Barrett's esophagus (BE) is a premalignant lesion that can lead to an invasive esophageal adenocarcinoma (EAC), a type of cancer that usually has a poor outcome. We have previously described a set of four microRNAs (miR-...Barrett's esophagus (BE) is a premalignant lesion that can lead to an invasive esophageal adenocarcinoma (EAC), a type of cancer that usually has a poor outcome. We have previously described a set of four microRNAs (miR-192, 194, 196a and b) that are markers of the disease's progression. To determine whether these miRNAs might also be drivers of invasive EAC development, their overexpression in EAC cells was analyzed. Only the overexpression of miR-196a and miR-196b induced a phenotype switch in non-invasive EAC cells, resembling epithelial-to-mesenchymal transition (EMT). The overexpression of miR-196a promoted EMT and increased cell motility and NFκB signaling. Mechanistically, miR-196a targets the inhibitor of NFκB alpha NFKBIa and also leads to c-MYC protein accumulation by down-regulating VCP expression. This in turn up-regulated TERT expression and reinforced NFκB signaling. NFκB signaling, TERT, and c-MYC inhibition resulted in a reversed-EMT phenotype, with decreased EMT hallmarks and cell motility in miR-196a overexpressing cells. Finally, an immunohistochemical analysis of BE tissue samples showed that c-MYC, TERT, and NFκB signaling increased in BE patients who developed EAC, more so than in patients that did not. The high expression of miR-196a induces aggressive features in non-invasive EAC cells. These effects are dependent on the c-MYC/TERT/NFκB signaling molecular axis. BE patients and non-invasive EAC patients with high miR-196a expression could benefit from therapeutic interventions to prevent EMT or activation of the molecular pathway described in this study.
Ercilla A, Crespo JR, Garcia-Longarte S
… +13 more, Fidalgo M, Del Palacio S, Martin-Martin N, Carlevaris O, Astobiza I, Fernández-Ruiz S, Guiu M, Bárcena L, Mendizabal I, Aransay AM, Graupera M, Gomis RR, Carracedo A
Prostate cancer is a prevalent tumor type that, despite being highly curable, progresses to metastatic disease in a fraction of patients, thus accounting for more than 350 000 annual deaths worldwide. In turn, uncovering...Prostate cancer is a prevalent tumor type that, despite being highly curable, progresses to metastatic disease in a fraction of patients, thus accounting for more than 350 000 annual deaths worldwide. In turn, uncovering the molecular insights of metastatic disease is instrumental in improving the survival rate of prostate cancer patients. By means of gene expression meta-analysis in multiple prostate cancer patient cohorts, we identified a set of genes that are differentially expressed in aggressive prostate cancer. Transcription factor 19 (TCF19) stood out as an unprecedented epithelial gene upregulated in metastatic disease, with prognostic potential and negatively associated with the activity of the androgen receptor. By combining computational and empirical approaches, our data revealed that TCF19 is required for full metastatic capacity, and its depletion influences core cancer-related processes, such as tumor growth and vascular permeability, supporting the role of this gene in the dissemination of prostate tumor cells.
