was used to identify the cancer types whose BCL7B gene expression was related to prognosis. The receiver operating characteristic (ROC) curve was used to elucidate the diagnosis value of BCL7B gene. Spearman’s rank correlation coefficient was used to explore the relationship between BCL7B gene expression and immune cell infiltration, immune checkpoints, DNA methylation, DNA repair genes, immune-activating genes, immune-suppressing genes, immune subtypes, tumor mutation burden (TMB), and microsatellite instability (MSI). The Wilcoxon rank sum test and Kruskal–Wallis test were used to compare the expression of BCL7B gene in tumor tissues with different clinicopathological features. Gene set enrichment analysis (GSEA) was conducted to identify the tumor-related pathways in pan-cancer. The Human Protein Atlas (HPA) database was used to verify the BCL7B gene expression at the protein level.Results: High expression of BCL7B was associated with an inferior prognosis in glioblastoma multiforme (GBM), glioma (GBMLGG), kidney chromophobe (KICH), brain lower grade glioma (LGG), oral squamous cell carcinoma (OSCC), rectum adenocarcinoma (READ), and uveal melanoma (UVM). Low expression of BCL7B was associated with a poor prognosis in kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), skin cutaneous melanoma (SKCM), thyroid carcinoma (THCA), and sarcoma (SARC). The BCL7B gene expression had varying degrees of correlation with 24 immune cell subsets in 37 tumor environments such as adrenocortical carcinoma (ACC) and bladder urothelial carcinoma (BCLA). Spearman’s rank correlation coefficient showed that BCL7B gene expression had different degrees of correlation with 47 immune checkpoints, 46 immune-activating genes, 24 immune-suppressing genes, 5 DNA repair genes, and DNA methylation, TMB, and MSI in 39 tumors. GSEA suggested that BCL7B was notably associated with cancer-related and immune-related pathways.Conclusion: In summary, BCL7B gene has a high diagnostic and prognostic value in pan-cancer and is related to the infiltration of 24 immune cell subsets in pan-cancer.

Abstract Background: GRIN2A is the encoding gene of GluN2A, which is a subunit of the N-methyl-D-aspartate receptor, and participates in the regulation of excitatory neurotransmission in the brain. GRIN2A is one of the key genes in epilepsy researches, however, only a few researches have been done on GRIN2A in cancer field. The existing studies showed that GRIN2A mutation was frequently found in melanoma and caused abnormal tumor suppressor function. Besides, GRIN2A mutation was associated with higher tumor mutation burden (TMB) in non-small-cell lung cancer, suggesting that GRIN2A-altered tumors might be more sensitive to immune checkpoint inhibitors (ICIs), but the correlation of GRIN2A mutation status with immune response in clinical remains unknown. Methods: Next generation sequencing (NGS) and clinical data of pan-cancer patients were obtained from two MSK-IMPACT Clinical Sequencing cohorts (MSK-2017, N=10336; MSK-2019, N=1661). The MSK-2019 cohort, which was treated with ICIs, were analyzed to explore the association between GRIN2A alteration and therapeutic efficacy of ICIs. Moreover, mRNA expression data of 10201 pan-cancer patients were obtained from the Cancer Genome Atlas (TCGA) database to explore the association between GRIN2A expression level and immune cell infiltration. Results: In total, 3.74% (387/10336) of pan-cancer patients in MSK-2017, and 7.47% (124/1661) in MSK-2019, carried GRIN2A alteration. In MSK-2017, the top three GRIN2A alteration frequency cancer types were melanoma (68/365, 18.63%), skin cancer (non-melanoma, 22/148, 14.86%) and small cell lung cancer (11/82, 13.41%), respectively. And the commonly mutation types of GRIN2A were missense mutation. In MSK-2019 treated with ICIs, the TMB level of GRIN2A-altered group was significantly higher than wild group (median TMB, altered-type vs. wild-type = 25.09 vs. 5.90 Muts/Mb, P<0.0001) and the overall survival (OS) of GRIN2A-altered group were significantly longer than wild group (OS, median, 44.00 vs. 15.00 months; HR=0.5812 [95%CI: 0,4474-0.7550], P=0.0008). But in MSK-2017 without immunotherapy, there was no difference in OS between GRIN2A-altered group and wild group (OS, median, 26.00 vs. 26.13 months; HR=1.194 [95%CI: 0.9588-1.487], P=0.0849). Furthermore, the GRIN2A expression level was positively correlated with the degree of immune cell infiltration in some tumor types, such as prostate adenocarcinoma (PRAD), while some tumors did the opposite, such as sarcoma (SARC). Conclusion: The results indicated that GRIN2A gene alteration was associated with a higher TMB level in pan-cancer patients, and patients carrying GRIN2A alteration might easily benefit from ICIs. Citation Format: Mei Jiang, Xuefeng Zhong, Mengli Huang. A pan-cancer analysis of GRIN2A as a potential biomarker for immune checkpoint therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5094.

