Aggressive Tumor Research Articles

Aggressive bone tumours: What a radiologist can offer to the surgeon?

The complexity of aggressive bone tumours necessitates a comprehensive approach that combines radiological assessments with clinical and pathological findings. Radiologists offer valuable insights to surgeons throughout the diagnostic and therapeutic journey, enhancing the precision and efficacy of surgical interventions. Radiologists contribute to definitive diagnosis in the majority of benign and certain aggressive tumours, although the complexity of aggressive bone tumours often requires histopathological confirmation. They assist in characterizing tumours and evaluating their extension, providing critical information for treatment planning. Radiologists guide biopsy procedures, ensuring representative tissue samples while minimizing morbidity and the risk of tumour spread. In preoperative planning, radiologists construct detailed 3D reconstructions of tumours, aiding surgeons in strategizing surgical approaches and anticipating challenges. During surgery, radiologists offer intraoperative guidance through techniques like image fusion and intraoperative MRI, enhancing surgical precision. Post-surgical surveillance for tumour recurrence heavily relies on radiological imaging, with functional MR sequences providing valuable insights. Radiologists also play a significant role in image-guided therapeutic interventions for aggressive bone tumours, offering procedures like osteoplasty and ablation techniques for pain relief and tumour control. In conclusion, radiologists are indispensable members of the multidisciplinary team and offer expertise in diagnosis, biopsy guidance, preoperative planning, intraoperative guidance, post-surgical surveillance, and interventional therapy. Their collaborative efforts significantly optimize patient's outcome and quality of life.

Primitive Resectable Small Bowel Cancer Clinical-Pathological Analysis: A 10-Year Retrospective Study in a General Surgery Unit.

Introduction: Small bowel cancer is very rare; although the incidence of adenocarcinoma and other anatomopathological forms has increased recently, the diagnosis and treatment of this disease are still debatable because of the clinical heterogeneity and the absence of studies including a large number of patients. Materials and Methods: We performed a retrospective study over 10 years in which we analyzed the clinical, imaging, and anatomopathological data of 46 patients hospitalized in a surgery clinic and diagnosed with small bowel cancer (duodenum, jejunum, and ileum). Results: After clinical assessment of these patients, including complications (occlusion, bleeding, and perforation), the CT scan established the diagnosis in over 90% of the cases of the complicated form of the disease. Surgery has a curative role in localized cancers; tumor location, local invasion, the presence of locoregional lymph nodes, and the number of multiple tumors influence the type of surgery. The conventional pathological exam was completed via immunohistochemical staining. Adjuvant oncological treatment was performed after surgery (according to the guidelines); in patients with exceptional histopathological forms, the therapy was personalized. Conclusions: Most small bowel cancers were diagnosed with complications (occlusion and bleeding); the tumor type, location, and presence of multiple bowel cancers significantly influenced its management. Independently of the surgical resection (R0/R1 or R2), the prognosis of the disease depends on the tumor aggressivity, location (single/multiple), and locoregional node invasion.

Additive Effects of Cu-ATSM and Radiation on Survival of Diffuse Intrinsic Pontine Glioma Cells.

Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive and treatment-resistant childhood primary brainstem tumors with a median survival of less than one year after diagnosis. The prevailing standard of care for DIPG, radiation therapy, does not prevent fatal disease progression, with most patients succumbing to this disease 3-8 months after completion of radiation therapy. This underscores the urgent need for novel combined-modality approaches for enhancing therapy responses. This study demonstrates that the cellular redox modulating drug, copper (II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) dose-dependently (1-3 μM) decreased clonogenic cell survival in SU-DIPG50 and SU-DIPG36 cell lines during 6 h of exposure but had no significant effect on survival in normal human astrocytes (NHA). Additional significant (>90%) decreases in DIPG clonogenic survival were observed at 24 h of Cu-ATSM exposure. However, NHAs also began to show dose-dependent 10-70% survival decreases at this point. Notably, 3 μM Cu-ATSM for 6 h resulted in additive clonogenic cell killing of DIPG lines when combined with radiation, which was not seen in NHAs and was partially inhibited by the copper chelator, bathocuproinedisulfonic acid. Cu-ATSM toxicity in DIPG cells was also inhibited by overexpression of mitochondrial-targeted catalase. These results support the hypothesis that Cu-ATSM is selectively cytotoxic to DIPGs by a mechanism involving H2O2 generation and copper and being additively cytotoxic with ionizing radiation.

