Common Human Cancers Research Articles

Prognostic significance of CTNNB1 mutation in hepatocellular carcinoma: a systematic review and meta-analysis.

Hepatocellular Carcinoma (HCC) is one of the most common malignant cancers in humans and has a high fatality rate. In recent years, researchers have verified that the Wnt/β-catenin signaling pathway affects the clinicopathological features and prognosis of patients with HCC. Although many studies have investigated the relationship between Wnt/β-catenin signaling pathway and HCC, the prognostic value of β-catenin in HCC remains inconclusive. CTNNB1 (Catenin Beta-1) is an important factor in the Wnt/β-catenin signaling pathway. However, no consensus has been reached on the clinical and prognostic significance of CTNNB1 mutations in HCCs. Eligible studies and relevant data were obtained from PubMed, Web of Science, Elsevier, Cochrane Library, Ovid, and Embase databases. The correlation between CTNNB1 mutations and clinical/prognosis of patients were evaluated. A fixed- or random-effects model was used to calculate pooled odds ratios (OR) and 95% confidence intervals (CI). Seventeen studies matched the selection criteria, and 1828 patients were included. This meta-analysis demonstrated that patients with HCC with CTNNB1 mutations had favorable clinicopathological features and survival. The combined ORs of 1-, 3- and 5-year overall survival were0.52 (n = 6 studies, 95% CI: 0.34-0.81, Z = 2.89, P =0.004, 0.28 (n =6 studies, 95% CI: 0.18-0.42, Z = 6.03, P<0.00001), -0.22 (n = 6 studies, 95% CI: 0.37-0.06, Z = 2.78, P = 0.005), respectively. Additionally, CTNNB1 mutation might be significantly associated with differentiation (OR = 0.54, 95% CI:0.36-0.81, Z = 2.98, P = 0.003), TMN stages (Tumor, Node, Metastasis staging classification) (OR = -0.25, 95% CI:-0.33--0.18, Z = 6.60, P<0.00001), liver cirrhosis (OR = 0.21, 95% CI:0.11-0.39, Z = 4.94, P< = 0.00001), and HBV (Hepatitis B Virus) infection (OR = 0.44, 95% CI:0.31-0.64, Z = 4.37, P<0.0001), but not with tumor size, metastasis, vascular invasion, and HCV infection. CTNNB1 mutation can serve as an indicator of favorable prognosis as well as a novel target for treatment in HCC.

Microwave assists synthesis of spirothiazolidine derivatives to induce cervical cancer cell death-mediated apoptosis in vitro

Herein, a new series of spirothiazolidine derivatives 1–14 are effectively produced using microwave irradiation in a quick and efficient manner. IR, NMR, and mass spectra were used to characterize all new formed substances. Newly created substances based on spirothiazolidinone ring system were tested for their anticancer effects on the common human cervical cancer cell lines HEp-2 and HeLa to produce effective initiative anti-cervical cancer analogs in order to complement or replace the existing anti-cervical cancer chemicals. Among the suggested compounds, compounds 7, 9d, 12, and 13 were found to be the most effective. In HeLa and HEp-2 cells, compounds 7 and 13 significantly increased the expression of CAS3 and Bax while significantly decreasing the expression of KRAS, NRAS, and Bcl-2. We are able to conclude that Compounds 7 and 13 inhibited the RAS gene in order to cause apoptosis.

Prognostic Role of CD68+ and CD163+ Tumour-Associated Macrophages and PD-L1 Expression in Oral Squamous Cell Carcinoma: A Meta-Analysis.