The aim of the study was to describe the CT features of focal splenic lesions (FSLs) in dogs in order to predict lesion histotype. Dogs that underwent a CT scan and had a FSL diagnosis by cytology or histopathology were retrospectively included in the study. For the statistical analysis the cases were divided into four groups, based on the results of cytopatholoy or hystopathology, namely: nodular hyperplasia (NH), other benign lesions (OBLs), sarcoma (SA), round cell tumour (RCT). Several qualitative and quantitative CT features were described for each case. The relationship occurring between each individual CT feature and the histopathological groups was explred by means of c chi-square test for the count data and by means of Kruskal-Wallis or ANOVA for the continuous data. Furthermore, the main features of each group were described using factorial discriminant analysis, and a decision tree for lesion classification was then developed. Sarcomas were characterised by large dimensions, a cystic appearance and an overall low post contrast-enhancement. NH and OBLs were characterised by small dimensions, a solid appearance and a high post-contrast enhancement. OBLs showed higher post-contrast values than NH. Lastly, RCTs did not exhibit any distinctive CT features. The proposed decision tree had a high accuracy for the classification of SA (0.89) and a moderate accuracy for the classification of OBLs and NH (0.79), whereas it was unable to classify RCTs. The results of the factorial analysis and the proposed decision tree could help the clinician in classifying FSLs based on their CT features. A definitive FSL diagnosis can only be obtained by microscopic examination of the spleen.

Mechanosensation by endothelial PIEZO1 is required for leukocyte diapedesis

Studies have shown that PCNA clamp associated factor (PCLAF) plays a paramount role in a variety of cancers; however, the expression profile and the specific molecular mechanism of PCLAF in cancer remains unclear, as is its value in the human pan-cancer analysis. Based on the publicly available datasets of The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), a comprehensive analysis of the probable carcinogenic effects of the PCLAF gene was performed in 33 human cancers. It was found that PCLAF is highly expressed in cancer tissues compared with normal tissues, and is significantly correlated with poor prognosis. We found that the eight tumors with significantly high PCLAF expression presented with decreased DNA methylation levels of PCLAF, including cholangiocarcinoma (CHOL), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), glioblastoma multiforme (GBM), pheochromocytoma and paraganglioma (PCPG), sarcoma (SARC), testicular germ cell tumor (TGCT), stomach adenocarcinoma (STAD), and uterine corpus endometrial carcinoma (UCEC). The expression of PCLAF was found to be positively correlated with activated CD4 T cells (Act CD4) and type 2 T helper (Th2) cells, suggesting that PCLAF may play a particular role in tumor immune infiltration. In addition, the functional mechanism of PCLAF also involves the mitotic cell cycle process, cell division, and DNA replication. Our first pan-cancer study provides a relatively extensive understanding of the carcinogenic effects of PCLAF in miscellaneous tumors.

BackgroundHuman sarcomas (SARC) are a group of malignant tumors that originated from mesenchymal lineages with more than 60 subtypes. However, potential biomarkers for the diagnosis and prognosis of SARC remain to be investigated.MethodsWe obtained three GSE raw matrix files (GSE39262, GSE21122, GSE48418) that related to various subtypes of sarcoma from the public GEO database and explored the widely differential expression genes in three obtained GSE files. Then common differential expression genes (CDGEs) were identified. We analyzed the correlation between the expression of the top five interacted genes of CDEGs and genome-wide differences, prognosis, genetic mutation, functional enrichment, immune infiltration, immune checkpoint, and marker genes’ expression of N6-methyladenosine (m6A) modification in SARC patients. Besides, a prognostic nomogram was constructed to predict the survival of SARC patients.ResultsAmong the three GSE files, 42 CDGEs were identified, and the top five interacted genes were ASPM, CCNB2, PRC1, AURKA, and SCM2. The expression levels of the five genes were higher in the SARC group than that in the normal group. The transcriptional level of CCNB2, PRC, and SCM2 was correlated to the worse survival of SARC. The constructed nomogram that combined CNB2, PRC1, and SCM2 showed a fairly good incredibility in predicting the survival of SARC (C-index: 0.711). Furthermore, the five genes were widely involved in immune infiltration, immune checkpoint, and m6A modification. In addition, we found a minor survival-related mutation rate (9%) of the five identified genes in SARC patients (p < 0.05).ConclusionThe results suggested the five identified genes widely participated in the prognosis, immune infiltration, immune checkpoint, and m6A modification of SARC patients. This study provided a theoretical basis for the research about the correlation between the level of five identified genes and sarcoma, but the further mechanism needs to be verified by experiments.

