Advancing Brain Research through Surface-Enhanced Raman Spectroscopy (SERS): Current Applications and Future Prospects.

Surface-enhanced Raman spectroscopy (SERS) has recently emerged as a potent analytical technique with significant potential in the field of brain research. This review explores the applications and innovations of SERS in understanding the pathophysiological basis and diagnosis of brain disorders. SERS holds significant advantages over conventional Raman spectroscopy, particularly in terms of sensitivity and stability. The integration of label-free SERS presents promising opportunities for the rapid, reliable, and non-invasive diagnosis of brain-associated diseases, particularly when combined with advanced computational methods such as machine learning. SERS has potential to deepen our understanding of brain diseases, enhancing diagnosis, monitoring, and therapeutic interventions. Such advancements could significantly enhance the accuracy of clinical diagnosis and further our understanding of brain-related processes and diseases. This review assesses the utility of SERS in diagnosing and understanding the pathophysiological basis of brain disorders such as Alzheimer's and Parkinson's diseases, stroke, and brain cancer. Recent technological advances in SERS instrumentation and techniques are discussed, including innovations in nanoparticle design, substrate materials, and imaging technologies. We also explore prospects and emerging trends, offering insights into new technologies, while also addressing various challenges and limitations associated with SERS in brain research.

Uncovering potential diagnostic and pathophysiological roles of α-synuclein and DJ-1 in melanoma.

BACKGROUND: Melanoma, the most lethal skin cancer type, occurs more frequently in Parkinson's disease (PD), and PD is more frequent in melanoma patients, suggesting disease mechanisms overlap. α-synuclein, a protein that accumulates in PD brain, and the oncogene DJ-1, which is associated with PD autosomal recessive forms, are both elevated in melanoma cells. Whether this indicates melanoma progression or constitutes a protective response remains unclear. We hereby investigated the molecular mechanisms through which α-synuclein and DJ-1 interact, suggesting novel biomarkers and targets in melanoma. METHODS: The Cancer Genome Atlas (TCGA) expression profiles derived from UCSC Xena were used to obtain α-synuclein and DJ-1 expression and correlated with survival in skin cutaneous melanoma (SKCM). Immunohistochemistry determined the expression in metastatic melanoma lymph nodes. Protein-protein interactions (PPIs) and molecular docking assessed protein binding and affinity with chemotherapeutic drugs. Further validation was performed using in vitro cellular models and ELISA immunoassays. RESULTS: α-synuclein and DJ-1 were upregulated in primary and metastatic SKCM. Aggregated α-synuclein was selectively detected in metastatic melanoma lymph nodes. α-synuclein overexpression in SK-MEL-28 cells induced the expression of DJ-1, supporting PPI and a positive correlation in melanoma patients. Molecular docking revealed a stable protein complex, with differential binding to chemotherapy drugs such as temozolomide, dacarbazine, and doxorubicin. Parallel reduction of both proteins in temozolomide-treated SK-MEL-28 spheroids suggests drug binding may affect protein interaction and/or stability. CONCLUSION: α-synuclein, together with DJ-1, may play a role in melanoma progression and chemosensitivity, constituting novel targets for therapeutic intervention, and possible biomarkers for melanoma.

An emerging paradigm of CXCL12 involvement in the metastatic cascade.

The chemokine CXCL12, also known as stromal cell-derived factor 1 (SDF1), has emerged as a pivotal regulator in the intricate molecular networks driving cancer progression. As an influential factor in the tumor microenvironment, CXCL12 plays a multifaceted role that spans beyond its traditional role as a chemokine inducing invasion and metastasis. Indeed, CXCL12 has been assigned functions related to epithelial-to-mesenchymal transition, cancer cell stemness, angiogenesis, and immunosuppression, all of which are currently viewed as specialized biological programs contributing to the "metastatic cascade" among other cancer hallmarks. Its interaction with its cognate receptor, CXCR4, initiates a cascade of events that not only shapes the metastatic potential of tumor cells but also defines the niches within the secondary organs that support metastatic colonization. Given the profound implications of CXCL12 in the metastatic cascade, understanding its mechanistic underpinnings is of paramount importance for the targeted elimination of rate-limiting steps in the metastatic process. This review aims to provide a comprehensive overview of the current knowledge surrounding the role of CXCL12 in cancer metastasis, especially its molecular interactions rationalizing its potential as a therapeutic target.