Background: Oral squamous cell carcinoma (OSCC) is a common malignant cancer in humans. An abundance of tumour associated macrophages (TAMs) create an immunosuppressive tumour microenvironment (TME). TAM markers (CD163 and CD68) are seen to serve as prognostic factors in OSCC. PD-L1 has seen to widely modulate the TME but its prognostic significance remains controversial. The aim of this meta-analysis is to evaluate the prognostic role of CD163+, CD68+ TAMs and PD-L1 in OSCC patients. Methods: Searches in PubMed, Scopus and Web of Science were performed; 12 studies were included in this meta-analysis. Quality assessment of included studies was performed according to REMARK guidelines. Risk of bias across studies was investigated according to the rate of heterogeneity. Meta-analysis was performed to investigate the association of all three biomarkers with overall survival (OS). Results: High expression of CD163+ TAMs were associated with poor overall survival (HR = 2.64; 95% Cl: [1.65, 4.23]; p < 0.0001). Additionally, high stromal expression of CD163+ TAMs correlated with poor overall survival (HR = 3.56; 95% Cl: [2.33, 5.44]; p < 0.00001). Conversely, high CD68 and PD-L1 expression was not associated with overall survival (HR = 1.26; 95% Cl: [0.76, 2.07]; p = 0.37) (HR = 0.64; 95% Cl: [0.35, 1.18]; p = 0.15). Conclusion: In conclusion, our findings indicate CD163+ can provide prognostic utility in OSCC. However, our data suggests CD68+ TAMs were not associated with any prognostic relevance in OSCC patients, whereas PD-L1 expression may prove to be a differential prognostic marker dependent on tumour location and stage of progression.

Assessment of the Anti-Breast Cancer Effects of Urolithin with Molecular Docking Studies in the In Vitro Condition: Introducing a Novel Chemotherapeutic Drug.

A lot of research has been done on using natural items as diabetes treatment. The molecular docking study was conducted to evaluate the inhibitory activities of urolithin A against α-amylase, α-glucosidase, and aldose reductase. The molecular docking calculations indicated the probable interactions and the characteristics of these contacts at an atomic level. The results of the docking calculations showed the docking score of urolithin A against α-amylase was -5.169kcal/mol. This value for α-glucosidase and aldose reductase was -3.657kcal/mol and -7.635kcal/mol, respectively. In general, the outcomes of the docking calculations revealed that urolithin A can construct several hydrogen bonds and hydrophobic contacts with the assessed enzymes and reduces their activities considerably. The properties of urolithin against common human breast cancer cell lines, i.e., SkBr3, MDA-MB-231, MCF-7, Hs578T, Evsa-T, BT-549, AU565 and 600MPE were evaluated. The IC50 of the urolithin was 400, 443, 392, 418, 397, 530, 566 and 551 against SkBr3, MDA-MB-231, MCF-7, Hs578T, Evsa-T, BT-549, AU565 and 600MPE, respectively. After doing the clinical trial studies, the recent molecule may be used as an anti-breast cancer supplement in humans. IC50 values of urolithin A on α-amylase, α-glucosidase, and aldose reductase enzymes were obtained at 16.14, 1.06 and 98.73µM, respectively.

Role of Vitamin D in Head and Neck Cancer-Immune Function, Anti-Tumour Effect, and Its Impact on Patient Prognosis.