MutS homolog 2 (MSH2) is a crucial participant in human DNA repair, and lots of the studies functionally associated with it were begun with hereditary nonpolyposis colorectal cancer (HNPCC). MSH2 has also been reported to take part in the progresses of various tumors' formation. With the help of GTEx, CCLE, and TCGA pan-cancer databases, the analysis of MSH2 gene distribution in both tumor tissues and normal control tissues was carried out. Kaplan-Meyer survival plots and COX regression analysis were conducted for the assessment into the MSH2's impact on tumor patients' clinical prognosis. In an investigation to the association of MSH2 expression with immune infiltration level of various tumors and a similar study on tumor immune neoantigens, microsatellite instability was subsequently taken. It was found that high expression of MSH2 is prevalent in most cancers. MSH2's efficacy on clinical prognosis as well as immune infiltration in tumor patients revealed a fact that expression of MSH2 in prostate adenocarcinoma (PRAD), brain lower-grade glioma (LGG), breast-invasive carcinoma (BRCA), and head and neck squamous cell carcinoma (HNSC) posed a significant correlation with the immune cell infiltration level of patients. Likewise as above, MSH2's expression comes in a similar trend with tumor immune neoantigens and microsatellite instability. MSH2's expression in the majority of tumors is a direct factor to the activation of tumor-associated pathways as well as immune-associated pathways. MSH2's early screening or even therapeutic target role for sarcoma (SARC) diagnosis is contributing to the efficiency of early screening and overall survival in SARC patients.

BackgroundThe tumor microenvironment (TME) plays a very important role in the development of sarcoma (SARC), but it is still unknown how to effectively regulate the TME.AimOur study aims to identify core molecules that can concurrently regulate immune and stromal cells in TME as potential therapeutic targets.Methods and ResultsWe used the ESTIMATE algorithm to score the immune and stromal components of 265 SARC samples and determined that increased immune and stromal components in TME were both associated with poor prognosis in SARC. Next, we identified differential genes that regulate both immune and stromal cells, and identified the core prognostic gene CCR2 through the protein–protein interaction (PPI) network, COX analysis, survival analysis, and GSEA enrichment analysis. Next, we calculated the content of infiltrating immune cells and stromal cells in tumors using the CIBERSORT and xcell algorithms, respectively. Using differential analysis and Spearman correlation analysis, we identified 12 immune cells and 7 stromal cells, including CD4+T cells, CD8+T cells, monocytes, macrophages, dendritic cells, NK cells, mesenchymal stem cells (MSC), Fibroblasts and Endothelial cells, all of which were regulated by CCR2.ConclusionIncreased immune and stromal cell components were associated with poor prognosis in SARC, and CCR2 had a prognostic role in TME, regulating multiple immune and stromal cells, and was an important target for TME remodeling as well as immunotherapy in SARC.