The Mechanism of Action of Exosomes Derived from Glioblastoma Cells.

Glioblastoma (GBM) is a highly aggressive and lethal brain tumor characterized by rapid growth, invasive behavior, and resistance to conventional therapies, such as surgery, radiotherapy, and chemotherapy. Despite these interventions, patient survival remains poor due to the tumor's ability to recur and adapt to treatments. The function of GBM-derived exosomes (GBM-exosomes) as essential mediators in tumor growth has drawn attention in recent years. These small extracellular vesicles are involved in the transfer of a variety of molecules, including cytokines, miRNAs, proteins, and DNA, facilitating intercellular communication that promotes GBM cell proliferation, angiogenesis, immune evasion, and resistance to therapies. This review aims to provide an in- -depth examination of the mechanisms through which GBM-exosomes contribute to these pathological processes, as well as to discuss the current methodologies for isolating and characterizing GBM exosomes. Additionally, we explore the potential of exosomes as biomarkers for diagnosis and prognosis and as novel therapeutic targets in the fight against GBM. By improving our understanding of GBM-exosomes, we can pave the way for the development of more effective, personalized treatment strategies that may improve patient outcomes and quality of life.

Surgical management of skull base and spinal chordomas: A case series with comprehensive review of the literature

BackgroundChordomas are rare, slow growing, locally aggressive malignant bone tumors that arise from remnants of the embryonic notochord with variable presenting symptoms depending on tumor location. MethodsAll patients with craniospinal chordoma managed at our institution between 1982 and 2023 were retrospectively reviewed. Demographics, tumor characteristics, clinical course and treatment, and long-term neurological and survival outcomes were collected. Adjuvant radiotherapy (RT) was stratified into standard dose fractionated radiotherapy (standard XRT) for doses of 50 to 60 Gy at 1.8 Gy fractions or high dose hyperfractionated stereotactic radiotherapy (HD-FSRT) for doses of 60 to 81 Gy at 1.2-1.5 Gy fractions per treatment. Descriptive statistics, univariate analysis, Log-rank test, and Kaplan-Meier survival analysis were performed. ResultsA total of 37 patients were included in our cohort (mean age 46.0 ± 20.8 years; 22 male). Clival chordomas accounted for the majority of patients (56.8%), followed by vertebral (27%) and sacral (10.8%) chordomas. Thirty-five patients (94.6%) underwent gross total resection (GTR) or subtotal resection (STR), and 2 patients underwent excisional biopsy only. Postoperatively, functional status trended towards improvement (KPS: Preop- 80 [range 40–100] vs. Post op- 90 [60–100], p = .0911) and all patients either maintained or improved their neurological function. Median overall survival (OS) after diagnosis was 16.5 years. Age < 65, clival tumor location, post-operative Frankel grade E, and administration of adjuvant RT following initial STR significantly improved OS. OS of GTR patients was not significantly affected by adjuvant RT treatment. ConclusionsOur results show the best long-term survival outcomes for chordoma patients undergoing GTR of tumor tissue. Higher postoperative neurological function was significantly associated with OS, highlighting the importance of maximal but safe total tumor resection. Moreover, adjuvant RT improved long-term survival for patients that underwent STR but had no effect on survival outcomes for patients that underwent GTR.

