Acute myeloid leukaemia (AML) is a therapeutically challenging malignancy driven by the self-renewal, quiescence, and therapy resistance of leukaemic stem cells (LSCs). CDK8, a kinase component of the Mediator complex, regulates oncogenic transcription, and the selective CDK8/CDK19 inhibitor RVU120 (Romaciclib) targets AML cells with CD34+/pSTAT5-high LSC-like characteristics; however, the epigenetic and transcriptional consequences of CDK8 blockade and actionable combinatorial strategies remain incompletely defined. Using the TEX cell line, an LSC-enriched surrogate model, we performed time-resolved RNA-seq, whole-proteome and phosphoproteomics mass spectrometry (MS), and CUT&Tag chromatin profiling following treatment with RVU120 and CCT251921. CDK8 protein-protein interactions were mapped by co-immunoprecipitation MS across five AML models, and synergy with Pelabresib (BET inhibitor) or CB6644 (RUVBL1/2 inhibitor) was assessed by high-content screening in three cell lines and three patient-derived xenograft (PDX) models. Both inhibitors suppressed STAT5 phosphorylation, induced loss of the CD34+/CD38- LSC-enriched phenotype, and drove erythromegakaryocytic differentiation. Transcriptomic and proteomic responses were concordant, and CDK8 inhibition triggered widespread enhancer activation with redistribution of RNAP2, BRD3, and NFRKB. CDK8 combined with Pelabresib acted synergistically in MOLM-16 cells and two of three PDX models. These findings identify CDK8 as a transcriptional node of LSC-associated programs and provide a mechanistic rationale for combined CDK8-BET inhibition in molecularly defined AML subsets, which will require validation in functional LSC assays and primary specimens.

Glutamate dehydrogenase (GLUD1) links glutamine metabolism and redox regulation, yet its prognostic and functional relevance across different glioma subtypes warrants further study. Here, we show that GLUD1 expression was inversely associated with tumor grade and positively associated with survival across glioma subtypes, a relationship not fully recapitulated by broader glutaminolysis-related gene signatures. To investigate the consequences of GLUD1 inhibition, we treated endogenous IDH-mutant and IDH-wildtype glioma cell lines with the reported GLUD1 inhibitor R162. GLUD1 inhibition reduced viability in all cell lines tested. This effect was not rescued by α-ketoglutarate (α-KG) supplementation, indicating that impaired tricarboxylic acid (TCA) cycle anaplerosis was not the primary mechanism underlying GLUD1 dependency. Instead, GLUD1 inhibition caused intracellular glutamate accumulation, increased reactive oxygen species (ROS), γ-H2AX induction, and elevated intracellular calcium, while complementary in silico analyses predicted disruption of mitochondrial membrane potential following R162 exposure. Together, these findings indicate that GLUD1 inhibition induces metabolic and redox stress associated with disrupted glutamate and calcium homeostasis and DNA damage. Our findings distinguish the favorable prognostic value of GLUD1 expression from the cellular vulnerability revealed by its inhibition, supporting further investigations of GLUD1 as both a prognostic biomarker and potential therapeutic target in glioma.

KMT2A-rearranged (MLL-r) leukemias are highly aggressive hematological malignancies that require improved targeted therapies. DOT1L (histone H3K79 methyltransferase) functions as a critical oncogenic driver and represents an important therapeutic target in these high-risk leukemias. However, clinical responses to the first-in-class DOT1L inhibitor pinometostat (EPZ5676) have been modest, attributed to suboptimal pharmacokinetics and, more fundamentally, to the recognition that DOT1L possesses methyltransferase-independent functions that evade catalytic inhibition. This highlights the need for strategies that abrogate the full spectrum of DOT1L activity to effectively treat these high-risk leukemias. Proteolysis-targeting chimeras (PROTACs), which induce selective degradation of the DOT1L protein rather than inhibiting its catalytic activity, have therefore emerged as a promising approach. Notably, VHL-recruiting DOT1L PROTACs, such as DOT1L808, have demonstrated improved pharmacokinetic profiles and potent antileukemic activity in preclinical in vivo models. However, these findings remain preclinical, and significant challenges including oral bioavailability, potential toxicity, and lack of clinical validation must be addressed before clinical translation. In this review, we provide an overview of the evolving understanding of the biology of DOT1L, discuss existing MLL small molecule therapies, and evaluate current advances in therapeutically targeting DOT1L, with particular focus on the targeted degradation of DOT1L as a promising therapeutic strategy for high-risk KMT2A-r leukemia.

