N1 versus N2 and PMN-MDSC: A critical appraisal of current concepts on tumor-associated neutrophils and new directions for human oncology.

Research on tumor-associated neutrophils (TAN) currently surges because of the well-documented strong clinical relevance of tumor-infiltrating neutrophils. This relevance is illustrated by strong correlations between high frequencies of intratumoral neutrophils and poor outcome in the majority of human cancers. Recent high-dimensional analysis of murine neutrophils provides evidence for unexpected plasticity of neutrophils in murine models of cancer and other inflammatory non-malignant diseases. New analysis tools enable deeper insight into the process of neutrophil differentiation and maturation. These technological and scientific developments led to the description of an ever-increasing number of distinct transcriptional states and associated phenotypes in murine models of disease and more recently also in humans. At present, functional validation of these different transcriptional states and potential phenotypes in cancer is lacking. Current functional concepts on neutrophils in cancer rely mainly on the myeloid-derived suppressor cell (MDSC) concept and the dichotomous and simple N1-N2 paradigm. In this manuscript, we review the historic development of those concepts, critically evaluate these concepts against the background of our own work and provide suggestions for a refinement of current concepts in order to facilitate the transition of TAN research from experimental insight to clinical translation.

The HHEX-ABI2/SLC17A9 axis induces cancer stem cell-like properties and tumorigenesis in HCC.

Accumulating evidence indicated that HHEX participated in the initiation and development of several cancers, but the potential roles and mechanisms of HHEX in hepatocellular carcinoma (HCC) were largely unclear. Cancer stem cells (CSCs) are responsible for cancer progression owing to their stemness characteristics. We reported that HHEX was a novel CSCs target for HCC. We found that HHEX was overexpressed in HCC tissues and high expression of HHEX was associated with poor survival. Subsequently, we found that HHEX promoted HCC cell proliferation, migration, and invasion. Moreover, bioinformatics analysis and experiments verified that HHEX promoted stem cell-like properties in HCC. Mechanistically, ABI2 serving as a co-activator of transcriptional factor HHEX upregulated SLC17A9 to promote HCC cancer stem cell-like properties and tumorigenesis. Collectively, the HHEX-mediated ABI2/SLC17A9 axis contributes to HCC growth and metastasis by maintaining the CSC population, suggesting that HHEX serves as a promising therapeutic target for HCC treatment.

Epigenetic MLH1 silencing concurs with mismatch repair deficiency in sporadic, naturally occurring colorectal cancer in rhesus macaques.

BACKGROUND: Naturally occurring colorectal cancers (CRC) in rhesus macaques share many features with their human counterparts and are useful models for cancer immunotherapy; but mechanistic data are lacking regarding the comparative molecular pathogenesis of these cancers. METHODS: We conducted state-of-the-art imaging including CT and PET, clinical assessments, and pathological review of 24 rhesus macaques with naturally occurring CRC. Additionally, we molecularly characterized these tumors utilizing immunohistochemistry (IHC), microsatellite instability assays, DNAseq, transcriptomics, and developed a DNA methylation-specific qPCR assay for MLH1, CACNA1G, CDKN2A, CRABP1, and NEUROG1, human markers for CpG island methylator phenotype (CIMP). We furthermore employed Monte-Carlo simulations to in-silico model alterations in DNA topology in transcription-factor binding site-rich promoter regions upon experimentally demonstrated DNA methylation. RESULTS: Similar cancer histology, progression patterns, and co-morbidities could be observed in rhesus as reported for human CRC patients. IHC identified loss of MLH1 and PMS2 in all cases, with functional microsatellite instability. DNA sequencing revealed the close genetic relatedness to human CRCs, including a similar mutational signature, chromosomal instability, and functionally-relevant mutations affecting KRAS (G12D), TP53 (R175H, R273*), APC, AMER1, ALK, and ARID1A. Interestingly, MLH1 mutations were rarely identified on a somatic or germline level. Transcriptomics not only corroborated the similarities of rhesus and human CRCs, but also demonstrated the significant downregulation of MLH1 but not MSH2, MSH6, or PMS2 in rhesus CRCs. Methylation-specific qPCR suggested CIMP-positivity in 9/16 rhesus CRCs, but all 16/16 exhibited significant MLH1 promoter hypermethylation. DNA hypermethylation was modelled to affect DNA topology, particularly propeller twist and roll profiles. Modelling the DNA topology of a transcription factor binding motif (TFAP2A) in the MLH1 promoter that overlapped with a methylation-specific probe, we observed significant differences in DNA topology upon experimentally shown DNA methylation. This suggests a role of transcription factor binding interference in epigenetic silencing of MLH1 in rhesus CRCs. CONCLUSIONS: These data indicate that epigenetic silencing suppresses MLH1 transcription, induces the loss of MLH1 protein, abrogates mismatch repair, and drives genomic instability in naturally occurring CRC in rhesus macaques. We consider this spontaneous, uninduced CRC in immunocompetent, treatment-naïve rhesus macaques to be a uniquely informative model for human CRC.