Glycosylation spectral signatures for glioma grade discrimination using Raman spectroscopy.

BACKGROUND: Gliomas are the most common brain tumours with the high-grade glioblastoma representing the most aggressive and lethal form. Currently, there is a lack of specific glioma biomarkers that would aid tumour subtyping and minimally invasive early diagnosis. Aberrant glycosylation is an important post-translational modification in cancer and is implicated in glioma progression. Raman spectroscopy (RS), a vibrational spectroscopic label-free technique, has already shown promise in cancer diagnostics. METHODS: RS was combined with machine learning to discriminate glioma grades. Raman spectral signatures of glycosylation patterns were used in serum samples and fixed tissue biopsy samples, as well as in single cells and spheroids. RESULTS: Glioma grades in fixed tissue patient samples and serum were discriminated with high accuracy. Discrimination between higher malignant glioma grades (III and IV) was achieved with high accuracy in tissue, serum, and cellular models using single cells and spheroids. Biomolecular changes were assigned to alterations in glycosylation corroborated by analysing glycan standards and other changes such as carotenoid antioxidant content. CONCLUSION: RS combined with machine learning could pave the way for more objective and less invasive grading of glioma patients, serving as a useful tool to facilitate glioma diagnosis and delineate biomolecular glioma progression changes.

Mucin 13 (MUC13) as a candidate biomarker for ovarian cancer detection: potential to complement CA125 in detecting non-serous subtypes.

OBJECTIVES: Ovarian cancer is the most lethal gynecological malignancy in developed countries. One of the key associations with the high mortality rate is diagnosis at late stages. This clinical limitation is primarily due to a lack of distinct symptoms and detection at the early stages. The ovarian cancer biomarker, CA125, is mainly effective for identifying serous ovarian carcinomas, leaving a gap in non-serous ovarian cancer detection. Mucin 13 (MUC13) is a transmembrane, glycosylated protein with aberrant expression in malignancies, including ovarian cancer. We explored the potential of MUC13 to complement CA125 as an ovarian cancer biomarker, by evaluating its ability to discriminate serous and non-serous subtypes of ovarian cancer at FIGO stages I-IV from benign conditions. METHODS: We used our newly developed, high sensitivity ELISA to measure MUC13 protein in a large, well-defined cohort of 389 serum samples from patients with ovarian cancer and benign conditions. RESULTS: MUC13 and CA125 serum levels were elevated in malignant compared to benign cases (p<0.0001). Receiver-operating characteristic (ROC) curve analysis showed similar area under the curve (AUC) of 0.74 (MUC13) and 0.76 (CA125). MUC13 concentrations were significantly higher in mucinous adenocarcinomas compared to benign controls (p=0.0005), with AUC of 0.80. MUC13 and CA125 showed significant elevation in early-stage cases (stage I-II) in relation to benign controls (p=0.0012 and p=0.014, respectively). CONCLUSIONS: We report the novel role of MUC13 as a serum ovarian cancer biomarker, where it could complement CA125 for detecting some subtypes of non-serous ovarian carcinoma and early-stage disease.

The diagnostic and prognostic potential of the EGFR/MUC4/MMP9 axis in glioma patients.

Glioblastoma is the most aggressive form of brain cancer, presenting poor prognosis despite current advances in treatment. There is therefore an urgent need for novel biomarkers and therapeutic targets. Interactions between mucin 4 (MUC4) and the epidermal growth factor receptor (EGFR) are involved in carcinogenesis, and may lead to matrix metalloproteinase-9 (MMP9) overexpression, exacerbating cancer cell invasiveness. In this study, the role of MUC4, MMP9, and EGFR in the progression and clinical outcome of glioma patients was investigated. Immunohistochemistry (IHC) and immunofluorescence (IF) in fixed tissue samples of glioma patients were used to evaluate the expression and localization of EGFR, MMP9, and MUC4. Kaplan-Meier survival analysis was also performed to test the prognostic utility of the proteins for glioma patients. The protein levels were assessed with enzyme-linked immunosorbent assay (ELISA) in serum of glioma patients, to further investigate their potential as non-invasive serum biomarkers. We demonstrated that MUC4 and MMP9 are both significantly upregulated during glioma progression. Moreover, MUC4 is co-expressed with MMP9 and EGFR in the proliferative microvasculature of glioblastoma, suggesting a potential role for MUC4 in microvascular proliferation and angiogenesis. The combined high expression of MUC4/MMP9, and MUC4/MMP9/EGFR was associated with poor overall survival (OS). Finally, MMP9 mean protein level was significantly higher in the serum of glioblastoma compared with grade III glioma patients, whereas MUC4 mean protein level was minimally elevated in higher glioma grades (III and IV) compared with control. Our results suggest that MUC4, along with MMP9, might account for glioblastoma progression, representing potential therapeutic targets, and suggesting the 'MUC4/MMP9/EGFR axis' may play a vital role in glioblastoma diagnostics.