Salvermoser L, Schäfer JN, Goldberg SN
… +12 more, Kazmierczak PM, Gröper MN, Linden PF, Öcal E, Burkard T, Corradini S, Ben Khaled N, Wildgruber M, Seidensticker M, Ricke J, Stechele M, Alunni-Fabbroni M
Tumor recurrence after local tumor ablation, including high dose rate brachytherapy (HDR-BT), represents a substantial challenge in hepatocellular carcinoma (HCC) treatment. This study aimed to investigate whether induce...Tumor recurrence after local tumor ablation, including high dose rate brachytherapy (HDR-BT), represents a substantial challenge in hepatocellular carcinoma (HCC) treatment. This study aimed to investigate whether induced factors that appear in patient serum after HDR-BT alter HCC growth in vitro, and whether this correlates with outcome. In total, 23 HCC patients [Barcelona clinic liver cancer (BCLC) stage A or B] were treated by HDR-BT (1 × 15 Gy) and classified as responders in case of no progression within 6 months and no diffuse systemic progression within 2 years (n = 12), or nonresponders with recurrence within 6 months and/or diffuse systemic tumor progression or extrahepatic disease within 2 years (n = 11). Patient serum was obtained at baseline and 48 h postprocedure. Two hepatoma cell lines (Huh7, HepG2) were incubated for 72 h in the presence of 20% serum. BrdU incorporation was assessed for serum incubation at baseline and 48 h post-HDR-BT. BrdU incorporation post-HDR-BT compared to baseline was significantly elevated in nonresponders compared to responders for both Huh7 and HepG2. Likewise, confirmatory Cyclin E studies revealed different induction kinetics between a subset of representative responders and nonresponders in HepG2. Time to systemic progression (TTSP) in patients with increased BrdU incorporation was significantly shorter compared to patients with decreased BrdU incorporation after serum incubation. These data indicate that poor outcome following HDR-BT is associated with increased measurable proliferation parameters of hepatoma cell lines in vitro after exposure to patient serum, offering insights into post-treatment tumor biology and a potential biomarker of clinical outcome.
Oudaert I, van den Broecke L, Aksoy O
… +11 more, Lind J, Vallet S, Van der Vreken A, Ates G, Massie A, Maes K, De Veirman K, De Bruyne E, Vanderkerken K, Podar K, Menu E
Despite significant advancements, multiple myeloma (MM) remains incurable, largely due to drug resistance. Our previous research has demonstrated that proline metabolism plays a role in MM progression and that inhibiting...Despite significant advancements, multiple myeloma (MM) remains incurable, largely due to drug resistance. Our previous research has demonstrated that proline metabolism plays a role in MM progression and that inhibiting PYCR1, the final enzyme in proline synthesis, enhances bortezomib sensitivity in MM cells. Given the high expression of PYCR1 in bone marrow stromal cells (BMSCs), we sought to investigate the effects of PYCR1 inhibition in BMSCs and its indirect influence on MM cell metabolism and viability. Culturing MM cells in conditioned medium (CM) of PYCR1-silenced BMSC significantly impaired oxidative phosphorylation and sensitised MM cells to bortezomib. Analysis of the CM secretome revealed a reduction in activin A release. Proline and activin A supplementation were able to counteract MM sensitivity to bortezomib. Combination therapy of the PYCR1 inhibitor pargyline and bortezomib reduced tumour load in a 3D model and reduced serum activin A levels in 5TGM1-bearing mice. This study demonstrates the contribution of stromal cell metabolism to MM progression. Inhibiting PYCR1 in BMSCs leads to less activin A release, limits oxidative phosphorylation in MM cells and enhances bortezomib efficacy.
Prostate cancer (PCa) is the second most lethal cancer in men in the US. African American (AA) men have twice the incidence and death rate of European American (EA) men. Advanced PCa shows increased expression and activi...Prostate cancer (PCa) is the second most lethal cancer in men in the US. African American (AA) men have twice the incidence and death rate of European American (EA) men. Advanced PCa shows increased expression and activity of the DNA damage/repair pathway enzyme, poly (ADP-ribose) polymerase 1 (PARP1). PARP1 inhibitors (PARPi) are FDA-approved for advanced PCa tumors with mutations in the homologous recombination repair (HRR) pathway. However, PARPi can provide benefit in model systems without HRR deficiencies. PARPi have distinct biochemical mechanisms, potencies, and toxicity profiles. While there is emerging evidence of differences in DNA damage/repair pathway enzyme expression between EA and AA men, PARP1 expression has not been fully explored in the context of race. This study hypothesized: (a) AA and EA PCa may respond differently to PARPi and (b) different PARPi may uniquely impact the transcriptome, irrespective of HRR status. Study results indicate a link between racial background and PARP1 expression/activity and define unique and overlapping transcriptional responses downstream of all five PARPi. These findings may lead to refined personalized recommendations for use of specific PARPi.