Assessing Circulating Tumour DNA (ctDNA) as a Biomarker for Anal Cancer Management: A Systematic Review.

This systematic review investigates the potential of circulating tumour DNA (ctDNA) as a predictive biomarker in the management and prognosis of squamous cell carcinoma of the anal canal (SCCA). PubMed, EMBASE, and Cochrane Central Registry of Controlled Trials were searched until 7 January 2024. Selection criteria included research articles exploring ctDNA in the context of anal cancer treatment response, recurrence risk assessment, and consideration of salvage surgery. A total of eight studies were therefore included in the final review, examining a total of 628 patients. These studies focused on three main themes: SCCA diagnosis and staging, treatment response, and patient outcomes. Significant heterogeneity was observed in terms of patient cohort, study methodology, and ctDNA biomarkers. Four studies provided information on the sensitivity of ctDNA biomarkers in SCCA, with a range of 82-100%. Seven studies noted a correlation between pre-treatment ctDNA levels and SCCA disease burden, suggesting that ctDNA could play a role as a biomarker for the staging of SCCA. Across all seven studies with paired pre- and post-treatment ctDNA samples, a trend was seen towards decreasing ctDNA levels post-treatment, with specific identification of a 'fast elimination' group who achieve undetectable ctDNA levels prior to the end of treatment and may be less likely to experience treatment failure. Residual ctDNA detection post-treatment was associated with poorer patient prognosis. This systematic review identifies the broad potential of ctDNA as a useful and decisive tool in the management of SCCA. Further analysis of ctDNA biomarkers that include larger patient cohorts is required in order to clearly evaluate their potential role in clinical decision-making processes.

Current updates on precision therapy for breast cancer associated brain metastasis: Emphasis on combination therapy.

Cancer therapies have undergone a tremendous progress over the past decade. Precision medicine provides a more tailored approach, making the combination of existing therapies more precise. Different types of cancers are characterized by unique biomarkers that are targeted using various genomic approaches by clinicians and companies worldwide to achieve efficient treatment with minimal side effects. Precision medicine has two broad approaches namely stratified and personalized medicine. The driver mutations could vary within a subtype while the same driver mutations could be found across different subtypes. Precision medicine has recently gained a lot of importance for breast cancer therapy. Various kinds of mutations like hotspot mutations, gene alterations, gene amplification mutations are targeted to design a more specific therapy. Apart from these known gene mutations there are various unknown mutations. Thus, tumor heterogeneity can pose a challenge to precision medicine. For breast cancer, one of the most successful models developed in case of precision medicine is the anti-HER2 therapies as HER2 was considered to have the worst prognosis being highly malignant. But now due to the advent of HER2 receptor targeted therapies, it has a good prognosis. Moreover, precision medicine helps in identifying if the drug molecules being used for the treatment of one kind of cancer can be beneficial in the treatment of another kind of cancer as well, considering the signaling pathways and machinery is similar in most of the cancers. This reduces the time for new drug development and is economically more feasible. Precision medicine will prove to be very advantageous in case of brain metastasis.

Integrative natural medicine inspired graphene nanovehicle-benzoxazine derivatives as potent therapy for cancer.