Head and neck squamous cell carcinoma (HNSCC) describes a heterogeneous group of human neoplasms of the head and neck with high rates of morbidity and mortality, constituting about 3% of all cancers and ~1.5% of all cancer deaths. HNSCC constituted the seventh most prevalent human malignancy and the most common human cancer in the world in 2020, according to multi-population observations conducted by the GLOBOCAN group. Since approximately 60-70% of patients present with stage III/IV neoplastic disease, HNSCC is still one of the leading causes of death in cancer patients worldwide, with an overall survival rate that is too low, not exceeding 40-60% of these patients. Despite the application of newer surgical techniques and the implementation of modern combined oncological treatment, the disease often follows a fatal course due to frequent nodal metastases and local neoplastic recurrences. The role of micronutrients in the initiation, development, and progression of HNSCC has been the subject of considerable research. Of particular interest has been vitamin D, the pleiotropic biologically active fat-soluble family of secosteroids (vitamin-D-like steroids), which constitutes a key regulator of bone, calcium, and phosphate homeostasis, as well as carcinogenesis and the further development of various neoplasms. Considerable evidence suggests that vitamin D plays a key role in cellular proliferation, angiogenesis, immunity, and cellular metabolism. A number of basic science, clinical, and epidemiological studies indicate that vitamin D has multidirectional biological effects and influences anti-cancer intracellular mechanisms and cancer risk, and that vitamin D dietary supplements have various prophylactic benefits. In the 20th century, it was reported that vitamin D may play various roles in the protection and regulation of normal cellular phenotypes and in cancer prevention and adjunctive therapy in various human neoplasms, including HNSCC, by regulating a number of intracellular mechanisms, including control of tumour cell expansion and differentiation, apoptosis, intercellular interactions, angio- and lymphogenesis, immune function, and tumour invasion. These regulatory properties mainly occur indirectly via epigenetic and transcriptional changes regulating the function of transcription factors, chromatin modifiers, non-coding RNA (ncRNAs), and microRNAs (miRs) through protein-protein interactions and signalling pathways. In this way, calcitriol enhances intercellular communication in cancer biology, restores the connection with the extracellular matrix, and promotes the epithelial phenotype; it thus counteracts the tumour-associated detachment from the extracellular matrix and inhibits the formation of metastases. Furthermore, the confirmation that the vitamin D receptor (VDR) is present in many human tissues confirmed the physiopathological significance of vitamin D in various human tumours. Recent studies indicate quantitative associations between exposure to vitamin D and the incidence of HNC, i.e., cancer risk assessment included circulating calcidiol plasma/serum concentrations, vitamin D intake, the presence of the VDR gene polymorphism, and genes involved in the vitamin D metabolism pathway. Moreover, the chemopreventive efficacy of vitamin D in precancerous lesions of the head and neck and their role as predictors of mortality, survival, and recurrence of head and neck cancer are also widely discussed. As such, it may be considered a promising potential anti-cancer agent for developing innovative methods of targeted therapy. The proposed review discusses in detail the mechanisms regulating the relationship between vitamin D and HNSCC. It also provides an overview of the current literature, including key opinion-forming systematic reviews as well as epidemiological, prospective, longitudinal, cross-sectional, and interventional studies based on in vitro and animal models of HNSCC, all of which are accessible via the PubMed/Medline/EMBASE/Cochrane Library databases. This article presents the data in line with increasing clinical credibility.

Overexpression of the lncRNA HOTAIRM1 promotes lenvatinib resistance by downregulating miR-34a and activating autophagy in hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is one of the most common malignant cancers in humans and has a high fatality rate. Despite pharmacological advances such as sorafenib and lenvatinib approval, responses are seen only in a limited fraction of HCCs, and the majority of HCC patients do not benefit from this treatment. In recent years, researchers have verified that the long noncoding RNAs (lncRNAs) impact the efficiency of lenvatinib and the prognosis of patients with HCC.Materials and methodsThis work obtained gene expression profile from an Arraystar lncRNA microarray. Expression of HOTAIRM1, Beclin-1, and p62 in HCC was characterized in clinical HCC tissues of 24 patients with HCC. Overexpression and knockdown experiments were performed in HCC cells to examine the effects of the HOTAIRM1 on lenvatinib sensitivity. The interactions between HOTAIRM1, miR-34a and Beclin-1 were predicted according to GSEA and CNC network. The effects of HOTAIRM1, autophagy and lenvatinib on tumor inhibit were validated in orthotopic tumor-bearing nude mouse model.ResultsLenvatinib-resistant HCC cell lines were established using the concentration gradient method. Data from an Arraystar lncRNA microarray indicated that HOTAIRM1, a specific lncRNA located in an evolutionarily highly conserved HOX gene cluster, was differentially expressed between lenvatinib-resistant HCC cells and their parental cells. Expression of HOTAIRM1 and Beclin-1 in HCC was characterized in clinical HCC tissues of 24 patients who have different sensitivity to lenvatinib. Knocking down of HOTAIRM1 decreased the autophagy level in lenvatinib-resistant HCC cells and increased their sensitivity to lenvatinib, especially when combined with autophagy inhibitors both in vitro and in vivo. Further study indicated that knocking down HOTAIRM1 in lenvatinib-resistant cell lines increased the level of miR-34a and inhibited the expression of Beclin-1 in Huh7-R and HepG2-R cells. Investigation according to GSEA and CNC network, lncRNA and nearby coding gene and lncRNA-miRNA analyses demonstrated that the resistance of HCC to lenvatinib was affected by the HOTAIRM1-miR-34a-Beclin-1 regulatory axis.ConclusionHOTAIRM1 is an independent drug resistance factor which significantly associated with the efficacy of lenvatinib in HCC. HOTAIRM1 may downregulation of miR-34a and upregulation of Beclin-1, leading to activation of autophagy, thereby inducing lenvatinib resistance in HCC.