Despite the development of new drugs, chemoresistance constitutes a major obstacle in cancer treatment. To investigate mechanisms of resistance and potential therapeutic targets, we developed doxorubicin-resistant models of HER2- (D2F2/Dox) and HER2+ (D2F2E2/Dox) breast cancer cells. Compared with parental cells, the D2F2/Dox and D2F2E2/Dox differed in morphology, increased migratory potential, elevated levels of the transcription factor signal transducer and activator of transcription 3 (Stat3), and a lower proliferation rate in D2F2E2/Dox. Moreover, D2F2/Dox and D2F2E2/Dox differed in the expression profiles of genes related to cell stemness, apoptosis, and drug efflux. Stat3 gene silencing in both doxorubicin-resistant cell types reversed the expression profiles of some genes (different in each resistant cell line), and decreased migratory potential was observed only in D2F2 cells. These data indicate that the acquired doxorubicin resistance was associated with Stat3 status; however, HER2- and HER2+ breast cancer cells did not indicate the same mechanism of chemoresistance acquisition. Importantly, Stat3 silencing did not substantially restore doxorubicin sensitivity, suggesting that effective therapy may require simultaneous targeting of multiple pathways. Furthermore, we demonstrated that siStat3 therapeutics could be selectively delivered to HER2+ cancer cells using H2.1MS1:MS2KN silk spheres, indicating their potential for targeted drug delivery in vivo.

Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with limited therapeutic options for patients at high risk of disease recurrence and metastasis. The cyclic nucleotide-degrading enzyme, phosphodiesterase 10A (PDE10), that hydrolyzes both cAMP and cGMP has been previously reported to be expressed in multiple cancers and regulates key cellular signaling pathways involved in cancer cell proliferation, survival, and maintenance of stem cell-like properties. We found that PDE10 overexpression was associated with poor relapse-free survival of TNBC patients and identified its potential as a therapeutic target for TNBC using a novel inhibitor, ADT-030. Our results showed that ADT-030 inhibited the growth of TNBC cells, reduced colony-forming efficiency and enhanced the therapeutic efficacy of paclitaxel. A TNBC mouse model demonstrated that oral administration of ADT-030 significantly suppressed syngeneic tumor growth and enhanced the antitumor efficacy of paclitaxel. ADT-030 treatment altered differentially expressed genes (DEGs), signaling pathways, and cellular processes. Overall, our findings suggest that ADT-030, as a monotherapy or in combination with standard-of-care chemotherapy, may be an effective therapeutic approach for TNBC. Further studies are warranted to better understand the oncogenic role of PDE10 in TNBC and the mechanisms by which ADT-030 modulates the tumor microenvironment (TME) and enhances chemotherapy response.

Hepatocellular carcinoma (HCC) remains one of the most aggressive and lethal malignancies worldwide, with high rates of metastasis and recurrence contributing to its poor prognosis. There is an urgent need to elucidate the molecular mechanisms driving HCC progression and to develop effective therapeutic strategies. Metabolic reprogramming, especially aerobic glycolysis known as the Warburg effect, is a well-established hallmark of cancer. Concurrently, cancer stem cells (CSCs) play crucial roles in tumor initiation, therapy resistance, and recurrence. However, the involvement of long non-coding RNAs (lncRNAs) in linking metabolic alterations and stemness remains poorly understood. In this investigation, we identified LINC02041 as a significantly upregulated lncRNA in HCC tissues and demonstrated its oncogenic role in promoting cell proliferation. We found that STAT3 transcriptionally activates LINC02041 expression. Mechanistically, LINC02041 enhances the stability of SRSF1 protein by suppressing its ubiquitin-mediated degradation, thereby facilitating HCC cell proliferation, migration, glycolytic metabolism, and acquisition of stem-like properties. Our findings delineate a novel STAT3/LINC02041/SRSF1 regulatory axis that coordinately modulates glycolytic reprogramming and stemness maintenance in hepatocarcinogenesis. This study not only advances our understanding of HCC pathophysiology but also identifies LINC02041 as a promising prognostic biomarker and a compelling therapeutic target for novel therapeutic strategies against this aggressive malignancy.