Natural products from medicinal plants have always attracted a lot of attention due to their diverse and interesting therapeutic properties. We have employed the principles of green chemistry involving isomerization, coupling and condensation reaction to synthesize a class of compounds derived from eugenol, a naturally occurring bioactive phytophenol. The compounds were characterized structurally by 1H-, 13C-NMR, FT-IR spectroscopy and mass spectrometry analysis. The purity of compounds was detected by HPLC. The synthesized compounds exhibited anti-cancer activity. A 10-12-fold enhancement in efficiency of drug molecules (~ 1 µM) was observed when delivered with graphene oxide (GO) as a nanovehicle. Our data suggest cell death via apoptosis in a dose-dependent manner due to increase in calcium levels in specific cancer cell lines. Interestingly, the benzoxazine derivatives of eugenol with GO nanoparticle exhibited enhanced therapeutic potential in cancer cells. In addition to anti-cancer effect, we also observed significant role of these derivatives on parasite suggesting its multi-pharmacological capability.

Murine models of osteosarcoma: A piece of the translational puzzle.

Osteosarcoma (OS) is the most common cancer of bone in children and young adults. Despite extensive research efforts, there has been no significant improvement in patient outcome for many years. An improved understanding of the biology of this cancer and how genes frequently mutated contribute to OS may help improve outcomes for patients. While our knowledge of the mutational burden of OS is approaching saturation, our understanding of how these mutations contribute to OS initiation and maintenance is less clear. Murine models of OS have now been demonstrated to be highly valid recapitulations of human OS. These models were originally based on the frequent disruption of p53 and Rb in familial OS syndromes, which are also common mutations in sporadic OS. They have been applied to significantly improve our understanding about the functions of recurrently mutated genes in disease. The murine models can be used as a platform for preclinical testing and identifying new therapeutic targets, in addition to testing the role of additional mutations in vivo. Most recently these models have begun to be used for discovery based approaches and screens, which hold significant promise in furthering our understanding of the genetic and therapeutic sensitivities of OS. In this review, we discuss the mouse models of OS that have been reported in the last 3-5 years and newly identified pathways from these studies. Finally, we discuss the preclinical utilization of the mouse models of OS for identifying and validating actionable targets to improve patient outcome.

Dendritic cell engineering for selective targeting of female reproductive tract cancers.

Female reproductive tract cancers (FRCs) are considered as one of the most frequently occurring malignancies and a foremost cause of death among women. The late-stage diagnosis and limited clinical effectiveness of currently available mainstay therapies, primarily due to the developed drug resistance properties of tumour cells, further increase disease severity. In the past decade, dendritic cell (DC)-based immunotherapy has shown remarkable success and appeared as a feasible therapeutic alternative to treat several malignancies, including FRCs. Importantly, the clinical efficacy of this therapy is shown to be restricted by the established immunosuppressive tumour microenvironment. However, combining nanoengineered approaches can significantly assist DCs to overcome this tumour-induced immune tolerance. The prolonged release of nanoencapsulated tumour antigens helps improve the ability of DC-based therapeutics to selectively target and remove residual tumour cells. Incorporation of surface ligands and co-adjuvants may further aid DC targeting (in vivo) to overcome the issues associated with the short DC lifespan, immunosuppression and imprecise uptake. We herein briefly discuss the necessity and progress of DC-based therapeutics in FRCs. The review also sheds lights on the future challenges to design and develop clinically effective nanoparticles-DC combinations that can induce efficient anti-tumour immune responses and prolong patients' survival.

The prognostic utility of the transcription factor SRF in docetaxel-resistant prostate cancer: in-vitro discovery and in-vivo validation.