Rho GTPase-activating protein 29 (ARHGAP29) is an inhibitor of the Ras homolog family member A (RhoA)/Rho-associated protein kinase (ROCK) signaling pathway. Studies in non-melanoma cancer entities described that ARHGAP2...Rho GTPase-activating protein 29 (ARHGAP29) is an inhibitor of the Ras homolog family member A (RhoA)/Rho-associated protein kinase (ROCK) signaling pathway. Studies in non-melanoma cancer entities described that ARHGAP29 modulates the actin cytoskeleton, promoting tumor cell invasion. In melanoma, its function has been completely unknown. Our transcriptomic analyses revealed a strong expression of ARHGAP29 in melanoma cell lines compared to melanocytes. Therefore, we hypothesized that ARHGAP29 affects the migratory potential of melanoma cells and drives melanoma progression. By knocking down ARHGAP29, we demonstrated that it promotes a spread cell morphology through regulating the RhoA/ROCK pathway. Further investigations indicated the role of ARHGAP29 on SMAD activity. Interestingly, our data showed that ARHGAP29 expression is promoting tumor cell plasticity through a mesenchymal-like, invasive phenotype. To summarize, this study gives insights into the functional role of ARHGAP29 and its downstream signaling in melanoma. Our findings provided evidence supporting the hypothesis that ARHGAP29 is an important player in melanoma progression, a promising and novel target in melanoma treatment.
Retroelements in the human genome are silenced via multiple mechanisms, including DNA methylation, to prevent their potential mutagenic effect. Retroelement activity, demonstrated by their expression and somatic retrotra...Retroelements in the human genome are silenced via multiple mechanisms, including DNA methylation, to prevent their potential mutagenic effect. Retroelement activity, demonstrated by their expression and somatic retrotransposition events, was shown to be deregulated in multiple tumors but not yet in leukemia. We hypothesized that treatment with hypomethylating agents, commonly used in myelodysplastic syndromes and acute myeloid leukemia, could lead to increased retroelement activity and somatic retrotranspositions, thus contributing to disease progression. To address this hypothesis, we induced the expression of ORF1p protein with hypomethylating agents in DAMI and HL-60 myeloid cell lines. To study whether long-term hypomethylating agent therapy induces somatic retrotranspositions, we analyzed (i) both cell lines treated for 4 weeks, and (ii) sequential samples from 17 patients with myelodysplastic syndrome treated with hypomethylating agents. Using a sensitive next-generation sequencing (NGS)-based method, no retroelement events were identified. To conclude, we show that although hypomethylating agents induce the expression of LINE-1-encoded proteins in myeloid cell lines, de novo somatic retrotransposition events do not arise during the long-term exposure to these agents.
The discovery of tumor-associated bacteria (TAB) challenges the traditional view of tumors as sterile environments. These microbes are engaged in a complex dialog with the other components of the tumor microenvironment (...The discovery of tumor-associated bacteria (TAB) challenges the traditional view of tumors as sterile environments. These microbes are engaged in a complex dialog with the other components of the tumor microenvironment (TME), influencing immunity, metastasis, and treatment response. Yet the precise mechanisms by which TAB influence tumor biology remains incompletely understood. Deciphering the complex host-microbe interactions could unlock novel therapeutic strategies to reshape the TME and improve treatment outcomes. Here we summarize the key findings in the field, highlighting the most outstanding questions regarding bacterial sources, the roles of TAB in cancer, and their interactions with the other cellular components of the TME.