Hypoxia-driven regulatory mechanisms play a critical role in tumor progression and therapeutic resistance in hepatocellular carcinoma (HCC), yet hypoxia-responsive microRNAs (HRMs) remain incompletely characterized. This study aimed to identify HRMs in canine HCC to evaluate their diagnostic potential and translational relevance to human disease. Next-generation sequencing of two canine HCC cell lines under normoxic and hypoxic conditions identified 332 and 321 differentially expressed miRNAs, respectively. Integrating these with tumor tissue data revealed 11 HRMs, featuring consistent upregulation of cfa-miR-210 and cfa-miR-34a, which was validated via RT-qPCR in hypoxic cells and clinical tissues. Both miRNAs were significantly elevated in plasma-derived extracellular vesicles (EVs), highlighting their value as promising circulating biomarkers (AUC 1.00 for miR-210; 0.98 for miR-34a). Target gene and pathway analyses identified shared regulatory nodes, including TGIF2 and SPRED1; and enrichment of MAPK, Ras, PI3K-Akt, and Rap1 signaling, broadly linked to hypoxia adaptation, cellular metabolism, and stress-response signaling. Cross-species comparison with human HCC datasets showed that, while miR-210 associates with poor prognosis in human HCC, miR-34a exhibits tumor-suppressive features. These findings define complementary HRM programs in canine HCC, reflecting conserved adaptive and stress-limiting regulatory mechanisms with potential diagnostic and translational relevance to human HCC.

Anti-CD38 monoclonal antibodies have substantially improved outcomes in multiple myeloma (MM). Although daratumumab and isatuximab target the same antigen, accumulating evidence indicates that they differ in epitope recognition, biological activity, and immunomodulatory properties, suggesting these agents may not be therapeutically interchangeable. This review summarizes the molecular and immunological mechanisms underlying their distinct antitumor effects and their implications for treatment selection. Isatuximab binds near the catalytic site of CD38, resulting in potent enzymatic inhibition, enhanced antibody internalization, FOXM1 suppression, and reactive oxygen species-mediated cytotoxicity, which may preferentially target MM cells harboring 1q21 amplification. In contrast, daratumumab exerts prominent Fc-dependent immune effects, including trogocytosis-mediated downregulation of CD38 and VLA-4, suppression of cell adhesion-mediated drug resistance, and modulation of the immune microenvironment, potentially enhancing subsequent T-cell-redirecting therapies. We further discuss the relevance of these mechanistic differences to measurable residual disease, extramedullary disease, and sequencing with BCMA- and GPRC5D-directed immunotherapies. Finally, we propose a biology-guided treatment-selection model integrating genomic alterations, tumor biology, and immune remodeling to support precision medicine for patients with MM.

Caspase-8 and the NF-κB essential modulator (NEMO, also referred to as IKKγ) play critical roles in controlling TNF-α-induced cell death and survival in hepatocytes. The aim of this study was to generate a hepatocyte-derived cell line in which the Casp8 and Nemo genes can be conditionally inactivated simultaneously to investigate the significance of the corresponding signaling pathways. To this end, we induced hepatocellular carcinoma in Casp8f/fNemof/f mice using diethylnitrosamine and established an immortalized hepatoma cell line from explanted liver tumors, which is subsequently referred to as ΔCN60. ΔCN60 cells still retain floxed Casp8 and Nemo alleles, allowing for efficient Cre-mediated deletion to generate Casp8ΔNemoΔ derivatives. Loss of both Caspase-8 and NEMO inhibits cell proliferation, increases the expression of tumor and progenitor markers (AFP, CD133), reduces albumin expression, and blocks TNF-α-induced NF-κB p65 nuclear translocation. ΔCN60 Casp8ΔNemoΔ cells display altered sensitivity to prolonged TNF-α exposure, suggesting a potential shift in necroptosis-associated signaling pathways, although necroptotic cell death was not directly demonstrated. ΔCN60 serves as a versatile hepatoma model for investigating Caspase-8/NEMO-dependent TNF-α signaling and hepatocyte plasticity and may help prioritize future in vivo experiments by enabling selected mechanistic questions to be addressed first in vitro.