BACKGROUND: Docetaxel based therapy is one of the first line chemotherapeutic agents for the treatment of metastatic castrate-resistant prostate cancer. However, one of the major obstacles in the treatment of these patients is docetaxel-resistance. Defining the mechanisms of resistance so as to inform subsequent treatment options and combinations represents a challenge for clinicians and scientists. Previous work by our group has shown complex changes in pro and anti-apoptotic proteins in the development of resistance to docetaxel. Targeting these changes individually does not significantly impact on the resistant phenotype but understanding the central signalling pathways and transcription factors (TFs) which control these could represent a more appropriate therapeutic targeting approach. METHODS: Using a number of docetaxel-resistant sublines of PC-3 cells, we have undertaken a transcriptomic analysis by expression microarray using the Affymetrix Human Gene 1.0 ST Array and in conjunction with bioinformatic analyses undertook to predict dysregulated TFs in docetaxel resistant prostate cancer. The clinical significance of this prediction was ascertained by performing immunohistochemical (IHC) analysis of an identified TF (SRF) in the metastatic sites from men who died of advanced CRPC. Investigation of the functional role of SRF was examined by manipulating SRF using SiRNA in a docetaxel-resistant PC-3 cell line model. RESULTS: The transcription factors identified include serum response factor (SRF), nuclear factor kappa-B (NFκB), heat shock factor protein 1 (HSF1), testicular receptor 2 & 4 (TR2 &4), vitamin-D and retinoid x receptor (VDR-RXR) and oestrogen-receptor 1 (ESR1), which are predicted to be responsible for the differential gene expression observed in docetaxel-resistance. IHC analysis to quantify nuclear expression of the identified TF SRF correlates with both survival from date of bone metastasis (p = 0.003), survival from androgen independence (p = 0.00002), and overall survival from prostate cancer (p = 0.0044). Functional knockdown of SRF by siRNA demonstrated a reversal of apoptotic resistance to docetaxel treatment in the docetaxel-resistant PC-3 cell line model. CONCLUSIONS: Our results suggest that SRF could aid in treatment stratification of prostate cancer, and may also represent a therapeutic target in the treatment of men afflicted with advanced prostate cancer.

The Dawning of Translational Breast Cancer: From Bench to Bedside.

Breast cancer is one of the world's leading causes of death in women. Although tumor initiation and progression are predominantly driven by somatic or acquired (epi) genetic alterations that govern signaling abnormalities, growing evidence suggests that the inflammatory microenvironments of cancer also play a role. Molecular characterization of breast cancer biology is essential for high-efficient management of this disease in clinical practice. Translating basic research into clinically valuable biomarkers for diagnosis, prognosis, and prediction of response to treatment and into precisely targeted therapies is crucial for the development of precision medicine in breast cancer. Such a process is known as "from bench to bedside." In this chapter, we will present an overview of breast cancer pathogenesis and selected translational advances in multistage clinical settings and aim to illustrate the dawning of precision medicine implementation in managing human breast malignancies.

Nanomedicine applied to translational oncology: A future perspective on cancer treatment.

The high global incidence of cancer is associated with high rates of mortality and morbidity worldwide. By taking advantage of the properties of matter at the nanoscale, nanomedicine promises to develop innovative drugs with greater efficacy and less side effects than standard therapies. Here, we discuss both clinically available anti-cancer nanomedicines and those en route to future clinical application. The properties, therapeutic value, advantages and limitations of these nanomedicine products are highlighted, with a focus on their increased performance versus conventional molecular anticancer therapies. The main regulatory challenges toward the translation of innovative, clinically effective nanotherapeutics are discussed, with a view to improving current approaches to the clinical management of cancer. Ultimately, it becomes clear that the critical steps for clinical translation of nanotherapeutics require further interdisciplinary and international effort, where the whole stakeholder community is involved from bench to bedside. From the Clinical Editor: Cancer is a leading cause of mortality worldwide and finding a cure remains the holy-grail for many researchers and clinicians. The advance in nanotechnology has enabled novel strategies to develop in terms of cancer diagnosis and therapy. In this concise review article, the authors described current capabilities in this field and outlined comparisons with existing drugs. The difficulties in bringing new drugs to the clinics were also discussed.

Cell cycle deregulation by methyl isocyanate: Implications in liver carcinogenesis.