Squamous cell lung carcinoma (SqCC) is the second most common histological subtype of lung cancer. Besides tumor-initiating and promoting DNA, RNA, and epigenetic alterations, aberrant cell metabolism is a hallmark of ca...Squamous cell lung carcinoma (SqCC) is the second most common histological subtype of lung cancer. Besides tumor-initiating and promoting DNA, RNA, and epigenetic alterations, aberrant cell metabolism is a hallmark of carcinogenesis. This study aimed to identify SqCC-specific key regulators that could eventually be used as new anticancer targets. Transcriptional and metabolomic data were gathered for a cohort of resected lung cancers. SqCC-specific differentially expressed genes were integrated with metabolic data. Findings were validated in cohorts of tumors, normal specimens, and cell lines. In situ protein expression of SLC6A8 was investigated. Differential gene expression analysis identified a subset of SqCC-specific genes with metabolic functions through the Reactome database, and/or correlated to specific metabolites through GEMs models. Metabolic profiling identified seven SqCC-specific metabolites, of which increased creatine levels, in particular, matched to SqCC-specific expression of SLC6A8. Expression of the gene appeared tumor cell-associated. Elevated creatine levels and overexpression of its transporter SLC6A8 appear a distinct metabolic feature of SqCC. Considering ongoing clinical trials in other malignancies, exploring SLC6A8 inhibition in SqCC appears motivated based on a metabolic addiction hypothesis.
Breast cancer (BC) diagnostics and prognostics traditionally rely on invasive tissue biopsies, presenting limitations for large-scale screening and continuous patient monitoring. Salivary biomarkers have recently emerged...Breast cancer (BC) diagnostics and prognostics traditionally rely on invasive tissue biopsies, presenting limitations for large-scale screening and continuous patient monitoring. Salivary biomarkers have recently emerged as a compelling noninvasive and accessible alternative, offering significant potential for population-level screening and long-term monitoring of BC. In this study, we conducted a comprehensive salivary transcriptomic profiling of BC patients using high-throughput RNA sequencing. Our analysis captured a wide spectrum of RNA species, including mRNAs, lncRNAs, miRNAs, and snRNAs, highlighting their collective contributions in the molecular landscape of BC patient saliva. We identified robust human gene expression signatures that distinguish BC patients from healthy individuals. Importantly, we discovered RNA profiles that were differentially expressed relative to control samples, enabling the discrimination of noninvasive, invasive, and mixed histological types, as well as hormone receptor-positive molecular subtypes. These salivary markers showed substantial concordance with established tumor gene expression datasets, strengthening their potential relevance in clinical stratification. Furthermore, we identified subsets of salivary genes associated with nodal involvement and others linked to poor survival outcomes, highlighting their potential as prognostic indicators. A prospective follow-up analysis revealed a decline in the expression of several cancer-related salivary transcripts 1-year posttreatment, indicating that salivary RNA might also reflect treatment response over time. This study establishes a proof-of-concept for salivary RNA biomarkers as a versatile, accessible, and robust tool for BC diagnosis, prognosis, and follow-up, paving the way for innovative biomarker-driven strategies in oncology.
Colorectal cancer (CRC) is a heterogenous disease with distinct biological and clinical subgroups, each with different prognoses and responses to therapy. In this case report, taking inspiration from a case of locally ad...Colorectal cancer (CRC) is a heterogenous disease with distinct biological and clinical subgroups, each with different prognoses and responses to therapy. In this case report, taking inspiration from a case of locally advanced CRC with serine/threonine-protein kinase B-raf (BRAF) V600E mutation, we highlight an atypical consensus molecular subtype 1 (CMS1). Deep multi-omic analyses showed a limited expression of programmed cell death protein 1 (PD-1) and reduced T-cell infiltration, including CD8 and natural killer (NK) cells, in the analyzed CMS1 tumor. In parallel, a reduced activation of the JAK/STAT pathway was detected, suggesting a lack of clinical response to immunotherapy with checkpoint inhibitors. Furthermore, the finding of up-regulated expression of WEE1 G2 checkpoint kinase (WEE1), checkpoint kinase 1 (CHK1), and checkpoint kinase 2 (CHK2), poly(ADP-ribose) polymerase (PARP), and heat shock protein 90 (HSP90) suggests a potential alternative therapeutic approach using inhibitors of the cell cycle, HSP90, or PARP in combination with conventional chemotherapy, targeted agents, or immunotherapy. This paradigmatic case should stimulate a regular deep omics analysis to improve precision medicine. We therefore suggest that full mutational and expression profiling analyses of CRC subtypes should be undertaken to improve therapeutic strategies in CRC treatment.