Allium ampeloprasum leaf aqueous extract green-formulated Ag nanoparticles: Determination of anti-human lung cancer and antioxidant effects

Allium ampeloprasum as an ethnomedicinal plant has many therapeutic effects in the traditional medicine. In the recent years, the silver nanoparticles green-mediated by ethno medicinal plants have been used for the treatment of several kinds of cancers. Now, we investigated the silver nanoparticles green-synthesized according to green chemistry rules using the aqueous extract of Allium ampeloprasum leaf for the treatment of lung carcinoma. The properties of silver nanoparticles against common human lung cancer cell lines i.e. HT144, SKMEL2, WM266-4, and IPC-298 were evaluated. The green-synthesized silver nanoparticles were characterized using different techniques such as FE-SEM, UV-Vis, and TEM. The FE-SEM and TEM results confirm spherical morphology for the nanoparticles with size of 11.9–46.7 nm. The IC50 of the silver nanoparticles was 125, 164, 180 and 149 µg/ml against HT144, SKMEL2, WM266-4, and IPC-298, respectively. After doing the clinical trial studies, the recent nanoparticles may be used as an anti-lung supplement in humans.

Wip1 phosphatase inhibition enhances etoposide mediated apoptosis by increasing p53 phosphorylation in Rhabdoid tumor cells

Protein phosphatase magnesium-dependent 1 delta (PPM1D/Wip1) is a genotoxic stress-activated serine/threonine phosphatase playing a central role in the timely termination of DNA damage response (DDR). Wip1 is frequently mutated, amplified, and overexpressed in common human cancers and is recognized as an oncogene. Rhabdoid tumors (RT) are a type of soft tissue sarcoma being quite aggressive and resistant to chemotherapy. In this study, the role of Wip1 in the regulation of genotoxic stress-induced apoptosis was studied in RT cell line A204. First PPM1D mRNA levels were analyzed in RT compared to normal tissues by in silico analysis utilizing RNA-seq data generated by TARGET from TCGA Pan Cancer. Second, MCF-7, BJ, and A204 cells were used to test the gene copy number and mRNA levels of Wip1 by qRT-PCR. Small molecule inhibitor GSK2830371 and etoposide were used to target Wip1 and to trigger genotoxic stress, respectively. MTT and AnexinV/7AAD analyzes were used to determine the viability and apoptotic response of A204 cells. Inhibition of Wip1 and total and phosphorylated levels of p53 was demonstrated by WB analysis. Thus, here we showed that Wip1 is overexpressed and amplified in the A204 RT cell line. Wip1 overexpressing A204 cells display resistance to etoposide-induced apoptosis due to decreased phosphorylation of p53. Targeting of Wip1 by GSK2830371 increased the phosphorylation of p53 in response to etoposide treatment. Additionally combined use of GSK2830371 and etoposide enhances p53-mediated apoptosis in A204 cells.

Investigating the immunomodulatory effects of histotripsy ablation for osteosarcoma

Abstract Osteosarcoma (OS) is the most common primary bone cancer in humans and dogs. Canine OS shares many biological similarities with human OS and is a valuable comparative oncology research model. In both species, metastasis remains a major hurdle against improved survival, thus warranting a novel therapeutic approach such as histotripsy, a non-thermal, non-invasive, focused ultrasound ablation modality. Histotripsy can mechanically disintegrate gross tumor and potentially induces an anti-tumor immune response to inhibit metastatic development. The objectiveof this in vitro study was to investigate the immunomodulatory effects of histotripsy ablation of canine OS. We hypothesizedthat histotripsy ablation of OS promotes a pro-inflammatory immune signature in primary monocytes and macrophages. We isolated CD14+ primary monocytes using positive selection immunomagnetic cell separation from peripheral blood mononuclear cells of healthy dogs, and differentiated primary macrophages by culturing primary monocytes with canine GM-CSF for 72 hours. We co-cultured primary monocytes and macrophages with histotripsy-ablated canine D17 OS cells for 24 hours, then characterized their cell surface markers using flow cytometry and performed multiplex supernatant cytokine analysis. We observed upregulation of CD80 and CD62L on primary monocytes and a downregulation of CD206 on macrophages exposed to histotripsy-ablated D17 cells compared to controls, suggesting immune activation. We observed decreased levels of the pro-tumor cytokine, TGF-β, from primary monocytes exposed to histotripsy-ablated D17s compared to controls. Our results indicate that histotripsy ablation of OS can induce a pro-inflammatory immune signature. This work is supported by grants from the American Kennel Club Canine Health Foundation, the Focused Ultrasound Foundation.

