A small subpopulation of cells within the bulk of tumors share features with somatic stem cells, in that, they are capable of self-renewal, they differentiate, and are highly resistant to conventional therapy. These cells have been referred to as cancer stem cells (CSCs). Recent reports support the central importance of a cancer stem cell-like niche that appears to help foster the generation and maintenance of CSCs. In response to signals provided by this microenvironment, CSCs express the tumorigenic characteristics that can drive tumor metastasis by the induction of epithelial-mesenchymal-transition (EMT) that in turn fosters the migration and recolonization of the cells as secondary tumors within metastatic niches. We summarize here recent advances in cancer stem cell research including the characterization of their genetic and epigenetic features, metabolic specialities, and crosstalk with aging-associated processes. Potential strategies for targeting CSCs, and their niche, by regulating CSCs plasticity, or therapeutic sensitivity is discussed. Finally, it is hoped that new strategies and related therapeutic approaches as outlined here may help prevent the formation of the metastatic niche, as well as counter tumor progression and metastatic growth.

Esophageal adenocarcinoma (EAC) is one of the most lethal malignancies, and limits promising treatments. AKR1C3 represents a therapeutic target to combat the resistance in many cancers. However, the molecular mechanism of AKR1C3 in the chemotherapy resistance of EAC is still unclear. We found that the mRNA level of AKR1C3 was higher in EAC tumor tissues, and that high AKR1C3 expression might be associated with poor overall survival of EAC patients. AKR1C3 overexpression decreased cell death induced by chemotherapeutics, while knockdown of AKR1C3 attenuated the effect. Furthermore, we found AKR1C3 was inversely correlated with ROS production. Antioxidant NAC rescued chemotherapy-induced apoptosis in AKR1C3 knockdown cells, while the GSH biosynthesis inhibitor BSO reversed a protective effect of AKR1C3 against chemotherapy. AKT phosphorylation was regulated by AKR1C3 and might be responsible for eliminating over-produced ROS in EAC cells. Intracellular GSH levels were modulated by AKR1C3 and the inhibition of AKT could reduce GSH level in EAC cells. Here, we reported for the first time that AKR1C3 renders chemotherapy resistance through controlling ROS levels via AKT signaling in EAC cells. Targeting AKR1C3 may represent a novel strategy to sensitize EAC cells to conventional chemotherapy.

In pancreatic ductal adenocarcinoma (PDAC), the tumor stroma constitutes most of the cell mass and contributes to therapy resistance and progression. Here we show a hitherto unknown metabolic cooperation between pancreatic stellate cells (PSCs) and tumor cells through Interleukin 17B/Interleukin 17B receptor (IL-17B/IL-17RB) signaling. Tumor-derived IL-17B carrying extracellular vesicles (EVs) activated stromal PSCs and induced the expression of IL-17RB. PSCs increased oxidative phosphorylation while reducing mitochondrial turnover. PSCs activated tumor cells in a feedback loop. Tumor cells subsequently increased oxidative phosphorylation and decreased glycolysis partially via IL-6. In vivo, IL-17RB overexpression in PSCs accelerated tumor growth in a co-injection xenograft mouse model. Our results demonstrate a tumor-to-stroma feedback loop increasing tumor metabolism to accelerate tumor growth under optimal nutritional conditions.