BackgroundProgrammed Cell Death 2 Like (PDCD2L) correlates with cell proliferation, apoptosis and mouse embryonic development. However, the role of PDCD2L in human cancers is unclear.MethodsMultiple bioinformatic methods, in vitro function experiments and validation were performed to clarify the oncogenic role of PDCD2L in human cancers.ResultsOur study found that PDCD2L was aberrantly expressed in multiple types of human cancers, and associated with clinical stage and molecular subtype. Furthermore, overexpression of PDCD2L predicted poor overall survival in adrenocortical carcinoma(ACC), kidney chromophobe(KICH), acute myeloid leukemia(LAML), brain lower grade glioma(LGG),liver hepatocellular carcinoma(LIHC), mesothelioma(MESO), uveal melanoma(UVM) and poor diseases free survival in ACC, bladder urothelial carcinoma(BLCA), cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), kidney renal clear cell carcinoma(KIRC), kidney renal papillary cell carcinoma(KIRP), LGG, LIHC, and UVM. PDCD2L expression was negatively associated with cancer associated fibroblast in breast invasive carcinoma (BRCA), lung squamous cell carcinoma (LUSC), sarcoma (SARC), stomach adenocarcinoma (STAD) and testicular germ cell tumors (TGCT). Mechanically, we found that PDCD2L expression was associated with apoptosis, invasion and cell cycle by investigating single cell sequencing data. For further validation, PDCD2Lwas highly expressed in colorectal cancer (CRC) cell lines and tissue samples compared with the normal colon cell line and non-tumor adjacent colorectal mucosa tissues. PDCD2L knockdown induced the apoptosis and proliferation of CRC cells.ConclusionsOur study shows that the oncogenic role of PDCD2L in various cancers and PDCD2L could be served as a biomarker of CRC.

Abstract Background: Within the Triple-Negative Breast Cancer (TNBC) subclass, metaplastic TNBC (MpBC) tumors are comprised of heterogeneous, malignant epithelial (carcinoma) and mesenchymal (sarcoma) elements and are rare, highly aggressive, poorly differentiated and chemorefractory. There is an unmet need to develop therapies that address and improve survival of MpBC TNBC patients. We and others found that protein and mRNA levels of tripartite motif-containing protein 24 (TRIM24) are elevated in breast cancers, and aberrant expression of TRIM24 is linked to poor patient survival. Our previous in vitro studies showed that TRIM24 is a multidomain protein with histone reader function via a PHD/bromodomain and E3 ligase function via a RING domain that targets p53 for degradation.Methods: To determine if TRIM24 is oncogenic in vivo, we created a mouse model with conditional over expression (COE) of TRIM24 in mammary epithelia (Trim24COE). Trim24COE mice develop tumors, which were subjected to pathology, immunohistochemistry, global transcriptional and single-cell protein expression profiling. Additionally, we determined expression of TRIM24 in MpBC patient-derived tumor arrays and xenografts (PDX). Trim24COE tumor-derived primary cell lines and 3D spheroids were assessed for function and response to targeted inhibition.Results: TRIM24 over expression is sufficient to drive development of murine metaplastic carcinosarcomas (70% of all tumors), which are highly penetrant and lacking ER, PR and HER2 expression. Using global RNA-sequencing and selected proteomic profiling (RPPA) followed by CyTOF, we found that EMT, glycolysis, angiogenesis, G2/M checkpoint regulators and cMET/PI3K/mTOR are top up-regulated pathways. We defined a TRIM24 gene expression signature for Trim24COE tumors to probe TNBC patient expression data and found that the TRIM24 signature positively correlates with MpBC TNBC. Using a PROTAC targeting TRIM24, we showed that degradation of TRIM24 reduces cell viability compared to control, both in TRIM24-driven primary tumor cell lines and MpBC PDX cell suspensions. Carbon 13 (C13) tracing and other metabolomics were used to determine the impact of TRIM24 in metabolic pathways, using 3D spheroids derived from Trim24COE carcinosarcomas. We found that up-regulation of TRIM24 lowers ROS to promote cell survival by increased production of NADPH via multiple metabolic pathways that can be reversed by knocking-down TRIM24 or with specific metabolic inhibitors.Conclusions: TRIM24 is a PHD/bromodomain histone reader and p53-targeting E3-ubiquitin ligase that, when aberrantly over expressed, promotes tumorigenesis in vivo. A majority of Trim24-driven tumors are carcinosarcomas, highly similar to MpBC TNBC. Genomewide RNA expression and protein profiling show TRIM24 over expression activates EMT and disrupts metabolic homeostasis. Findings from our mouse model are relevant to tumors derived from MpBC patients, as PDXs show high expression of TRIM24 and respond to PROTAC treatment of TRIM24. Further establishment of TRIM24’s role in metabolic pathways to reduce ROS and increase cell survival may reveal potential combinatorial therapeutic approaches for MpBC. These findings suggest exciting opportunities to exploit the Trim24COE mouse model as a means of understanding mechanisms of MpBC tumor development and for preclinical studies of new, epigenetic-based therapeutic approaches. Citation Format: Vrutant Shah, Shucheng Miao, Clinton Yam, Jeffrey T Chang, Michelle Barton, Helen Piwnica-Worms, Stacy Moulder, Guillermina Lozano. Role of TRIM24 in metaplastic breast cancer and nomination of potential therapeutic targets [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-05-01.