Liver is often exposed to plethora of chemical toxins. Owing to its profound physiological role and central function in metabolism and homeostasis, pertinent succession of cell cycle in liver epithelial cells is of prime importance to maintain cellular proliferation. Although recent evidence has displayed a strong association between exposures to methyl isocyanate (MIC), one of the most toxic isocyanates, and neoplastic transformation, molecular characterization of the longitudinal effects of MIC on cell cycle regulation has never been performed. Here, we sequentially delineated the status of different proteins arbitrating the deregulation of cell cycle in liver epithelial cells treated with MIC. Our data reaffirms the oncogenic capability of MIC with elevated DNA damage response proteins pATM and γ-H2AX, deregulation of DNA damage check point genes CHK1 and CHK2, altered expression of p53 and p21 proteins involved in cell cycle arrest with perturbation in GADD-45 expression in the treated cells. Further, alterations in cyclin A, cyclin E, CDK2 levels along with overexpression of mitotic spindle checkpoints proteins Aurora A/B, centrosomal pericentrin protein, chromosomal aberrations, and loss of Pot1a was observed. Thus, MIC impacts key proteins involved in cell cycle regulation to trigger genomic instability as a possible mechanism of developmental basis of liver carcinogenesis.

The Genomic, Transcriptomic, and Immunologic Landscape of HRAS Mutations in Solid Tumors.

Tipifarnib is the only targeted therapy breakthrough for HRAS-mutant (HRASmt) recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). The molecular profiles of HRASmt cancers are difficult to explore given the low frequency of HRASmt. This study aims to understand the molecular co-alterations, immune profiles, and clinical outcomes of 524 HRASmt solid tumors including urothelial carcinoma (UC), breast cancer (BC), non-small-cell lung cancer (NSCLC), melanoma, and HNSCC. HRASmt was most common in UC (3.0%), followed by HNSCC (2.82%), melanoma (1.05%), BC (0.45%), and NSCLC (0.44%). HRASmt was absent in Her2+ BC regardless of hormone receptor status. HRASmt was more frequently associated with squamous compared to non-squamous NSCLC (60% vs. 40% in HRASwt, p = 0.002). The tumor microenvironment (TME) of HRASmt demonstrated increased M1 macrophages in triple-negative BC (TNBC), HNSCC, squamous NSCLC, and UC; increased M2 macrophages in TNBC; and increased CD8+ T-cells in HNSCC (all p < 0.05). Finally, HRASmt was associated with shorter overall survival in HNSCC (HR: 1.564, CI: 1.16-2.11, p = 0.003) but not in the other cancer types examined. In conclusion, this study provides new insights into the unique molecular profiles of HRASmt tumors that may help to identify new targets and guide future clinical trial design.

The Current Landscape of Clinical Trials for Immunotherapy in Pancreatic Cancer: A State-of-the-Art Review.

BACKGROUND: Pancreatic cancer remains a lethal malignancy with a 5-year survival rate below 6% and about 500,000 deaths annually worldwide. Pancreatic adenocarcinoma, the most prevalent form, is commonly associated with diabetes, chronic pancreatitis, obesity, and smoking, mainly affecting individuals aged 60 to 80 years. This systematic review aims to evaluate the efficacy of immunotherapeutic approaches in the treatment of pancreatic cancer. METHODS: A systematic search was conducted to identify clinical trials (Phases I-III) assessing immunotherapy in pancreatic cancer in PubMed/Medline, CINAHL, Scopus, and Web of Science, adhering to PRISMA Statement 2020 guidelines. The final search was completed on May 25, 2024. Ongoing trials were sourced from ClinicalTrials.gov and the World Health Organization's International Clinical Trials Registry Platform (ICTRP). Keywords such as "pancreatic," "immunotherapy," "cancer," and "clinical trial" were used across databases. Gray literature was excluded. RESULTS: Phase I trials, involving 337 patients, reported a median overall survival (OS) of 13.6 months (IQR: 5-62.5 months) and a median progression-free survival (PFS) of 5.1 months (IQR: 1.9-11.7 months). Phase II/III trials pooled in a total of 1463 participants had a median OS of 12.2 months (IQR: 2.5-35.55 months) and a median PFS of 8.8 months (IQR: 1.4-33.51 months). CONCLUSIONS: Immunotherapy shows potential for extending survival among pancreatic cancer patients, though results vary. The immunosuppressive nature of the tumor microenvironment and diverse patient responses underline the need for further research to optimize these therapeutic strategies.

Intraoperative Flow Cytometry for the Rapid Diagnosis and Validation of Surgical Clearance of Non-Melanoma Skin Cancer: A Prospective Clinical Feasibility Study.