Development, characterization and in vitro cytotoxicity of kaempferol-loaded nanostructured lipid carriers in glioblastoma multiforme cells

Glioblastoma multiforme is the most common and most aggressive human brain cancer. GBM treatment is still a challenge because many drugs are not able to cross the blood-brain barrier, in addition to the increasing resistance to currently available chemotherapy. New therapeutic alternatives are emerging, and, in this context, we highlight kaempferol, a flavonoid with remarkable anti-tumor activity but with limited bioavailability due to its strong lipophilic property. A promising tool to improve the biopharmaceutical properties of molecules such as kaempferol is the use of drug-delivery nanosystems, such as nanostructured lipid carriers (NLC), which can facilitate the dispersion and delivery of highly lipophilic molecules. The present work aimed at the development and characterization of kaempferol-loaded NLC (K-NLC) and the evaluation of its biological properties using in vitro models. The K-NLC showed an average size of 120 nm, zeta potential of − 21 mV, and polydispersity index of 0.099. The K-NLC presented high kaempferol encapsulation efficiency (93%), a drug loading of 3.58%, and a sustained kaempferol release profile for up to 48 h. In addition to presenting a 7-fold increase in kaempferol cytotoxicity, its encapsulation in NLC promoted a cellular uptake of 75%, which corroborates with increased cytotoxicity in U-87MG cells, as observed. Together, these data reinforce the promising antineoplastic properties of kaempferol in addition to the key role of NLC as a platform for the efficient delivery of lipophilic drugs to neoplastic cells, which improved their uptake and therapeutic efficacy in glioblastoma multiforme cells.

MiR-1 Variations in Colorectal Cancer: Possible Implementation as a Potential Accessory Biomarker

Background and Aims: Colorectal cancer (CRC) is one of the most common human cancers. Currently, carcinoembryonic antigen (CEA) is used as the main standard biomarker of CRC, though this biomarker is not specifically made for CRC and, in a minority of cases, shows inadequate sensitivity. Therefore, searching for novel accessory biomarkers may fill these gaps in clinical management. miRNAs physiologically regulate various metabolic processes and are misregulated in various cancers. Therefore, the present investigation was conducted to evaluate miR-1 levels in CRC samples.&#x0D; Materials and Methods: The CRC and adjacent tissue samples were obtained from 24 patients. In addition, sera were collected from the patient group and 24 healthy controls. Total RNA was extracted from tissue samples, and cDNA was synthesized. Real-time PCR determined the expression of miR-1. Serum levels of CEA were also measured using a Monobind ELISA assay kit.&#x0D; Results: The level of miR-1 in CRC tumors was significantly down-regulated. Moreover, patients with metastasis showed lower expression of miR-1 compared to cases without metastasis; however, this difference was not statistically significant. The ROC curve for miR-1 showed an AUC of 0.69. In addition, ROC analysis revealed a sensitivity of 70.27% and a specificity of 62.96% for miR-1.&#x0D; Conclusion: There is still a need for new upcoming markers in addition to the main CRC biomarker, CEA. The levels of miR-1 in colorectal cancer tissue samples may provide additional information for the management and follow-up of CRC patients; though, the clinical application needs further studies.