In chronic lymphocytic leukemia (CLL), epigenetic alterations are considered to centrally shape the transcriptional signatures that drive disease evolution and that underlie its biological and clinical subsets. Characterizations of epigenetic regulators, particularly histone-modifying enzymes, are very rudimentary in CLL. In efforts to establish effectors of the CLL-associated oncogene T-cell leukemia 1A (TCL1A), we identified here the lysine-specific histone demethylase KDM1A to interact with the TCL1A protein in B-cells in conjunction with an increased catalytic activity of KDM1A. We demonstrate that KDM1A is upregulated in malignant B-cells. Elevated KDM1A and associated gene expression signatures correlated with aggressive disease features and adverse clinical outcomes in a large prospective CLL trial cohort. Genetic Kdm1a knockdown (Kdm1a-KD) in Eμ-TCL1A mice reduced leukemic burden and prolonged animal survival, accompanied by upregulated p53 and pro-apoptotic pathways. Genetic KDM1A depletion also affected milieu components (T-, stromal, monocytic cells), resulting in significant reductions of their capacity to support CLL cell survival and proliferation. Integrated analyses of differential global transcriptomes (RNA-seq) and H3K4me3 marks (ChIP-seq) in Eµ-TCL1A vs. iKdm1aKD;Eµ-TCL1A mice (confirmed in human CLL) implicate KDM1A as an oncogenic transcriptional repressor in CLL by altering histone methylation patterns with pronounced effects on defined cell death and motility pathways. Finally, pharmacologic KDM1A inhibition altered H3K4/9 target methylation and revealed marked anti-B-cell-leukemic synergisms. Overall, we established the pathogenic role and effector networks of KDM1A in CLL, namely via tumor-cell intrinsic mechanisms and impacts in cells of the microenvironment. Our data also provide rationales to further investigate therapeutic KDM1A targeting in CLL.

Introduction: Immune checkpoint inhibitors (ICIs) targeting PD-1 have revolutionized melanoma treatment, yet their clinical efficacy is frequently limited by immune-related adverse events (irAEs). The underlying mechanisms of irAEs remain poorly defined, particularly in the acral melanoma subtype. Methods: To identify peripheral immune signatures associated with irAE development, we performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) from eight acral melanoma patients: three who developed irAEs on anti-PD-1 therapy (AE), three treated patients without irAEs (NAE), and two untreated controls (UNT). Cellular composition, transcriptional profiles, and differentiation trajectories were analyzed. Results: Analysis of 54,793 high-quality cells revealed a profound reconfiguration of the CD8+ T cell compartment specifically in AE patients. This was characterized by an expansion of cytotoxic CD8+ T cells (enriched for GZMB , GNLY , NKG7 ) and a concurrent contraction of a transitional CD8+ T cell population marked by GZMK expression. Consequently, the ratio of transitional to cytotoxic CD8+ T cells was decreased in the AE group. Pseudotime trajectory analysis confirmed that GZMK+ transitional cells represent an intermediate differentiation state between naïve and terminal cytotoxic phenotypes. Additionally, AE patients exhibited an elevated proportion of proliferating T cells and enrichment of cell-killing gene pathways. Discussion: Our findings propose a model wherein an imbalance in CD8+ T cell differentiation, favoring aggressive cytotoxic effectors over a putative buffering transitional population, underpins irAEs pathogenesis in acral melanoma patients receiving anti-PD-1 therapy. The transitional-to-cytotoxic CD8+ T cell ratio emerges as an exploratory candidate biomarker for irAEs risk, warranting validation in larger prospective cohorts.

Pancreatic ductal adenocarcinoma (PDAC) presents significant treatment challenges, primarily due to its propensity for developing resistance to therapeutic interventions. While the underlying mechanisms remain elusive, they are closely associated with mitochondrial adaptation in response to treatment. Mitophagy, a selective subtype of autophagy that eliminates damaged or surplus mitochondria, is crucial for tumorigenesis, progression, and treatment resistance in cancers. This review discusses the intricate regulatory pathways of mitophagy in PDAC, focusing on the PINK1/Parkin pathway and receptor-mediated pathways. Furthermore, it explores the therapeutic potential of targeting mitophagy to increase the effectiveness of existing treatments and improve patient survival. Current evidence indicates that combining mitophagy inhibition with conventional chemotherapy yields promising yet inconsistent results, which may be attributed to the context-dependent functions of mitophagy and a lack of specific inhibitors. This review highlights the therapeutic potential of targeting mitophagy in PDAC and underscores the necessity for biomarker-driven patient stratification and the development of pathway-specific modulators in future clinical efforts.