Clinical outcomes in ROS1-fusion positive (ROS1+) non-small cell lung cancer (NSCLC) by fusion partner and resistance mechanisms are limited. This cohort study included 56 ROS1+ patients (FISH or NGS confirmed); fusion p...Clinical outcomes in ROS1-fusion positive (ROS1+) non-small cell lung cancer (NSCLC) by fusion partner and resistance mechanisms are limited. This cohort study included 56 ROS1+ patients (FISH or NGS confirmed); fusion partners were identified in 27 cases, including CD74 (n = 10), EZR (n = 7), and SDC4 (n = 7). Clinical data were available for 50 patients (median age 62; 51% female; 32% never-smokers). Forty patients received tyrosine kinase inhibitors (TKIs), mostly crizotinib (n = 38). Crizotinib showed a 55% objective response rate (ORR) and a median progression-free survival (mPFS) of 5.3 months. Brain metastases (HR 2.65, 95% CI 1.06-6.60, P = 0.037) and prior chemotherapy (HR 3.17, 95% CI 1.35-7.45, P = 0.008) had a higher risk of progression. Sixteen patients received subsequent lorlatinib, with an ORR of 28% and mPFS of 3.7 months. G2032R and L2026M resistance mutations were identified in four lorlatinib non-responders, and in vitro studies confirmed resistance to lorlatinib. Fusion partners did not affect crizotinib outcomes. Lorlatinib was ineffective against on-target resistance. Real-world data showed lower TKI efficacy than clinical trials, highlighting the role of clinical and molecular factors in treatment response.
Proteasomes are involved in the maintenance of cellular protein homeostasis and the control of numerous cellular pathways. Single proteasome genes or subunits have been identified as important players in cancer developme...Proteasomes are involved in the maintenance of cellular protein homeostasis and the control of numerous cellular pathways. Single proteasome genes or subunits have been identified as important players in cancer development and progression without considering the proteasome as a multisubunit protease. We here conducted a comprehensive pan-cancer analysis encompassing transcriptional, epigenetic, mutational landscapes, pathway enrichments, and survival outcomes linked to the 20S proteasome core complex. The impact of proteasome gene expression on patient survival exhibited a cancer type-dependent pattern. Increased proteasome expression correlated with elevated activation of oncogenic pathways, such as DNA repair, MYC-controlled gene networks, MTORC1 signalling, oxidative phosphorylation, as well as metabolic pathways including glycolysis and fatty acid metabolism. Accordingly, potential loss of function variants of proteasome subunit genes are associated with improved patient survival. The TCGA-derived outcomes were further supported by gene expression analysis of THP-1 cells. Our study highlighted the importance of studying the proteasome as an enzymatic functional unit rather than separated subunits.
We investigated whether DNA methylation and cell-free DNA (cfDNA) fragmentation patterns can improve circulating tumor DNA (ctDNA) detection in advanced pancreatic cancer. In a cohort of 33 patients, ctDNA detection was...We investigated whether DNA methylation and cell-free DNA (cfDNA) fragmentation patterns can improve circulating tumor DNA (ctDNA) detection in advanced pancreatic cancer. In a cohort of 33 patients, ctDNA detection was performed in a tumor-agnostic fashion using DNA methylation, cfDNA fragment lengths, and 4-mer 5' end motifs. Machine learning models estimating ctDNA levels were built for each individual detection method and their combination. All models significantly differentiated ctDNA levels in patients from healthy individuals (P < 0.001). Using the highest estimated levels in healthy volunteers as cutoffs, ctDNA was detected in 79%, 67%, 67%, and 55% of patients using methylation, fragment length, end motifs, and the combined model, respectively. Univariable Cox regression showed that all ctDNA level estimates were associated with increased hazard ratios (HR, all P < 0.001) for progression-free survival (PFS) and overall survival (OS). Multivariable Cox regression confirmed ctDNA levels as an independent predictor of PFS (HR = 1.9, P < 0.001) and OS (HR = 2.7, P < 0.001). Our findings suggest that machine learning models based on DNA methylation, cfDNA fragment lengths, and cfDNA end motifs can estimate ctDNA levels and predict clinical outcomes in advanced pancreatic cancer.