VCP enhances autophagy-related osteosarcoma progression by recruiting USP2 to inhibit ubiquitination and degradation of FASN

Osteosarcoma (OS) is a highly aggressive malignant tumor with a high rate of disability and mortality rates, and dysregulated autophagy is a crucial factor in cancer. However, the molecular mechanisms that regulate autophagy in OS remain unclear. This study aimed to explore key molecules that affect autophagy in OS and their regulatory mechanisms. We found that fatty acid synthase (FASN) was significantly increased in activated autophagy models of OS and promoted OS proliferation in an autophagy-dependent manner, as detected by LC3 double-labeled fluorescence confocal microscopy, western blotting, transmission electron microscopy (TEM), and cell functional experiments. Furthermore, co-immunoprecipitation combined with mass spectrometry (Co-IP/MS), ubiquitination modification, molecular docking, and protein truncation methods were used to identify FASN-interacting proteins and analyze their effects on OS. Valosin-containing protein (VCP) enhanced the FASN stability by recruiting ubiquitin specific peptidase-2 (USP2) to remove the K48-linked ubiquitin chains from FASN; domain 2 of VCP and the amino acid sequence () of USP2 were critical for their interactions. Gain- and loss-of-function experiments showed that the inhibition of FASN or USP2 attenuated the stimulatory effect of VCP overexpression on autophagy and the malignant phenotypes of OS cells in vitro and in vivo. Notably, micro-CT indicated that VCP induced severe bone destruction in nude mice, which was abrogated by FASN or USP2 downregulation. In summary, VCP recruits USP2 to stabilize FASN by deubiquitylation, thereby activating autophagy and promoting OS progression. The identification of the VCP/USP2/FASN axis, which mediates autophagy regulation, provides important insights into the underlying mechanisms of OS and offers potential diagnostic and therapeutic strategies for patients with OS.

Expression of myoglobin by tumor cells and its role in progression of malignancy

The review examines available literature data on the expression of myoglobin in various tumors and tumor cell lines of non-muscle nature, and the effect of hypoxia, reactive oxygen and nitrogen species, hormones, growth factors, gender and age on this process. The influence of tumor myoglobin on processes occurring in cells – oxidative stress, inhibition of mitochondrial respiration by nitric oxide and fatty acid metabolism is also analyzed, both in the case of intrinsic endogenous (ectopic) expression of small amounts (~1 µM) of myoglobin and overexpression of the protein (~150 µM) via the myoglobin gene embedded in the tumour cell genome. It is concluded that hypoxia-induced intrinsic expression of low concentrations of myoglobin, due to its ability to utilise reactive oxygen and nitrogen species that can damage tumour cells, ensures their better survival, promoting tumour progression and metastasis. Accordingly, this myoglobin expression is generally associated with a more aggressive tumour type and poor prognosis for the course and outcome of the disease, and may thus serve as a “marker” of an aggressive malignancy. In contrast, artificial overexpression of myoglobin can significantly inhibit tumour development and improve disease course by switching cancer cell metabolism from tumour-specific glycolysis to oxidative phosphorylation inherent in healthy tissue. Myoglobin overexpression may thus be an effective therapeutic tool in oncology.

Desmoplastic Fibroblastoma (Collagenous Fibroma) of the Knee: A Case Report and Literature Review.

Desmoplastic fibroblastoma, also known as collagenous fibroma, is a rare benign mesenchymal neoplasm that primarily arises in the subcutaneous tissue of upper extremities and limb girdles. The knee is an uncommon location for desmoplastic fibroblastoma. Recent studies have demonstrated the presence of immunoreactivity for FOS like 1 (FOSL1) and rearrangements of FOSL1. A 70-year-old woman presented with a 1-year history of a palpable mass in the medial aspect of the right knee. Physical examination revealed a 4-cm, elastic hard, mobile, nontender mass. Magnetic resonance imaging (MRI) showed a well-defined mass with prominent low signal intensity on all pulse sequences. Contrast-enhanced MRI demonstrated mild internal enhancement with rim enhancement. After an open biopsy, the lesion was successfully treated by complete excision. Histologically, the tumor was composed of bland spindle or stellate-shaped cells embedded in an abundant collagenous stroma. Immunohistochemically, the tumor cells showed diffuse nuclear positivity for FOSL1. These findings were consistent with a diagnosis of desmoplastic fibroblastoma. The patient was asymptomatic and there was no evidence of local recurrence eight months after surgery. Desmoplastic fibroblastoma is a distinctive benign soft-tissue tumor with FOSL1 immunoreactivity and should be clearly distinguished from more biologically aggressive mesenchymal neoplasms.