Non-melanoma skin cancer (NMSC) is the most prevalent cancer in humans, with a high global incidence. We present a prospective clinical feasibility study on the use of intraoperative flow cytometry (iFC) for the instant diagnosis of NMSC and its complete surgical clearance. Flow cytometry, a laser-based technique, quantifies cell features, which has applications in cancer research. This study aim is to explore the potential applicability of iFC in detecting and characterizing NMSC and its surgical margins. In total, 30 patients who underwent diagnosis for NMSC were recruited. The method demonstrated high sensitivity (95.2%) and specificity (87.1%), with an accuracy of 91.1%, as confirmed with a receiver operating characteristic curve analysis. The results also indicated that most tumors were diploid, with two cases being hypoploid. The average G0/G1 fractions for normal and tumor tissue samples were 96.03 ± 0.30% and 88.03 ± 1.29%, respectively, with the tumor index escalating from 3.89 ± 0.30% to 11.95 ± 1.29% in cancerous cells. These findings underscore iFC's capability for precise intraoperative NMSC characterization and margin evaluation, promising enhanced complete tumor excision rates. Given the technique's successful application in various other malignancies, its implementation in NMSC diagnosis and treatment holds significant promise and warrants further research in clinical trials.

Reimbursement in the Context of Precision Oncology Approaches in Metastatic Breast Cancer: Challenges and Experiences.

Background: Precision oncology programs using next-generation sequencing to detect predictive biomarkers are extending therapeutic options for patients with metastatic breast cancer (mBC). Regularly, based on the recommendations of the interdisciplinary molecular tumor board (iMTB), an inclusion in a clinical trial is not possible. In this case, the German health insurance system allows for the application of reimbursement for an off-label drug use. Here, we describe the current challenges and our experience with reimbursement of molecular therapies in mBC. Methods: A total of 100 applications for reimbursement of off-label therapies recommended by an iMTB were filed for patients with mBC, of which 89 were evaluable for this analysis. The approval rate was correlated with the molecular level of evidence of the respective therapy according to the National Center for Tumor Diseases (NCT) and European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT) classification as well as with pretreatment therapy lines. Findings: Overall, 53.9% (48/89) of reimbursement applications were approved. Applications for therapies based on level of evidence m1 (NCT classification), tier I and II (ESCAT classification) had a significantly and clinically relevant increased chance of reimbursement, while a greater number of previous treatment lines had no significantly increased chance of approval, though a trend of approval toward higher treatment lines was detectable. Interpretation: Currently, the German jurisdiction seems to aggravate the clinical implementation of clinically urgently needed molecular therapies.

Evaluating the value of individualized 3D printed models for examination, diagnosis and treatment planning of cervical cancer.

BACKGROUND: 3D printing holds great potential of improving examination, diagnosis and treatment planning as well as interprofessional communication in the field of gynecological oncology. In the current manuscript we evaluated five individualized, patient-specific models of cervical cancer FIGO Stage I-III, created with 3D printing, concerning their value for translational oncology. METHODS: Magnetic resonance imaging (MRI) of the pelvis was performed on a 3.0 Tesla MRI, including a T2-weighted isotropic 3D sequence. The MRI images were segmented and transferred to virtual 3D models via a custom-built 3D-model generation pipeline and printed by material extrusion. The 3D models were evaluated by all medical specialties involved in patient care of cervical cancer, namely surgeons, radiologists, pathologists and radiation oncologists. Information was obtained from evaluated profession-specific questionnaires which were filled out after inspecting all five models. The questionnaires included multiple-select questions, questions based on Likert scales (1 = "strongly disagree " or "not at all useful " up to 5 = "strongly agree " or "extremely useful ") and dichotomous questions ("Yes" or "No"). RESULTS: Surgeons rated the models as useful during surgery (4.0 out of 5) and for patient communication (4.7 out of 5). Furthermore, they believed that the models had the potential to revise the patients' treatment plan (3.7 out of 5). Pathologists evaluated with mean ratings of 3.0 out of 5 for the usefulness of the models in diagnostic reporting and macroscopic evaluation. Radiologist acknowledged the possibility of providing additional information compared to imaging alone (3.7 out of 5). Radiation oncologists strongly supported the concept by rating the models highly for understanding patient-specific pathological characteristics (4.3 out of 5), assisting interprofessional communication (mean 4.3 out of 5) and communication with patients (4.7 out of 5). They also found the models useful for improving radiotherapy treatment planning (4.3 out of 5). CONCLUSION: The study revealed that the 3D printed models were generally well-received by all medical disciplines, with radiation oncologists showing particularly strong support. Addressing the concerns and tailoring the use of 3D models to the specific needs of each medical speciality will be essential for realizing their full potential in clinical practice.