Emerging Roles of Immune Cells in Cancer Development and Progression.

Immune cells are a major constituent of the tumor microenvironment, and participate in interactions with tumor cells to promote the acquisition of critical hallmarks of cancer [...].

Transcriptome profiling and proteomic validation reveals targets of the androgen receptor signaling in the BT-474 breast cancer cell line.

BACKGROUND: Accumulating evidence suggests that the androgen receptor (AR) and its endogenous ligands influence disease progression in breast cancer (BCa). However, AR-mediated changes in BCa differ among the various BCa subtypes according to their hormone receptor profile [i.e., presence/absence of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2, (HER2)]. Thus, we explored the androgen-regulated transcriptomic changes in the ER+PR+HER2+ BCa cell line, BT-474, and compared them with PR-mediated changes. METHODS: We performed RNA sequencing analysis in treated BT-474 cells with dihydrotestosterone (DHT) and progesterone. Validation of the top ten differentially androgen-regulated genes and a number of other genes found in enriched signaling pathways was performed by qRT-PCR in BT-474 and other BCa cell lines. In addition, a parallel reaction monitoring targeted proteomic approach was developed to verify selected transcripts at the protein level. RESULTS: In total 19,450 transcripts were detected, of which 224 were differentially regulated after DHT treatment. The increased expression of two well-known androgen-regulated genes, KLK2 (p < 0.05) and KLK3 (p < 0.001), confirmed the successful androgen stimulation in BT-474 cells. The transcription factor, ZBTB16, was the most highly upregulated gene, with ~ 1000-fold change (p < 0.001). Pathway enrichment analysis revealed downregulation of the DNA replication processes (p < 0.05) and upregulation of the androgen signaling and fatty acid metabolism pathways (p < 0.05). Changes related to progesterone treatment showed opposite effects in gene expression than DHT treatment. Similar expression profiles were observed among other BCa cell lines expressing high levels of AR (ZR75.1 and MBA-MB-453). The parallel reaction monitoring targeted proteomic analysis further confirmed that altered protein expression (KLK3, ALOX15B) in the supernatant and cell lysate of DHT-treated BT-474 cells, compared to control cells. DISCUSSION: Our findings suggest that AR modulates the metabolism of BT-474 cells by affecting the expression of a large number of genes and proteins. Based on further pathway analysis, we suggest that androgen receptor acts as a tumor suppressor in the BT-474 cells.

Message in the bottle: regulation of the tumor microenvironment via exosome-driven proteolysis.

Exosomes comprise a subtype of extracellular vesicles involved in cell-to-cell communication, specifically by transporting biological molecules, such as proteins and nucleic acids, to either local or more distant recipient cells, thus triggering distinct biological behaviors. Included in the exosome cargo is frequently a wide range of proteolytic enzymes, such as the matrix metalloproteinases (MMPs), the disintegrin and metalloproteinases (ADAMs), and the ADAM with thrombospondin-like motifs (ADAMTSs), whose functions contribute to the development and progression of cancer. In recent years, extensive research on the potential use of exosomes in diagnostic and therapeutic applications for personalized medicine has emerged, but the targeting of the proteolytic cargo of exosomes has not been fully exploited in this direction. In this review, we aim to explore both the mechanistic and the translational importance of proteolytic enzymes carried by the tumor cell-derived exosomes, as well as their role in the acquisition and support of certain hallmarks of cancer.

Systems biology reveals key tissue-specific metabolic and transcriptional signatures involved in the response of Medicago truncatula plant genotypes to salt stress.