Basal Cell Carcinoma—A Retrospective Descriptive Study Integrated in Current Literature

Basal cell carcinoma (BCC) is considered to be the most common cancer in humans. It has a slow growth rhythm, and for this reason, metastases are rare. For our retrospective study, we selected 180 patients from those who underwent surgery for a variety of skin tumours between January 2019 and August 2022 and whose histopathological examination revealed basal cell carcinoma. All surgeries were performed by plastic surgeons at the "St. John" hospital in Bucharest. The aim of this article is to provide observational data regarding BCC-in terms of histopathology and diagnostic and therapeutic management and to integrate these data into the current knowledge of this pathology.

Pan-cancer analysis identifies PD-L2 as a tumor promotor in the tumor microenvironment.

Programmed cell death protein 1 (PD-1) receptor has two ligands,programmed death-ligand 1 (PD-L1) and PD-L2. When compared with PD-L1, PD-L2 has not received much attention, and its role remains unclear. The expression profiles of pdcd1lg2 (PD-L2-encoding gene) mRNA and PD-L2 protein were analyzed using TCGA, ICGC, and HPA databases. Kaplan-Meier and Cox regression analyses were used to assess the prognostic significance of PD-L2. We used GSEA, Spearman's correlation analysis and PPI network to explore the biological functions of PD-L2. PD-L2-associated immune cell infiltration was evaluated using the ESTIMATE algorithm and TIMER 2.0. The expressions of PD-L2 in tumor-associated macrophages (TAMs) in human colon cancer samples, and in mice in an immunocompetent syngeneic setting were verified using scRNA-seq datasets, multiplex immunofluorescence staining, and flow cytometry. After fluorescence-activated cell sorting, flow cytometry and qRT-PCR and transwell and colony formation assays were used to evaluate the phenotype and functions of PD-L2+TAMs. Immune checkpoint inhibitors (ICIs) therapy prediction analysis was performed using TIDE and TISMO. Last, a series of targeted small-molecule drugs with promising therapeutic effects were predicted using the GSCA platform. PD-L2 was expressed in all the common human cancer types and deteriorated outcomes in multiple cancers. PPI network and Spearman's correlation analysis revealed that PD-L2 was closely associated with many immune molecules. Moreover, both GSEA results of KEGG pathways and GSEA results for Reactome analysis indicated that PD-L2 expression played an important role in cancer immune response. Further analysis showed that PD-L2 expression was strongly associated with the infiltration of immune cells in tumor tissue in almost all cancer types, among which macrophages were the most positively associated with PD-L2 in colon cancer. According to the results mentioned above, we verified the expression of PD-L2 in TAMs in colon cancer and found that PD-L2+TAMs population was not static. Additionally, PD-L2+TAMs exhibited protumor M2 phenotype and increased the migration, invasion, and proliferative capacity of colon cancer cells. Furthermore, PD-L2 had a substantial predictive value for ICIs therapy cohorts. PD-L2 in the TME, especially expressed on TAMs, could be applied as a potential therapeutic target.

Prevention and Treatment of HPV-Induced Skin Tumors.

Non-melanoma skin cancer (NMSC) is the most common cancer in humans with increasing incidence. Meanwhile, a growing body of evidence has provided a link between skin infections with HPV of the genus beta (betaHPV) and the development of cutaneous squamous cell carcinomas (cSCCs). Based on this association, the development of vaccines against betaHPV has become an important research topic. This review summarizes the current advances in prophylactic and therapeutic betaHPV vaccines, including progresses made in preclinical testing and clinical trials.

Abstract P6-14-05: Regulation of cellular identity and spatial organization during collective breast cancer invasion