Therapeutic Contribution of Tau-Binding Thiazoloflavonoid Hybrid Derivatives Against Glioblastoma Using Pharmacological Approach in 3D Spheroids.

Growing evidence has unveiled the pathological significance of Tau in many cancers, including the most aggressive and lethal brain tumor glioblastoma multiform (GBM). In this regard, we have recently examined the structure-activity relationship of a new series of seventeen 2-aminothiazole-fused to flavonoid hybrid compounds (TZF) on Tau-overexpressing GBM cells. Here, we evaluated the anticancer activities of the two lead compounds 2 and 9 using multi-cellular spheroids (MCSs) which represent an easy 3D human cell model to mimic GBM organization, physical constraints and drug penetration. The two compounds reduced cell evasion from spheroids up to three times, especially for Tau-expressing cells. As a first step towards a therapeutic approach, we quantified the effects of these compounds on MCS growth using two complementary protocols: single and repeated treatments. A single injection with compound 9 slowed down the growth of MCSs formed with U87 shCTRL cells by 40% at 10 µM. More interestingly, multiple treatment with compound 9 slowed the growth of U87 shCTRL spheroids by 40% at a concentration of 5 µM, supporting the increased bioavailability of compound 9 within MCSs. In conclusion, compound 9 deserves particular attention as promising candidate for specifically targeting Tau-expressing cancers such as GBM.

Ruta graveolens, but Not Rutin, Inhibits Survival, Migration, Invasion, and Vasculogenic Mimicry of Glioblastoma Cells.

Glioblastoma (GBM) is the most aggressive type of brain tumor, characterized by poor outcome and limited therapeutic options. During tumor progression, GBM may undergo the process of vasculogenic mimicry (VM), consisting of the formation of vascular-like structures which further promote tumor aggressiveness and malignancy. The resulting resistance to anti-angiogenetic therapies urges the identification of new compounds targeting VM. Extracts of natural plants may represent potential therapeutic tools. Among these, components of Ruta graveolens water extract (RGWE) display a wide range of biological activities. To test the effect of RGWE on human GBM and rat glioma cell line VM, tube formation on a gelled matrix was monitored. Quantitative assessment of VM formation shows the clear-cut inhibitory activity of RGWE. Unlike rutin, one of the most abundant extract components, the whole RGWE strongly reduced the migration and invasion of GBM tumor cells. Moreover, RGWE induced cell death of GBM patient-derived cancer stem cells and impaired VM at sub-lethal doses. Overall, our data reveal a marked RGWE-dependent inhibition of GBM cell survival, migration, invasion, and VM formation. Thus, the clear-cut ability of RGWE to counteract GBM malignancy deserves attention, holding the promise to bring natural products to clinical use, thus uncovering new therapeutic opportunities.

Scalp Lesion as the First Manifestation of Pancreatic Adenocarcinoma, A Very Rare Case.