Immune checkpoint blockade (ICB) is standard treatment in several cancer types, despite not being proven efficacious in metastatic hormone receptor-positive breast cancer (HR+ mBC). The gut microbiota is associated with...Immune checkpoint blockade (ICB) is standard treatment in several cancer types, despite not being proven efficacious in metastatic hormone receptor-positive breast cancer (HR+ mBC). The gut microbiota is associated with patient outcome and toxicity from cancer therapy, although limited data are available for breast cancer. In the randomized phase 2b trial ICON, immunomodulating chemotherapy was investigated in combination with dual ICB in HR+ mBC. To determine whether gut microbiota could inform prognosis, we performed 16S (V3-V4) rRNA sequencing on fecal samples collected at baseline and after 8 weeks of study treatment. We showed that high alpha diversity before treatment was associated with prolonged progression-free survival (PFS; primary trial endpoint) and overall survival. Alpha diversity was lower in patients with prior chemotherapy in the metastatic setting. However, alpha diversity remained significantly associated with PFS after correcting for prior chemotherapy and other factors in bivariate analyses. High-grade immune-related toxicity was also associated with high alpha diversity. These findings suggest that high alpha diversity should be further investigated as a positive prognostic factor in HR+ mBC and approaches to increase alpha diversity could potentially improve clinical outcome.
Protumoral myelopoiesis is a determinant of immunoevasion and tumor spread in many malignancies. In a recent issue of Cancer Discovery, Bleve and colleagues point to cholesterol-driven RORγ activation as the molecular tr...Protumoral myelopoiesis is a determinant of immunoevasion and tumor spread in many malignancies. In a recent issue of Cancer Discovery, Bleve and colleagues point to cholesterol-driven RORγ activation as the molecular trigger of myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) expansion, resulting in defective antitumor response and disease progression.
The rare vascular sarcoma epithelioid hemangioendothelioma (EHE) is defined by WWTR1 or YAP1 gene rearrangements that result in functional fusion proteins. Previous studies have demonstrated the ability of these gene fus...The rare vascular sarcoma epithelioid hemangioendothelioma (EHE) is defined by WWTR1 or YAP1 gene rearrangements that result in functional fusion proteins. Previous studies have demonstrated the ability of these gene fusions to function as constitutively active TEAD coactivators, while also retaining the ability to drive transcription of canonical CAMTA1 or TFE3 genes, respectively. To better understand the biology underlying EHE, we generated EHE in vitro models using endothelial cell lines and found that inducible expression of YAP1::TFE3 (YT) caused a significant change in cellular plasticity. Specifically, YT expression led to endothelial-to-mesenchymal transition (EndMT), a process in which endothelial cells lose their highly specialized identity and gain expression of genes typically associated with mesenchymal cells. This plasticity is associated with anoikis resistance and increased migratory phenotypes. Notably, YT drives this phenotypic change independent of TEAD activity but requires dimerization and DNA binding domains encoded by the C-terminal TFE3 gene. Overexpression of TFE3 is insufficient to fully recapitulate the EndMT phenotypes driven by YT; implying that, although dispensable for EndMT, YAP-TEAD activity provides a meaningful contribution. This work supports a growing body of evidence that YT and WWTR1-CAMTA1 driven EHE may have distinct biological mechanisms, underscoring a potentially targetable oncogenic molecular dependency.