Acyl-CoA Synthetase long-chain family member 4 (ACSL4) is a member of acyl-CoA synthetase protein long-chain family, which is associated with amino acid synthesis, lipid synthesis and lipid peroxidation dependent iron death. However, the role of ACSL4 in generalized carcinoma remains unclear. We aim to analyze the expression and prognostic value of ACSL4 in pan-cancer, and further explore the correlation between ACSL4 and immune infiltration. Through ONCOMINE, TIMER (Tumor Immune Estimation Resource), GEPIA (Gene expression Profiling Interactive), UALCAN and HPA, ACSL4 expression patterns of in pan-cancer were analyzed. The prognostic value of ACSL4 was analyzed using PrognoScan and Kaplan-Meier Plotter databases. Furthermore, gene variation and epigenetic modification of ACSL4 were analyzed by cBioPortal and GSCA databases. Meanwhile, GEPIA and TIMER databases applied to evaluate the relationship between ACSL4 expression and immune infiltration. These results indicate that ACSL4 expression is down-regulated and associated with prognosis in most tumors. In general, lower ACSL4 expression shows more beneficial prognosis. The most common genetic alteration of ACSL4 is point mutation. ACSL4 is negatively correlated with DNA methylation levels in most cancers. ACSL4 mutations or hypomethylation are associated with poor prognosis. In addition, ACSL4 is positively correlated with immune infiltration in cancers. ACSL4 and immune infiltration are strongly associated with prognosis in BRCA (Breast invasive carcinoma) and SKCM (Skin Cutaneous Melanoma). ACSL4 mutation caused significant changes of immune infiltration in UCEC (Uterine Corpus Endometrial Carcinoma) and SARC (Sarcoma). ACSL4 may be a promising prognostic biomarker for pan-cancer and is closely associated with immune infiltration in the tumor microenvironment.

Solitary abdominal muscle metastasis of cervical cancer after surgery mimicking mesenchymal sarcoma on MRI and 18F-FDG PET/CT imaging

Background Sarcomas (SARC) have been found as rare and heterogeneous malignancies with poor prognosis. PTBP1, belonging to the hnRNPs family, plays an essential role in some biological functions (e.g., pre-mRNA splicing, cell growth, and nervous system development). However, the role of PTBP1 in SARC remains unclear. In this study, the aim was to investigate the potential role of PTBP1 with a focus on SARC. Methods The expression, prognostic value, possible biological pathways of PTBP1, and its relationship with immune infiltration and drug sensitivity were comprehensively analyzed based on multiple databases. PTBP1 was further validated in osteosarcoma as the most prominent bone SARC. The expression of PTBP1 was investigated through IHC. The prognostic value of PTBP1 was verified in TARGET-OS databases. CRISPR/Cas9-mediated PTBP1 knockout HOS human osteosarcoma cell lines were used to assess the effect of PTBP1 on cell proliferation, migration, metastasis and cell cycle by CCK-8, Transwell migration, invasion, and FACS experiment. Result PTBP1 was highly expressed and significantly correlated with poor prognosis in several cancers, especially in SARC, which was validated in the clinical cohort and osteosarcoma cell lines. The genetic alteration of PTBP1 was found most frequently in SARC. Besides, PTBP1 played a role in oncogenesis and immunity through cell cycle, TGFB, autophagy, and WNT pathways at a pan-cancer level. Knockout of PTBP1 was observed to negatively affect proliferation, migration, metastasis, and cell cycle of osteosarcoma in vitro. Furthermore, PTBP1 was significantly correlated with tumor immune infiltration, DNA methylation, TMB, and MSI in a wide variety of cancers. Moreover, the potential of the expression level of PTBP1 in predicting drug sensitivity was assessed. Conclusions PTBP1 is highly expressed and correlated with prognosis and plays a vital pathogenic role in oncogenesis and immune infiltration of various cancers, especially for SARC, which suggests that it may be a promising prognostic marker and therapeutic target in the future.