Pancreatic adenocarcinoma is one of the most aggressive tumors. Its diagnosis is usually made in locally advanced or metastatic disease and survival is less than one year. The most frequent sites of metastatic involvement are the liver, peritoneum and lungs. Other organs such as the bones or the brain may be affected to a lesser extent. Cutaneous involvement of pancreatic adenocarcinoma is extremely rare with less than 150 cases reported in the literature since 1960. Most cases with cutaneous involvement involve the periumbilical region, in a lesion known as "Sister Mary Joseph's Node". Scalp metastases are very rare and their diagnosis suggests advanced disease and the prognosis will be dismal. It is very important to perform a complete physical examination and a global anamnesis to guide the request for diagnostic tests. Once the diagnosis of pancreatic adenocarcinoma has been made, a global assessment will be necessary, involving different medical specialists, nurses, psychologists and social workers among others. In many cases, supportive care is the mainstay of treatment.

Blood-brain barrier permeability increases with the differentiation of glioblastoma cells in vitro

BackgroundGlioblastoma multiforme (GBM) is an aggressive tumor, difficult to treat pharmacologically because of the blood-brain barrier (BBB), which is rich in ATP-binding cassette (ABC) transporters and tight junction (TJ) proteins. The BBB is disrupted within GBM bulk, but it is competent in brain-adjacent-to-tumor areas, where eventual GBM foci can trigger tumor relapse. How GBM cells influence the permeability of BBB is poorly investigated.MethodsTo clarify this point, we co-cultured human BBB models with 3 patient-derived GBM cells, after separating from each tumor the stem cell/neurosphere (SC/NS) and the differentiated/adherent cell (AC) components. Also, we set up cultures of BBB cells with the conditioned medium of NS or AC, enriched or depleted of IL-6. Extracellular cytokines were measured by protein arrays and ELISA. The intracellular signaling in BBB cells was measured by immunoblotting, in the presence of STAT3 pharmacological inhibitor or specific PROTAC. The competence of BBB was evaluated by permeability assays and TEER measurement.ResultsThe presence of GBM cells or their conditioned medium increased the permeability to doxorubicin, mitoxantrone and dextran-70, decreased TEER, down-regulated ABC transporters and TJ proteins at the transcriptional level. These effects were higher with AC or their medium than with NS. The secretome analysis identified IL-6 as significantly more produced by AC than by NS. Notably, AC-conditioned medium treated with an IL-6 neutralizing antibody reduced the BBB permeability to NS levels, while NS-conditioned medium enriched with IL-6 increased BBB permeability to AC levels. Mechanistically, IL-6 released by AC GBM cells activated STAT3 in BBB cells. In turn, STAT3 down-regulated ABC transporter and TJ expression, increased permeability and decreased TEER. The same effects were obtained in BBB cells treated with STA-21, a pharmacological inhibitor of STAT3, or with a PROTAC targeting STAT3.ConclusionsOur work demonstrates for the first time that the degree of GBM differentiation influences BBB permeability. The crosstalk between GBM cells that release IL-6 and BBB cells that respond by activating STAT3, controls the expression of ABC transporters and TJ proteins on BBB. These results may pave the way for novel therapeutic tools to tune BBB permeability and improve drug delivery to GBM.

Prediction of early recurrence of adult-type diffuse gliomas following radiotherapy using multi-modal magnetic resonance images.