Background: Recent evidence suggests that the antidepressant vortioxetine (Vx) inhibits the growth of glioblastoma (GBM), the most aggressive primary malignant tumor of the CNS. We used five patient-derived GBM cell lines to confirm the anti-GBM effect of Vx and explore its mechanism(s) of action. Methods: We performed in silico analysis, PCR, TUNEL assay, colony assay, and proliferation assay. Results: Vx potently inhibited GBM cell growth, and showed efficacy at concentrations of 0.1 μM that roughly correspond to therapeutic concentrations of Vx in major depression. Other antidepressants, i.e., fluoxetine and duloxetine, inhibited GBM cell growth only at high concentrations. Computational analysis showed that at least three receptor targets of Vx (5-HT7, 5-HT1D, and 5-HT1B) were expressed at moderate/high levels in GBM. The 5-HT1B receptor transcript was found in all GBM cell lines and was the only detectable Vx target in three of the five cell lines. Blocking 5-HT1B with SB224289 abolished the anti-GBM effect of Vx, even in cells expressing other Vx. Conclusions: These findings demonstrate that therapeutic concentrations of Vx inhibit GBM cell proliferation and suggest that this action may be mediated, at least in part, by 5-HT1B receptor activation.

Metastasis remains the principal cause of cancer mortality, with the lungs representing one of the most frequent and clinically challenging sites. The tumor microenvironment, particularly tumor-associated macrophages (TAMs), plays a pivotal role in establishing and maintaining metastatic niches. Yet, how host ketone bodies influence the immune microenvironment to govern metastatic progression is poorly defined.

Nuclear receptor coactivator 3 (NCOA3) is associated with various cancers, but its function and mechanism in glioblastoma multiforme (GBM) are still unclear. Bioinformatics analysis, in vitro cell experiments (NCOA3 silencing (si-NCOA3) or NCOA3 small-molecule inhibitor SI-2), in vivo animal models, and metabolic level detection were used to elucidate the activity of NCOA3 in GBM. The data revealed that GBM tissues had NCOA3 overexpression, which was linked with poor prognosis. It regulates pathways related to glycolysis, the cell cycle, and immunosuppression. Functionally, si-NCOA3/SI-2 suppressed GBM cell proliferation and migration. In vivo, sh-NCOA3/SI-2 demonstrated anti-glioma effects. Metabolically, treatment with si-NCOA3/SI-2 reduced glucose uptake, pyruvate and lactate production, ATP levels, and glycolysis-related enzyme expression in GBM cells. Combination therapy with SI-2 and TMZ enhanced GBM cell sensitivity to TMZ. Single-cell RNA sequencing revealed high NCOA3 expression in glioma stem cells (GSCs). si-NCOA3 inhibited GSCs proliferation and self-renewal while reducing the expression of Nestin and SOX2. NCOA3 is an oncogene in GBM. In mechanism, NCOA3 promotes GBM progression by enhancing the Warburg effect. In addition, NCOA3 is also highly expressed in GSCs and significantly promotes their proliferation and self-renewal ability. NCOA3 may represent a promising therapeutic target for GBM.

Clear cell renal cell carcinoma (ccRCC) exhibits substantial molecular and clinical heterogeneity, contributing to variable disease progression and therapeutic outcomes. We previously identified a de-clear cell differentiation (DCCD) tumor state characterized by loss of canonical clear-cell features and aggressive clinical behavior. This study aimed to translate DCCD-associated biology into a prognostic framework and investigate its underlying molecular basis. Using TCGA-KIRC as the training cohort, we developed a five-gene prognostic signature comprising COL7A1, IGFN1, AJAP1, SMIM24, and ADGRV1, which consistently stratified patient survival across multiple public and institutional cohorts. Comparison with SSIGN, Leibovich, and ClearCode34-like models demonstrated that the DCCD signature provided complementary prognostic information. High-risk tumors exhibited enhanced proliferative and invasive programs, increased IL6-JAK-STAT3 pathway activity, and an immune-excluded microenvironment. Associations with treatment response were also observed in retrospective therapeutic cohorts. Integrated analyses of bulk and single-cell transcriptomics, spatial transcriptomics, tissue microarrays, CPTAC proteomics, and molecular interaction networks identified SMIM24 as an epithelial-associated factor linked to favorable outcomes and preserved metabolic programs. Functional experiments showed that SMIM24 overexpression suppressed migration, invasion, three-dimensional spheroid invasion, and clonogenic growth in ccRCC cells, accompanied by reduced JAK1 and STAT3 phosphorylation and decreased PD-L1 expression. Pharmacological activation of STAT3 with Colivelin partially restored PD-L1 expression in SMIM24-overexpressing cells. Collectively, these findings support the reproducibility of the DCCD-associated prognostic framework and identify SMIM24 as a candidate suppressor of ccRCC aggressiveness and PD-L1 expression, potentially acting in part through reduced STAT3 activation.