Molecular diagnostics has revolutionized cancer management, enabling the identification of diagnostic, prognostic, and predictive biomarkers. Despite advancements in technologies such as whole genome sequencing, their tr...Molecular diagnostics has revolutionized cancer management, enabling the identification of diagnostic, prognostic, and predictive biomarkers. Despite advancements in technologies such as whole genome sequencing, their translation into clinical practice remains challenging due to insufficiently demonstrated clinical utility. This study identifies unmet clinical needs and requirements for innovative molecular technologies in oncology through interviews (n = 22) and an online survey (n = 116), gathering insights from hospital professionals, industry representatives, and health policy and quality assessment experts. Our findings emphasize the increasing importance of liquid biopsies (LBx), particularly plasma-based assays. Key unmet needs in this area include therapy response monitoring, minimal residual disease detection, and predictive biomarker testing. Additionally, we outline technology requirements tailored to diverse clinical biomarker applications and both centralized and decentralized laboratory settings. A central challenge lies in achieving an optimal balance between multiplexing capacity and turnaround time. By bridging the gap between technology development and real-world application, this study paves the way for the implementation of new molecular technologies that better meet the needs of the oncology community, ensuring clinical utility and ultimately improving patient care.
Prostate cancer (PCa) is the fifth leading cause of cancer-related death. The lack of data linking genomic alterations to targeted treatment strategies has hindered progress in disease management. Genomic rearrangements...Prostate cancer (PCa) is the fifth leading cause of cancer-related death. The lack of data linking genomic alterations to targeted treatment strategies has hindered progress in disease management. Genomic rearrangements involving the ETS transcription factors ERG or ETV1 are among the most frequent genetic alterations in PCa; however, their clinical utility remains elusive. Using PCa cells overexpressing ETV1 or ERG, representing early and advanced disease stages, we unveiled a positive feedback loop between ETV1 and EGFR, with STAT3 acting as a downstream effector of ETV1-EGFR signaling. Analysis of external datasets revealed that both EGFR and STAT3 are significantly upregulated in ETV1-positive PCa, consistent with ChIP-seq data identifying them as direct ETV1 targets. Accordingly, combined inhibition of EGFR and STAT3 using Erlotinib and TTI-101, respectively, led to a significant reduction in 2D and 3D cell growth of early and advanced PCa cells overexpressing ETV1. Collectively, our findings highlight EGFR-STAT3 activation as a novel ETV1-regulated oncogenic pathway, providing a rationale for repurposing EGFR inhibitors in combination with STAT3 inhibitors as a therapeutic strategy for the 8-10% of prostate carcinomas characterized by ETV1 rearrangements/overexpression.
Acute lymphoblastic leukemia (ALL), the most common cancer in children, is overall divided into two subtypes, B-cell precursor ALL (B-ALL) and T-cell ALL (T-ALL), which have different molecular characteristics. Despite m...Acute lymphoblastic leukemia (ALL), the most common cancer in children, is overall divided into two subtypes, B-cell precursor ALL (B-ALL) and T-cell ALL (T-ALL), which have different molecular characteristics. Despite massive progress in understanding the disease trajectories of ALL, ALL remains a major cause of death in children. Thus, further research exploring the biological foundations of ALL is essential. Here, we examined the diagnostic, prognostic, and therapeutic potential of gene expression data in pediatric patients with ALL. We discovered a subset of expression markers differentiating B- and T-ALL: CCN2, VPREB3, NDST3, EBF1, RN7SKP185, RN7SKP291, SNORA73B, RN7SKP255, SNORA74A, RN7SKP48, RN7SKP80, LINC00114, a novel gene (ENSG00000227706), and 7SK. The expression level of these markers all demonstrated significant effects on patient survival, comparing the two subtypes. We also discovered four expression subgroups in the expression data with eight genes driving separation between two of these predicted subgroups. A subset of the 14 markers could distinguish B- and T-ALL in an independent cohort of patients with ALL. This study can enhance our knowledge of the transcriptomic profile of different ALL subtypes.