Adult-type diffuse gliomas are among the central nervous system's most aggressive malignant primary neoplasms. Despite advancements in systemic therapies and technological improvements in radiation oncology treatment delivery, the survival outcome for these patients remains poor. Fast and accurate assessment of tumor response to oncologic treatments is crucial, as it can enable the early detection of recurrent or refractory gliomas, thereby allowing timely intervention with life-prolonging salvage therapies. Radiomics is a developing field with great potential to improve medical image interpretation. This study aims to apply a radiomics-based predictive model for classifying response to radiotherapy within the first 3 months post-treatment. Ninety-five patients were selected from the Burdenko Glioblastoma Progression Dataset. Tumor regions were delineated in the axial plane on contrast-enhanced T1(CE T1W) and T2 fluid-attenuated inversion recovery (T2_FLAIR) magnetic resonance imaging (MRI). Hand-crafted radiomic (HCR) features, including first- and second-order features, were extracted using PyRadiomics (3.7.6) in Python (3.10). Then, recursive feature elimination with a random forest (RF) classifier was applied for feature dimensionality reduction. RF and support vector machine (SVM) classifiers were built to predict treatment outcomes using the selected features. Leave-one-out cross-validation was employed to tune hyperparameters and evaluate the models. For each segmented target, 186 HCR features were extracted from the MRI sequence. Using the top-ranked radiomic features from a combination of CE T1W and T2_FLAIR, an optimized classifier achieved the highest averaged area under the curve (AUC) of 0.829±0.075 using the RF classifier. The HCR features of CE T1W produced the worst outcomes among all models (0.603±0.024 and 0.615±0.075 for RF and SVM classifiers, respectively). We developed and evaluated a radiomics-based predictive model for early tumor response to radiotherapy, demonstrating excellent performance supported by high AUC values. This model, harnessing radiomic features from multi-modal MRI, showed superior predictive performance compared to single-modal MRI approaches. These results underscore the potential of radiomics in clinical decision support for this disease process.

A Multifunctional Low-Temperature Photothermal Nanomedicine for Melanoma Treatment via the Oxidative Stress Pathway Therapy.

Melanoma is a highly aggressive and dangerous malignant skin tumor and there is an urgent need to develop effective therapeutic approaches against melanoma. The main objective of this study was to construct a multifunctional nanomedicine (GNR@PEG-Qu) to investigate its therapeutic effect on melanoma from the oxidative stress pathway. First, the nanomedicine GNR@PEG-Qu was synthesized and characterized, and its photothermal and antioxidant properties were confirmed. In addition, in vivo imaging capabilities were observed. Finally, the tumor inhibitory effects of GNR@PEG-Qu in vivo and in vitro as well as its biosafety were observed. GNR@PEG-Qu shows good photothermal and anti-oxidation properties. Following exposure to 1064 nm laser irradiation in the second near-infrared II (NIR-II) window, GNR@PEG-Qu shows anti-tumor ability through low-temperature photothermal therapy (PTT) adjuvant drug chemotherapy. GNR@PEG-Qu makes full use of the antioxidant capacity of quercetin, reduces ROS levels in melanoma, alleviates oxidative stress state, and achieves "oxidative stress avoidance" at the tumor site. Quercetin can also downregulate the expression of the heat shock protein Hsp70, which will improve the thermal sensitivity of the tumor site and enhance the efficacy of low-temperature PTT. GNR@PEG-Qu nanoagent exhibits synergistic treatment and high tumor inhibition effects, which is a promising strategy developed to achieve oxidative stress avoidance and synergistic therapy of melanoma using quercetin (Qu)-coated gold nanorod (GNR@PEG).

Deciphering the role of NcRNAs in Pancreatic Cancer immune evasion and drug resistance: a new perspective for targeted therapy.

Pancreatic cancer (PC) is a very aggressive digestive system tumor, known for its high mortality rate, low cure rate, low survival rate and poor prognosis. In particular, pancreatic ductal adenocarcinoma (PADC), which accounts for more than 90% of PC cases, has an overall 5-year survival rate of only 5%, which is an extremely critical situation. Early detection and effective treatment of PC is extremely difficult, which leads many patients to despair. In the current medical context, targeted therapy, as an important strategy for cancer treatment, is expected. However, the problems of immune escape and drug resistance in PC have become two major obstacles that are difficult to be overcome by targeted therapy. How to break through these two difficulties has become a key issue to be solved in the field of PC therapy. In recent years, non-coding RNAs (ncRNAs) have continued to heat up in the field of cancer research. NcRNAs play a pivotal role in gene regulation, cell differentiation, development, and disease processes, and their important roles in the genesis, development, and therapeutic response of PC have been gradually revealed. More importantly, ncRNAs have many advantages as therapeutic targets, such as high specificity and low side effects, making them a new favorite in the field of PC therapy. Therefore, the aim of this paper is to provide new ideas and methods for the targeted therapy of PC by reviewing the mechanism of action of four major ncRNAs (circRNAs, lncRNAs, miRNAs, siRNAs) in both immune escape and drug resistance of PC. It is expected that an effective way to overcome immune escape and drug resistance can be found through in-depth study of ncRNA, bringing a ray of hope to PC patients.