R-CHOP-treated diffuse large B-cell lymphoma (DLBCL) shows heterogeneous outcomes. High-risk relapsed/refractory (R/R) patients, especially activated B-cell (ABC) and double-/triple-hit subtypes, have poor prognosis, highlighting an urgent need to uncover the underlying aggressive molecular mechanisms. Epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties drive its invasion, metastasis, and drug resistance. This study investigated the regulatory role and mechanism of Hedgehog (Hh) pathway key factor GLI1 in DLBCL. Immunohistochemistry detected GLI1, Bmi1, and SOX2 expression in DLBCL tissues. DLBCL cell lines (HBL-1, SUDHL-2) were treated with pan-GLI inhibitor GANT61, or transfected with GLI1 overexpression/silencing plasmids combined with Bmi1 intervention. CCK-8, flow cytometry, RT-qPCR, Western blot, Co-IP, tumor sphere, and immunofluorescence assays were performed. In vivo xenograft experiments were conducted to verify GANT61's anti-tumor effect. GLI1 was aberrantly activated in DLBCL tissues and positively correlated with Bmi1/SOX2. GANT61 inhibited DLBCL cell proliferation, induced G0/G1 arrest and apoptosis, reversed EMT, and reduced CSC-related molecules. Co-IP confirmed GLI1-Bmi1 interaction. GLI1 overexpression enhanced proliferation, EMT, and CSC properties, while GLI1 silencing exerted opposite effects. Bmi1 inhibitor reversed GLI1's pro-tumor effects, and Bmi1 agonist partially restored GLI1 silencing-induced inhibition. In vivo, GANT61 significantly reduced tumor volume/weight in HBL-1 xenografts with good tolerability. GLI1 modulates EMT-like plasticity and stem cell traits in DLBCL via direct protein interaction with Bmi1, confirming a functional regulatory connection between these two molecules that forms the core Hh-GLI1-Bmi1 regulatory pathway. Targeting this axis provides a novel therapeutic strategy for DLBCL. Key words: Hedgehog signaling pathway; Diffuse large B-cell lymphoma (DLBCL); Epithelial-mesenchymal transition (EMT); Cancer stem cell properties; GLI1-Bmi1 axis; GANT61; Xenograft model.

Population-based genomic newborn screening identifying newborns at risk for early-onset cancers has not been evaluated. Here, within a Michigan birth cohort (1987-2020), we identify all children developing a solid or central nervous system malignancy by age 8 years (n = 1948). We perform targeted sequencing of 11 cancer predisposition genes using archived newborn dried blood spot DNA. We find pathogenic or likely-pathogenic germline variants (P/LP) in 6.8% of cases (n = 132): RB1 (n = 69), TP53 (n = 24), SMARCB1 (n = 8), WT1 (n = 7), RET (n = 6), SUFU (n = 6), PTCH1 (n = 4), DICER1 (n = 4), APC (n = 3) and PHOX2B (n = 1). We show approximately 1/27,000 newborns develop an early-onset malignancy with an associated pathogenic or likely-pathogenic variant. Germline variant prevalence is 100% in medullary thyroid carcinoma, 40% in retinoblastoma, and 11-30% across five additional diagnoses, with strong gene-tumor specificity (p < 0.001). P/LP variants are rare in comparison datasets from healthy newborns and gnomAD. Our data support newborn screening for selected cancer-risk genes.

Transcription factor SNAI1 guides plasticity and invasiveness in cancer. Using a complete SNAI1 knockout in mesenchymal, triple-negative breast cancer cells, unbiased genome-wide transcriptomic analysis revealed a marked under-expression of integrin-based adhesion and endocytic components. Utilizing this knockout cell model, complementary breast cancer cell models and functional screening of multiple differentially expressed genes, we found that the pioneering transcription factor FOXA1, whose expression is repressed by SNAI1, associates with several key mediators of the cellular phenotype. FOXA1 represses the small GTPase ARF6 and its exchange factor PSD4. In addition, some of the integrin and matrix metalloproteinase genes are regulated by the transcriptional FOXA1 signal. Accordingly, SNAI1 knockout cells presented poor adhesion to collagen type I or fibronectin, formed defective invadopodia and focal adhesions with weakened FAK/SRC signaling. SNAI1 knockout cells performed ineffective receptor-mediated internalization, including nanoparticle and extracellular vesicle (EV) uptake, exhibited reduced lysosomal content, lacked multivesicular bodies enriched in intraluminal vesicles and showed decreased EV secretion. Gain-of-function experiments demonstrated that SNAI1 has an impact on the PSD4/ARF6 signaling module, using FOXA1 as an intermediate factor to regulate EV release by tumor cells. We propose that the SNAI1-FOXA1 transcriptional mechanism operates at the level of membrane and vesicular trafficking control, which interlinks cell plasticity, adhesion and invasiveness through the extracellular environment, with the associated process of EV secretion.