Salt stress is an important factor limiting plant productivity by affecting plant physiology and metabolism. To explore salt tolerance adaptive mechanisms in the model legume Medicago truncatula, we used three genotypes with differential salt-sensitivity: TN6.18 (highly sensitive), Jemalong A17 (moderately sensitive), and TN1.11 (tolerant). Cellular damage was monitored in roots and leaves 48 h after 200 mM NaCl treatment by measuring lipid peroxidation, nitric oxide, and hydrogen peroxide contents, further supported by leaf stomatal conductance and chlorophyll readings. The salt-tolerant genotype TN1.11 displayed the lowest level of oxidative damage, in contrast to the salt sensitive TN6.18, which showed the highest responses. Metabolite profiling was employed to explore the differential genotype-related responses to stress at the molecular level. The metabolic data in the salt tolerant TN1.11 roots revealed an accumulation of metabolites related to the raffinose pathway. To further investigate the sensitivity to salinity, global transcriptomic profiling using microarray analysis was carried out on the salt-stressed sensitive genotypes. In TN6.18, the transcriptomic analysis identified a lower expression of many genes related to stress signalling, not previously linked to salinity, and corresponding to the TIR-NBS-LRR gene class. Overall, this global approach contributes to gaining significant new insights into the complexity of stress adaptive mechanisms and to the identification of potential targets for crop improvement.

The Cancer Cell Dissemination Machinery as an Immunosuppressive Niche: A New Obstacle Towards the Era of Cancer Immunotherapy.

Although cancer immunotherapy has resulted in unpreceded survival benefits to subsets of oncology patients, accumulating evidence from preclinical animal models suggests that the immunosuppressive tumor microenvironment remains a detrimental factor limiting benefit for many patient subgroups. Recent efforts on lymphocyte-mediated immunotherapies are primarily focused on eliminating cancer foci at primary and metastatic sites, but few studies have investigated the impact of these therapies on the highly complex process of cancer cell dissemination. The metastatic cascade involves the directional streaming of invasive/migratory tumor cells toward specialized blood vessel intravasation gateways, called TMEM doorways, to the peripheral circulation. Importantly, this process occurs under the auspices of a specialized tumor microenvironment, herewith referred to as "Dissemination Trajectory", which is supported by an ample array of tumor-associated macrophages (TAMs), skewed towards an M2-like polarization spectrum, and which is also vital for providing microenvironmental cues for cancer cell invasion, migration and stemness. Based on pre-existing evidence from preclinical animal models, this article outlines the hypothesis that dissemination trajectories do not only support the metastatic cascade, but also embody immunosuppressive niches, capable of providing transient and localized immunosubversion cues to the migratory/invasive cancer cell subpopulation while in the act of departing from a primary tumor. So long as these dissemination trajectories function as "immune deserts", the migratory tumor cell subpopulation remains efficient in evading immunological destruction and seeding metastatic sites, despite administration of cancer immunotherapy and/or other cytotoxic treatments. A deeper understanding of the molecular and cellular composition, as well as the signaling circuitries governing the function of these dissemination trajectories will further our overall understanding on TAM-mediated immunosuppression and will be paramount for the development of new therapeutic strategies for the advancement of optimal cancer chemotherapies, immunotherapies, and targeted therapies.

Involvement of Polyamine Metabolism in the Response of Medicago truncatula Genotypes to Salt Stress.

Salinity constitutes one of the most important causes leading to severe reduction in plant yield. Several reports correlate the accumulation of polyamines in plants with tolerance to abiotic stress cues. The present study examined three Medicago truncatula genotypes with differing sensitivities to salinity (TN1.11, tolerant; Jemalong A17, moderately sensitive; TN6.18, sensitive), with the aim of examining the genotype-specific involvement of the polyamine metabolic pathway in plant response to salinity. The study was carried out with leaves harvested 48 h after watering plants with 200 mM NaCl. A comprehensive profile of free polyamines was determined using high performance liquid chromatography. All genotypes showed spermidine and spermine as the most abundant polyamines under control conditions. In salinity conditions, spermine levels increased at the expense of putrescine and spermidine, indicating a drift of polyamine metabolism towards the synthesis of increasing polycationic forms as a stress response. The increasing balance between high and low polycationic forms was clearly diminished in the salt-sensitive genotype TN6.18, showing a clear correlation with its sensitive phenotype. The polyamine metabolic profile was then supported by molecular evidence through the examination of polyamine metabolism transcript levels by RT-qPCR. General suppression of genes that are involved upstream in the PA biosynthetic pathway was determined. Contrarily, an induction in the expression of genes involved in the biosynthesis of spermine and spermidine was observed, in agreement with the metabolic analysis. A significant induction in diamino oxidase expression, involved in the catabolism of putrescine, was specifically found in the sensitive genotype ΤΝ6.18, indicating a distinct metabolic response to stress. Present findings highlight the involvement of polyamines in the defense response of Medicago genotypes showing sensitivity to salt stress.