Measurable progression of giant cell tumour of bone associated with pregnancy - A tertiary sarcoma centre analysis

IntroductionGiant cell tumour of bone (GCTB) is a benign but locally aggressive bone tumour with a higher predilection for females of reproductive age. GCTB management poses a unique set of challenges during pregnancy due to risks associated with imaging and treatment options. Pregnancy has been implicated in GCTB progression and tumour recurrence, however an exact mechanism has not been established. This study aims to confirm the relationship between the diagnosis and progression of GCTB during pregnancy. MethodsA 17-year retrospective analysis of our tertiary sarcoma referral centre database was performed to identify the relevant patients. Pregnancy-associated tumours were defined by those already present or diagnosed during pregnancy, and up to 12 months postpartum. Lesion volume was determined by mathematical ellipsoidal modelling technique to simplify the estimation, with cross-sectional measurements obtained from the three standard orthogonal planes on initial and surveillance imaging. Due to logistical challenges, follow-up imaging was performed at either our tertiary sarcoma centre or under guidance at regional imaging centres convenient to the patient. ResultsThe diagnosis of GCTB was made in 113 female patients during this 17-year period, of which 20 were associated with pregnancy with a mean age of 28.8 years (range 19–40 years). 12 patients had their primary or recurrent GCTB diagnosed, or known tumour progress during pregnancy, whilst the remaining 8 were diagnosed shortly thereafter to within 12 months postpartum. The most common tumour sites were located around the knee (30 %) and distal radius (25 %). A statistically significant pattern of growth was observed through the surveillance period (p 0.018), within a relatively short mean follow-up period of only 89.8 days (SD 54.5; 13–192 days). ConclusionThis study demonstrates the significant association that pregnancy has with the growth and progression of both primary and recurrent GCTB. Pregnant patients should be subject to close surveillance well into the postpartum period due to possible accelerated disease progression and potential for disease recurrence.

CRISPR targeting of mmu-miR-21a through a single adeno-associated virus vector prolongs survival of glioblastoma-bearing mice

Glioblastoma (GB), the most aggressive tumor of the central nervous system (CNS), has poor patient outcomes with limited effective treatments available. MicroRNA-21 (miR-21(a)) is a known oncogene, abundantly expressed in many cancer types. MiR-21(a) promotes GB progression, and lack of miR-21(a) reduces the tumorigenic potential. Here, we propose a single adeno-associated virus (AAV) vector strategy targeting mmu-miR-21a using the Staphylococcus aureus Cas9 ortholog (SaCas9) guided by a single-guide RNA (sgRNA). Our results demonstrate that AAV8 is a well-suited AAV serotype to express SaCas9-KKH/sgRNA at the tumor site in an orthotopic GB model. The SaCas9-KKH induced a genomic deletion, resulting in lowered mmu-miR-21a levels in the brain, leading to reduced tumor growth and improved overall survival. In this study, we demonstrated that disruption of genomic mmu-miR-21a with a single AAV vector influenced glioma development resulting in beneficial anti-tumor outcomes in GB-bearing mice.

Disabled 2 (Dab2) Regulates Tumour Progression in Skin Squamous Cell Carcinoma.