Tumor necrosis factor-α-inducible protein 8-like 2 (TIPE2) is encoded by TNFAIP8L2 and is a newly identified negative regulator of natural and acquired immunity that plays a critical function in maintaining immune homeostasis. Recently, CAR-NK immune cell therapy has been a focus of major research efforts as a novel cancer therapeutic strategy. TIPE2 is a potential checkpoint molecule for immune cell maturation and antitumor immunity that could be used as a novel NK cell-based immunotherapeutic approach. In this study, we explored the expression of TNFAIP8L2 across various tumor types and found that TNFAIP8L2 was highly expressed in most tumor types and correlated with prognosis. Survival analysis showed that TNFAIP8L2 expression was predictive of improved survival in cervical-squamous-cell-carcinoma (CESC), sarcoma (SARC) and skin-cutaneous-melanoma (SKCM). Conversely, TNFAIP8L2 expression predicted poorer survival in acute myeloid leukemia (LAML), lower-grade-glioma (LGG), kidney-renal-clear-cell-carcinoma (KIRC) and uveal-melanoma (UVM). Analysis of stemness features and immune cell infiltration indicated that TNFAIP8L2 was significantly associated with cancer stem cell index and increased macrophage and dendritic cell infiltration. Our data suggest that TNFAIP8L2 may be a novel immune checkpoint biomarker across different tumor types, particularly in LAML, LGG, KIRC and UVM, and may have further utility as a potential target for immunotherapy.

CDK4 as a phytochemical based anticancer drug target

The angiopoietin-like protein (ANGPTL) family members, except for the novel atypical member ANGPTL8/betatrophin, have been reported to participate in angiogenesis, inflammation and cancer. ANGPTL8/betatrophin is a metabolic regulator that is involved in lipid metabolism and glucose homeostasis. However, little is known about the expression and prognostic value of ANGPTL8/betatrophin in human cancers. In this study, we first conducted detailed analyses of ANGPTL8/betatrophin expression in cancer/normal samples via the Human Protein Atlas (HPA), Gene Expression Profiling Interactive Analysis (GEPIA), DriverDBv3, ENCORI and UALCAN databases. ANGPTL8/betatrophin showed high tissue specificity (enriched in the liver) and cell-type specificity (enriched in HepG2 and MCF7 cell lines). More than one databases demonstrated that the gene expression of ANGPTL8/betatrophin was significantly lower in cholangiocarcinoma (CHOL), breast invasive carcinoma (BRCA), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), uterine corpus endometrial carcinoma (UCEC), and significantly higher in kidney renal clear cell carcinoma (KIRC) compared with that in normal samples. However, the protein expression of ANGPTL8/betatrophin displayed opposite results in clear cell renal cell carcinoma (ccRCC)/KIRC. Based on the expression profiles, the prognostic value was evaluated with the GEPIA, DriverDBv3, Kaplan Meier plotter and ENCORI databases. Two or more databases demonstrated that ANGPTL8/betatrophin significantly affected the survival of KIRC, uterine corpus endometrial carcinoma (UCEC), pheochromocytoma and paraganglioma (PCPG) and sarcoma (SARC); patients with PCPG and SARC may benifit from high ANGPTL8/betatrophin expression while high ANGPTL8/betatrophin expression was associated with poor prognosis in KIRC and UCEC. Functional analyses with the GeneMANIA, Metascape and STRING databases suggested that ANGPTL8/betatrophin was mainly involved in lipid homeostasis, especially triglyceride and cholesterol metabolism; glucose homeostasis, especially insulin resistance; AMPK signaling pathway; PI3K/Akt signaling pathway; PPAR signaling pathway; mTOR signaling pathway; HIF-1 signaling pathway; autophagy; regulation of inflammatory response. ANGPTL8/betatrophin may be a promising prognostic biomarker and therapeutic target, thus providing evidence to support further exploration of its role in defined human cancers.