Abstract An early step in breast cancer progression is invasion of tumor cells into surrounding tissues. In many breast cancers, particularly ductal carcinomas, this invasion is accomplished by tumor cells migrating as a cohesive group. This often involves cells that take on heterogeneous roles as either leader or follower cells. While studies in common mouse and human breast cancer models have established that leader cells express high levels of keratin-14 (K14) and other basal epithelial markers, the molecular mechanisms regulating K14+ leader cell identity remain obscure. Here we performed time-sampled single cell RNA-sequencing in 3D type I collagen-embedded tumor organoids isolated from the MMTV-PyMT luminal B model of breast cancer. 11 distinct cellular transcriptional states were identified and correlated with K14 expression and invasive strand formation. Having identified the leader cell state we next asked what transcription factors were enriched, reasoning that transcription factors could be master regulators of leader cell fate. 30 different shRNAs targeting 10 genes were systematically evaluated for their effects on collective invasion. From this screen, suppression of Hes1, the downstream target of Notch signaling, yielded a marked switch from collective to single cell invasion. Disseminating single tumor cells maintained high expression of K14 in Hes1 knockdown organoids which was phenocopied by gamma-secretase inhibition in a human TNBC PDX model. Because K14+ tumor cells highly express the Notch ligand Jag1, these results support a model in which Notch signaling, specifically through activation of Hes1, dictates leader cell identity and spatial organization during collective invasion. Studies are ongoing investigating the impact of Hes1 dynamics on leader cell adhesion, hybrid EMT state, and preference for single versus collective metastasis. Because Notch suppression induces leader cell dissemination, we propose that Notch targeted therapy should be combined with therapies eradicating leader cells. Citation Format: Andrea E. Doak, Kevin J. Cheung. Regulation of cellular identity and spatial organization during collective breast cancer invasion. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-05.

Prediction of disease-linked miRNAs based on SODNMF-DM

Motivation:MicroRNAs (miRNAs) play a crucial role in the life processes of organisms and affect the occurrence of many complex human diseases. Discovering potential links between diseases and miRNAs can aid in the prevention, diagnosis, and therapy of complex human diseases. Description:Identifying diseases and miRNA associations through existing biological experiments is expensive, while scientific computing approaches can quickly and efficiently predict the potential links between diseases and miRNAs. We propose SODNMF-DM, a SODNMF based Disease-MiRNA matrix factorisation algorithm. Result:The SODNMF-DM model exhibited an AUC of 0.9051 and an AUPR of 0.4774, respectively. To directly verify the effectiveness of SODNMF-DM, we studied three common human cancers. The experimental results showed that 25 of the top 30 potential miRNAs predicted by our proposed SODNMF-DM model were confirmed by HMDDv3.0 database. Conclusion: SODNMF-DM outperformed four other approaches in AUC and AUPR. In addition, our proposed approach exhibited good performance in practical cases. The approach presented in this study is thus expected to complement the field of biological research.

An immune score reflecting pro- and anti-tumoural balance of tumour microenvironment has major prognostic impact and predicts immunotherapy response in solid cancers.

Cancer immunity is based on the interaction of a multitude of cells in the spatial context of the tumour tissue. Clinically relevant immune signatures are therefore anticipated to fundamentally improve the accuracy in predicting disease progression. Through a multiplex in situ analysis we evaluated 15 immune cell classes in 1481 tumour samples. Single-cell and bulk RNAseq data sets were used for functional analysis and validation of prognostic and predictive associations. By combining the prognostic information of anti-tumoural CD8+ lymphocytes and tumour supportive CD68+CD163+ macrophages in colorectal cancer we generated a signature of immune activation (SIA). The prognostic impact of SIA was independent of conventional parameters and comparable with the state-of-art immune score. The SIA was also associated with patient survival in oesophageal adenocarcinoma, bladder cancer, lung adenocarcinoma and melanoma, but not in endometrial, ovarian and squamous cell lung carcinoma. We identified CD68+CD163+ macrophages as the major producers of complement C1q, which could serve as a surrogate marker of this macrophage subset. Consequently, the RNA-based version of SIA (ratio of CD8A to C1QA) was predictive for survival in independent RNAseq data sets from these six cancer types. Finally, the CD8A/C1QA mRNA ratio was also predictive for the response to checkpoint inhibitor therapy. Our findings extend current concepts to procure prognostic information from the tumour immune microenvironment and provide an immune activation signature with high clinical potential in common human cancer types. Swedish Cancer Society, Lions Cancer Foundation, Selanders Foundation, P.O. Zetterling Foundation, U-CAN supported by SRA CancerUU, Uppsala University and Region Uppsala.

Understanding the squamous cell carcinoma immune microenvironment.