Cancer and Parkinson's Disease: Common Targets, Emerging Hopes.

Cancer and neurodegeneration are two major leading causes of morbidity and death worldwide. At first sight, the two fields do not seem to share much in common and, if anything, might be placed on opposite ends of a spectrum. Although neurodegeneration results in excessive neuronal cell death, cancer emerges from increased proliferation and resistance to cell death. Therefore, one might expect significant differences in the underlying pathophysiological mechanisms. However, the more we deepen our understanding of these two types of diseases, the more we appreciate the unexpected overlap between them. Although most epidemiological studies support an inverse association between the risk for development of neurodegenerative diseases and cancer, increasing evidence points to a positive correlation between specific types of cancer, like melanoma, and neurodegenerative diseases, like Parkinson's disease (PD). We believe that deciphering the molecular processes and pathways underlying one of these diseases may significantly increase our understanding about the other. Therefore, the identification of novel biomarkers and therapeutic approaches in cancer, may lead to improved diagnosis and treatment of neurodegeneration, and vice versa. In this Viewpoint, we summarize recent findings connecting both diseases and speculate that insights from one disease may inform on mechanisms, and help identify novel biomarkers and targets for intervention, possibly leading to improved management of both diseases. © 2020 International Parkinson and Movement Disorder Society.

Extracellular proteolysis in glioblastoma progression and therapeutics.

Gliomas encompass highly invasive primary central nervous system (CNS) tumours of glial cell origin with an often-poor clinical prognosis. Of all gliomas, glioblastoma is the most aggressive form of primary brain cancer. Current treatments in glioblastoma are insufficient due to the invasive nature of brain tumour cells, which typically results in local tumour recurrence following treatment. The latter represents the most important cause of mortality in glioblastoma and underscores the necessity for an in-depth understanding of the underlying mechanisms. Interestingly, increased synthesis and secretion of several proteolytic enzymes within the tumour microenvironment, such as matrix metalloproteinases, lysosomal proteases, cathepsins and kallikreins for extracellular-matrix component degradation may play a major role in the aforementioned glioblastoma invasion mechanisms. These proteolytic networks are key players in establishing and maintaining a tumour microenvironment that promotes tumour cell survival, proliferation, and migration. Indeed, the targeted inhibition of these proteolytic enzymes has been a promisingly useful therapeutic strategy for glioblastoma management in both preclinical and clinical development. We hereby summarize current advances on the biology of the glioblastoma tumour microenvironment, with a particular emphasis on the role of proteolytic enzyme families in glioblastoma invasion and progression, as well as on their subsequent prognostic value as biomarkers and their therapeutic targeting in the era of precision medicine.

The Contribution of Race to Breast Tumor Microenvironment Composition and Disease Progression.

Breast cancer is the second most commonly diagnosed cancer in American women following skin cancer. Despite overall decrease in breast cancer mortality due to advances in treatment and earlier screening, black patients continue to have 40% higher risk of breast cancer related death compared to white patients. This disparity in outcome persists even when controlled for access to care and stage at presentation and has been attributed to differences in tumor subtypes or gene expression profiles. There is emerging evidence that the tumor microenvironment (TME) may contribute to the racial disparities in outcome as well. Here, we provide a comprehensive review of current literature available regarding race-dependent differences in the TME. Notably, black patients tend to have a higher density of pro-tumorigenic immune cells (e.g., M2 macrophages, regulatory T cells) and microvasculature. Although immune cells are classically thought to be anti-tumorigenic, increase in M2 macrophages and angiogenesis may lead to a paradoxical increase in metastasis by forming doorways of tumor cell intravasation called tumor microenvironment of metastasis (TMEM). Furthermore, black patients also have higher serum levels of inflammatory cytokines, which provide a positive feedback loop in creating a pro-metastatic TME. Lastly, we propose that the higher density of immune cells and angiogenesis observed in the TME of black patients may be a result of evolutionary selection for a more robust immune response in patients of African geographic ancestry. Better understanding of race-dependent differences in the TME will aid in overcoming the racial disparity in breast cancer mortality.