KIF15 upregulation promotes leiomyosarcoma cell growth via promoting USP15-mediated DEK deubiquitylation

Abstract The high mortality (&amp;gt;80%) seen in high-grade serous ovarian cancer (HGSOC) highlights the unmet clinical need for treatments capable of producing long-term sustained responses. The related cancer, ovarian carcinosarcoma (OCS), has even poorer survival rates, which is due in part to being a rare cancer but also because of its unique phenotype. OCS are composed of both epithelial (carcinoma) and mesenchymal (sarcoma) components and molecular analysis has shown that most OCS are monoclonal and are derived from a common progenitor with sarcomatous transformation occurring by a stable epithelial-to-mesenchymal transition (EMT) process involving reprogramming of gene expression. Paclitaxel is an effective microtubule-stabilizing drug that is used in the treatment of HGSOC and OCS, however, resistance to platinum-taxane treatment usually occurs within 2-3 years and earlier in many OCS. We have been investigating the microtubule inhibitors, vinorelbine and eribulin, which each bind to distinct regions of microtubules and have a different mechanism of inhibition compared to paclitaxel. Eribulin has also been shown to reverse EMT, inducing vasculature remodeling and changes to the tumor-immune microenvironment. This dual activity of eribulin provides greater potential for improved efficacy in the clinic. Focusing on platinum resistant/refractory patient-derived xenografts (PDX) of HGSOC and OCS we assessed response to paclitaxel, vinorelbine and eribulin treatment and observed that around 50% of PDX were sensitive (HGSOC 8/13, 8/13 and 4/8 respectively; OCS 3/6 for all treatments). To deliver higher doses of drug to tumors but also limit toxicity, antibody-drug conjugates (ADCs) are being developed. MORAb-202 is an eribulin-anti-folate receptor alpha (FRα) ADC. It has been reported that 80-90% of HGSOC express FRα and in our HGSOC PDX cohort 14/15 (93%) were positive. However, only 1/5 (20%) OCS model showed any FRα and this was restricted to epithelial glandular structures, &amp;lt;5% of total area. We treated HGSOC and OCS PDX models with a single dose of MORAb-202, equivalent to a single ¼ dose of eribulin. Impressive sensitivity to MORAb-202 was observed in 2/3 HGSOC PDX, with the third model showing a response initially, then relapsing around 60 days post treatment. Two OCS PDX assessed were refractory to MORAb-202 due to insufficient FRα expression. These data provide validation that MORAb-202 is targeted to FRα-expressing tumors exclusively and in this preclinical setting is highly efficacious. This work was funded by Eisai Inc. Citation Format: Cassandra J. Vandenberg, Gwo-Yaw Ho, Ksenija Nesic, Elizabeth M. Swisher, Sean M. Grimmond, Matthew J. Wakefield, Holly E. Barker, David D. Bowtell, Clare L. Scott. Improving efficacy of microtubule inhibitors in the treatment of high-grade serous ovarian cancer and ovarian carcinosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1074.

BackgroundUndifferentiated embryonal sarcoma of liver (UESL) and hepatic mesenchymal hamartoma (HMH) are two rare entities which mainly affect the pediatric population. The aim of this investigation was to provide a comprehensive overview of the clinicopathologic characteristics of the patients diagnosed with these two conditions in a tertiary referral center in Iran.MethodsIn this retrospective study patients diagnosed with UESL or HMH between 2012 and 2020 were studied. A comprehensive histopathologic evaluation of the cases along with immunohistochemistry evaluation using a panel of antibodies was conducted. Furthermore, clinical, paraclinical, and treatment data and follow up information was collected.ResultsA total of 16 patients (8 UESL, 8 HMH) were studied in this investigation. Patients with UESL had a significantly (p = 0.002) higher age at diagnosis compared with those with HMH. Histologically, UESL cases were characterized by anaplastic cells with eosinophilic cytoplasm and bizarre nuclei and frequent atypical mitosis and spindling in a myxoid stroma while disordered arrangement of hepatic parenchyma, bile ducts, and primitive mesenchyme was seen in HMH. Furthermore, small round cells and extramedullary hematopoiesis were seen in 2 UESL and 3 HMH cases, respectively. Concurrent HMH was also seen in two UESL cases. Immunohistochemistry panel showed positive staining for Vimentin, Glypican-3, Desmin, CD56, CD10, and BCL2 in UESL cases and immunoreactivity for Vimentin, HepPar 1, Glypican-3, SMA, CD56, BCL2, and CD34 in various components of HMH.ConclusionsIn this study, the clinicopathologic features of UESL and HMH cases are presented. We also evaluated the utility of an immunohistochemistry panel in the diagnosis of these two rare entities and suggested novel markers. Our study corroborated the findings of previous investigations and expanded the clinicopathologic features of these two rare entities with diagnostic and potential therapeutic implications.