Interplay Between Fatty Acids, Stearoyl-Co-A Desaturase, Mechanistic Target of Rapamycin, and Yes-Associated Protein/Transcriptional Coactivator With PDZ-Binding Motif in Promoting Hepatocellular Carcinoma.

Nonalcoholic fatty liver disease has reached pandemic proportions with one of its most consequential complications being hepatocellular carcinoma (HCC). Nonalcoholic fatty liver disease-related HCC is becoming the leading indication for liver transplantation in the United States. Given the scarcity of available organs, early detection and prevention remain key in prevention and management of the disease. Over the years, the yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) pathway emerged as a key signal transduction pathway in the pathogenesis of HCC. In this review, we explore the interplay between the YAP/TAZ pathway as a point of convergence in HCC pathogenesis. We review the evidence of how lipid reprogramming and key lipid pathways, saturated and monounsaturated fatty acids (through the rate-limiting enzyme stearoyl Co-A desaturase), the mevalonic acid pathway (the role of statins), and mechanistic target of rapamycin all play critical roles in intricate and complex networks that tightly regulate the YAP/TAZ pro-oncogenic pathway.

The challenge of making the right choice: patient avatars in the era of cancer immunotherapies.

Immunotherapies are a key therapeutic strategy to fight cancer. Diverse approaches are used to activate tumor-directed immunity and to overcome tumor immune escape. The dynamic interplay between tumor cells and their tumor(immune)microenvironment (T(I)ME) poses a major challenge to create appropriate model systems. However, those model systems are needed to gain novel insights into tumor (immune) biology and a prerequisite to accurately develop and test immunotherapeutic approaches which can be successfully translated into clinical application. Several model systems have been established and advanced into so-called patient avatars to mimic the patient´s tumor biology. All models have their advantages but also disadvantages underscoring the necessity to pay attention in defining the rationale and requirements for which the patient avatar will be used. Here, we briefly outline the current state of tumor model systems used for tumor (immune)biological analysis as well as evaluation of immunotherapeutic agents. Finally, we provide a recommendation for further development to make patient avatars a complementary tool for testing and predicting immunotherapeutic strategies for personalization of tumor therapies.

EpCAM tumor specificity and proteoform patterns in urothelial cancer.

BACKGROUND: The role of the epithelial cell adhesion molecule (EpCAM) in cancer is still unclear. EpCAM cleavage through regulated intramembrane proteolysis results in fragments which interact with both oncogenic and tumor suppressive pathways. Additionally, the EpCAM molecule itself is used as a descriptive therapeutic target in urothelial cancer (UC), while data on its actual tumor specificity remain limited. METHODS: Samples from diagnostic formalin-fixed paraffin-embedded (FFPE) UC tissue and fresh-frozen UC cells were immunoblotted and used for qualitative characterization of five different EpCAM fragments. These expression patterns were quantified across a cohort of 76 samples with 52 UC and 24 normal urothelial samples. Cell viability effects of the extracellular EpEX fragment were assessed in the UC cell lines T24 and HT1376. RESULTS: The proteolytic EpCAM fragments could be identified in clinical FFPE tissue specimens too. Neither overall nor fragment-specific EpCAM expression showed relevant tumor specificity. EpEX and its deglycosylated variant showed an inverse relationship across healthy and tumor tissue with a decrease of deglycosylated EpEX in tumors. However, extracellular EpEX did not show a relevant effect in vitro. CONCLUSIONS: EpCAM should not be regarded as tumor-specific in UC without patient-specific predictive testing. EpCAM fragment patterns indicate cancer-specific changes and could be involved in its complex tumor-biological role.