Liraglutide: New Perspectives for the Treatment of Polycystic Ovary Syndrome.

Polycystic ovary syndrome is a complex and heterogenous disorder involving multiple organ systems and different molecular pathways. It is tightly associated with obesity and especially abdominal obesity. As body weight reduction is the main modifiable risk factor for polycystic ovary syndrome, therapeutic approaches in overweight or obese women with polycystic ovary syndrome have been developed. Liraglutide is a glucagon-like peptide-1 receptor agonist that promotes sustained weight loss, as well as abdominal fat reduction, in individuals with obesity, prediabetes, and type 2 diabetes mellitus. The majority of current clinical studies have demonstrated that liraglutide therapy achieved significant reductions in body weight, body mass index, and abdominal circumference in overweight and obese women with polycystic ovary syndrome. Liraglutide therapy promoted significant improvements in free testosterone and sex hormone-binding globulin levels in some studies. Important metabolic and hormonal improvements were also reported after the combination of liraglutide with metformin. Increased menstrual frequency, as well as potential positive effects in reproduction, were described. However, the small number of participants, short duration, and low daily liraglutide dose are some of the main limitations of these studies. Larger and longer, multi-centred, double-blind, placebo-controlled trials of liraglutide monotherapy or combination therapy, with prolonged post-interventional monitoring, are crucially anticipated. Metabolic, hormonal, and reproductive primary outcomes should be uniformly addressed, to tailor future targeted treatment approaches, according to the patient phenotype and needs. This will improve long-term therapeutic outcomes in this population.

Kallikrein-related peptidases protein expression in lymphoid tissues suggests potential implications in immune response.

OBJECTIVES: Kallikrein-related peptidases (KLKs) are a subgroup of 15 secreted chymotrypsin- and trypsin-like serine proteases that have been reported to possess novel functions in innate immunity and inflammation. Since the potential role of KLKs in immunity has not been studied in detail at the protein level, we examined the expression pattern of 12 members of the KLK family in immune-related tissues. DESIGN & METHODS: Protein expression in tissue extracts was evaluated using immunoassays (ELISA). Immunohistochemistry (IHC) was performed on representative sections of tonsil and lymph nodes to determine the cellular localization of the KLK family members. RESULTS: ELISA profiling of KLK3-KLK15 (except KLK12) revealed higher protein levels in the tonsil, compared to the lymph nodes and spleen. Relatively high protein levels in the tonsil were observed for KLK7, KLK9, KLK10 and KLK13. Expression of these KLKs was significantly lower in lymph nodes and spleen. IHC analysis in tonsil unveiled that KLK9 and KLK10 were differentially expressed in lymphoid cells. KLK9 was strongly expressed in the germinal center of lymphoid follicles where activated B-cells reside, whereas KLK10 was expressed in the follicular dendritic cells (FDCs) that are vital for maintaining the cycle of B cell maturation. CONCLUSION: Overall, our study revealed the possible implications of KLK expression and regulation in the immune cells of lymphoid tissues.

Midkine (MDK) growth factor: a key player in cancer progression and a promising therapeutic target.

Midkine is a heparin-binding growth factor, originally reported as the product of a retinoic acid-responsive gene during embryogenesis, but currently viewed as a multifaceted factor contributing to both normal tissue homeostasis and disease development. Midkine is abnormally expressed at high levels in various human malignancies and acts as a mediator for the acquisition of critical hallmarks of cancer, including cell growth, survival, metastasis, migration, and angiogenesis. Several studies have investigated the role of midkine as a cancer biomarker for the detection, prognosis, and management of cancer, as well as for monitoring the response to cancer treatment. Moreover, several efforts are also being made to elucidate its underlying mechanisms in therapeutic resistance and immunomodulation within the tumor microenvironment. We hereby summarize the current knowledge on midkine expression and function in cancer development and progression, and highlight its promising potential as a cancer biomarker and as a future therapeutic target in personalized cancer medicine.