Mefatinib, a novel second-generation epidermal growth factor (EGFR) tyrosine kinase inhibitor that has shown promising antitumor activity in targeting non-small cell lung cancer (NSCLC) with common and uncommon EGFR-activating mutations. In this phase III, randomized, double-blind trial in China, 336 eligible patients with advanced nonsquamous NSCLC harboring EGFR L858R or exon 19 deletion (ex19del) were assigned (2:1) to receive either mefatinib (60 mg daily, n = 223) or gefitinib (250 mg daily, n = 113). The primary endpoint was progression-free survival (PFS), assessed by an independent review committee (IRC). The trial is registered with chinadrugtrials.org.cn (CTR20192297). After a median follow-up of 15.9 months for mefatinib and 18.5 months for gefitinib, mefatinib demonstrated a significantly longer median IRC-assessed PFS compared to gefitinib (13.7 vs. 9.7 months; hazard ratio [HR] = 0.68; 95% confidence intervals [CI]: 0.53-0.87; p = 0.002). The 30-month overall survival rate was 60.2% for mefatinib and 54.3% for gefitinib. Patients with EGFR ex19del had comparable PFS for both treatment arms (p > 0.100), whereas patients with EGFR L858R had significantly longer median PFS when treated with mefatinib than gefitinib (13.7 vs 8.3 months HR = 0.55 [95% CI: 0.38-0.78]; p = 0.001). Patients with EGFR L858R had a 30-month overall survival rate of 56.6% with mefatinib and 43.7% with gefitinib. Treatment-related adverse events ≥grade 3 were reported in 45.7% of the mefatinib group and 24.8% of the gefitinib group. No new safety signals were observed for mefatinib. Mefatinib demonstrated superior efficacy to gefitinib with a similar tolerability profile in the first-line treatment of EGFR-mutated advanced NSCLC.

Cancer stem cells (CSCs) are tumor cell subsets with self-renewal, multilineage differentiation, and tumor-initiating capacity that sustain cancer initiation, progression, metastasis, and relapse. Targeting CSCs therefore represents a promising route to improve the durability of cancer treatment. However, translation of this approach into routine care has been slow because of the biological complexity and clinical constraints. This review discusses current concepts of CSC origin and plasticity, the criteria used to define CSCs across different tumor types, and the marker systems as well as high-resolution technologies that are used to track CSC states. Developmental pathways, growth factor and cytokine cascades, as well as microenvironmental and stress responses that control CSC maintenance and therapy resistance are explored with a focus on their tractability as drug targets. We then discuss mechanisms through which CSCs escape chemotherapy, radiotherapy, and targeted agents. We review current efforts to use these pathways in designing small molecules, antibodies, cellular therapies, and vaccines aimed at CSC compartments. Heterogeneity within and between tumors, dynamic interconversion between CSC and non-CSC states, and support from specialized niches are considered as major barriers for clinical trial design, biomarker development, and response assessment. Emerging single-cell, spatial, and lineage tracing approaches, together with organoid and ex vivo platforms, are reviewed as tools that can bridge preclinical models and patient samples and guide the development of CSC-directed combination regimens. The goal is to outline translational principles that can guide future strategies for integrating CSC-focused interventions with established therapies to improve long-term disease control.

KRAS mutations are highly prevalent in pancreatic cancer and are critical for epithelial reprogramming during tumor initiation. In this issue of Developmental Cell, Grimont et al.1 demonstrate that the three most common KRAS mutations differentially activate downstream signaling pathways, resulting in distinct capacities to develop pancreatic pre-neoplastic lesions.

Comprehensive genomic profiling (CGP) is increasingly adopted in the management of patients affected by GI cancers. However, the applicability, performance, and clinical utility of CGP in the real-world setting are still undefined.