Dab2 is an endocytic adaptor protein involved in various physiological processes and signaling pathways. Dab2 is deregulated in various cancers; however, its role in skin squamous cell carcinoma ( SCC) has not been elucidated yet. In the present study, we used the DMBA/TPA induced murine skin carcinogenesis model to examine the role of Dab2 in skin tumour progression. We generated tamoxifen inducible Dab2 conditional knockout system for our study. Loss of Dab2 led to delayed papilloma initiation and reduced papilloma burden. Delayed papilloma initiation was due to reduce proliferative potential of the papillomas due to Dab2 loss. Furthermore, while the WT papillomas progressed to SCC, the papillomas formed in Dab2 cKO mice failed to undergo malignant conversion to SCC. Dab2 cKO tumours showed reduced expression of K8, a marker for aggressive tumour. Moreover, Dab2 ckO tumours failed to undergo EMT as shown by reduced expression of Vimentin and Twist1. Dab2 cKO tumours also showed reduced expression of Sox2, a stem cell marker. Furthermore, qPCR analysis showed upregulation of Dab2 expression in the human skin cancer cell lines as compared to normal human skin keratinocytes. In patients, TCGA data analysis of skin cancer melanoma (SKCM) showed a trend where high levels of Dab2 correlated with poor overall survival. The present study shows that Dab2 promotes tumour progression in skin SCC.

Tumor architecture and emergence of strong genetic alterations are bottlenecks for clonal evolution in primary prostate cancer

Prostate cancer (PCA) exhibits high levels of intratumoral heterogeneity. In this study, we developed a mathematical model to study the growth and genetic evolution of PCA. We explored the possible evolutionary patterns and demonstrated that tumor architecture represents a major bottleneck for divergent clonal evolution. Early consecutive acquisition of strong genetic alterations serves as a proxy for the formation of aggressive tumors. A limited number of clonal hierarchy patterns were identified. A biopsy study of synthetic tumors shows complex spatial intermixing of clones and delineates the importance of biopsy extent. Deep whole-exome multiregional next-generation DNA sequencing of the primary tumors from five patients was performed to validate the results, supporting our main findings from mathematical modeling. In conclusion, our model provides qualitatively realistic predictions of PCA genomic evolution, closely aligned with the evidence available from patient samples. We share the code of the model for further studies. A record of this paper's transparent peer review process is included in the supplemental information.

A luminal non-coding RNA-based genomic classifier confirms favourable outcomes in patients with clinically organ-confined bladder cancer treated with radical cystectomy.

To further evaluate a genomic classifier (GC) in a cohort of patients undergoing radical cystectomy (RC), as long non-coding RNA (lncRNA)-based genomic profiling has suggested utility in identifying a distinct tumour subgroup corresponding to a favourable prognosis in patients with bladder cancer. Transcriptome-wide expression profiling using Decipher Bladder was performed on transurethral resection of bladder tumour samples from a cohort of patients with high-grade, clinically organ-confined (cTa-T2N0M0) urothelial carcinoma (UC) who subsequently underwent RC without any neoadjuvant therapy (n = 226). The lncRNA-based luminal favourable status was determined using a previously developed GC. The primary endpoint was overall survival (OS) after RC. Secondary endpoints included cancer-specific mortality and upstaging at RC. In the study, 134 patients were clinical non-muscle-invasive bladder cancer (cTa/Tis/T1) and 92 patients were cT2. We identified 60 patients with luminal favourable subtype, all of which showed robust gene expression patterns associated with less aggressive bladder cancer biology. On multivariate analysis, patients with the luminal favourable subtype (vs without) were significantly associated with lower odds of upstaging to pathological (p)T3+ disease (odds ratio [OR] 0.32, 95% confidence interval [CI] 0.12-0.82; P = 0.02), any upstaging (OR 0.41, 95% CI 0.20-0.83; P = 0.01), and any upstaging and/or pN+ (OR 0.50, 95% CI 0.25-1.00; P = 0.05). Luminal favourable bladder cancer was significantly associated with better OS (hazard ratio 0.33, 95% CI 0.15-0.74; P = 0.007). This study validates the performance of the GC for identifying UCs with a luminal favourable subtype, harbouring less aggressive tumour biology.