Primary cutaneous squamous cell carcinoma (cSCC) is the second most common human cancer with a rising incidence of about 1.8 million in the United States annually. Primary cSCC is usually curable by surgery; however, in some cases, cSCC eventuates in nodal metastasis and death from disease specific death. cSCC results in up to 15,000 deaths each year in the United States. Until recently, non-surgical options for treatment of locally advanced or metastatic cSCC were largely ineffective. With the advent of checkpoint inhibitor immunotherapy, including cemiplimab and pembrolizumab, response rates climbed to 50%, representing a vast improvement over chemotherapeutic agents used previously. Herein, we discuss the phenotype and function of SCC associated Langerhans cells, dendritic cells, macrophages, myeloid derived suppressor cells and T cells as well as SCC-associated lymphatics and blood vessels. Possible role(s) of SCC-associated cytokines in progression and invasion are reviewed. We also discuss the SCC immune microenvironment in the context of currently available and pipeline therapeutics.

Colorectal Cancer-The Worst Enemy Is the One We Do Not Know.

Colorectal cancer is one of the most common cancers in humans. It is the third most frequently diagnosed malignant neoplasm and is the second highest cause of cancer mortality in the world. Every year, more and more people die of colorectal cancer because the diagnosis is conducted too late. This shows how important a role screening tests and the awareness of the population about the symptoms play in this aspect. This article aimed to determine the knowledge of the Polish population about morbidity, symptoms, prevention, and subjective feelings about the level of availability of knowledge about colorectal cancer. In 2020, a study was conducted using an online questionnaire assessing the awareness of the Polish population about colorectal cancer. A self-authored questionnaire including questions about socio-demographic characteristics, and 18 questions related to substantive issues, was used. A research group was selected (n = 633). The substantive part of the questionnaire included questions examining the respondents' knowledge about morbidity, symptoms, prevention, and subjective feelings about the level of availability of knowledge about colorectal cancer. The respondents' awareness level was influenced by demographic factors, such as gender: (p < 0.05) and age (p < 0.05) and social factors, such as: level of education (p < 0.05) or professional situation (p < 0.05). Compared to thematic articles from other countries, the research group was divided into smaller subgroups due to the abovementioned factors, due to which it was possible to stratify and analyze the significance of differences between them.

Abstract A014: Transcriptional regulation of basal leader cell identity during collective breast cancer invasion

Abstract An early step in breast cancer progression is invasion of tumor cells into surrounding tissues. In many breast cancers, particularly ductal carcinomas, this invasion is accomplished by tumor cells migrating as a cohesive group. This often involves cells that take on heterogeneous roles as either leader or follower cells. Studies in common mouse and human breast cancer models have established that leader cells express high levels of keratin-14 (K14) and other basal epithelial markers. The presence of these K14+ cells promote metastasis and predict poor prognosis. The molecular mechanisms regulating K14+ leader cell identity and the methods for targeted depletion of these cells remain obscure. Here we performed time-sampled single cell RNA-sequencing in 3D type I collagen-embedded tumor organoids isolated from the MMTV-PyMT luminal B model of breast cancer. 11 distinct cellular transcriptional states were identified, and through correlation with K14 expression and invasive strand formation we classified one of the states as leader cells. Having confirmed the leader cell cluster markers spatially localize to the invasive front, we next asked which transcription factors were enriched, reasoning that transcription factors could be master regulators of leader cell fate. Three different shRNAs targeting ten genes were systematically evaluated for their effects on collective invasion and keratin-14 transcription. Each transcription factor was designated as either an invasion promoter or invasion suppressor depending on the correlation between transcription factor expression and organoid invasion. Studies are ongoing investigating the impact of invasion-promoting and invasion-suppressing transcription factors on cellular transcriptional states and metastatic dissemination in-vivo. We propose that targeting invasion-suppressing pathways could be combined with therapies that specifically target and eliminate K14+ invasive cells. To this end, we have identified multiple candidate druggable targets and specific surface markers expressed in K14+ invasive cells. Citation Format: Andrea E. Doak, Rose Qu, Kevin J. Cheung. Transcriptional regulation of basal leader cell identity during collective breast cancer invasion [abstract]. In: Proceedings of the AACR Special Conference: Cancer Metastasis; 2022 Nov 14-17; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_2):Abstract nr A014.