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The role of fatty acid metabolism, including both anabolic and catabolic reactions in cancer has gained increasing attention in recent years. Many studies have shown that aberrant expression of the genes involved in fatty acid synthesis or fatty acid oxidation correlate with malignant phenotypes including metastasis, therapeutic resistance and relapse. Such phenotypes are also strongly associated with the presence of a small percentage of unique cells among the total tumor cell population. This distinct group of cells may have the ability to self-renew and propagate or may be able to develop resistance to cancer therapies independent of genetic alterations. Therefore, these cells are referred to as cancer stem cells/tumor-initiating cells/drug-tolerant persisters, which are often refractory to cancer treatment and difficult to target. Moreover, interconversion between cancer cells and cancer stem cells/tumor-initiating cells/drug-tolerant persisters may occur and makes treatment even more challenging. This review highlights recent findings on the relationship between fatty acid metabolism, cancer stemness and therapeutic resistance and prompts discussion about the potential mechanisms by which fatty acid metabolism regulates the fate of cancer cells and therapeutic resistance.

Characterised by high intra‐ and inter‐tumor heterogeneity, metastatic renal cell carcinoma (RCC) is resistant to chemo‐ and radiotherapy. Therefore, the development of new prognostic and diagnostic markers for RCC patients is needed. Cancer stem cells (CSCs) are a small population of neoplastic cells within a tumor which present characteristics reminiscent of normal stem cells. CSCs are characterised by unlimited cell division, maintenance of the stem cell pool (self‐renewal), and capability to give rise to all cell types within a tumor; and contribute to metastasis in vivo (tumourigenicity), treatment resistance and recurrence. So far, many studies have tried to establish unique biomarkers to identify CSC populations in RCC. At the same time, different approaches have been developed with the aim to isolate CSCs. Consequently, several markers were found to be specifically expressed in CSCs and cancer stem‐like cells derived from RCC such as CD105, ALDH1, OCT4, CD133, and CXCR4. However, the contribution of genetic and epigenetic mechanisms, and tumor microenvironment, to cellular plasticity have made the discovery of unique biomarkers a very difficult task. In fact, contrasting results regarding the applicability of such markers to the isolation of renal CSCs have been reported in the literature. Therefore, a better understanding of the mechanism underlying CSC may help dissecting tumor heterogeneity and drug treatment efficiency.

Mitochondria Sirtuins including SIRT4 erase a variety of posttranslational modifications from mitochondria proteins, leading to metabolic reprogramming that acts as a tumor suppressor, oncogenic promotor, or both. However, the factors and the underlying mechanisms that stimulate and relay such a signaling cascade are poorly understood. Here, we reveal that the voltage‐gated calcium channel subunit α2δ1‐mediated calcium signaling can upregulate the expression of SIRT4, which is highly expressed in α2δ1‐positive pancreatic tumor‐initiating cells (TICs). Furthermore, SIRT4 is functionally sufficient and indispensable to promote TIC properties of pancreatic cancer cells by directly deacetylating ENO1 at K358, leading to attenuated ENO1's RNA‐binding capacity, enhanced glycolytic substrate 2‐PG affinity, and subsequently robust catalytic activity with boosted glycolytic ability and increased production of lactate acid. Interestingly, both SIRT4 and deacetylated mimetic of ENO1‐K358 can increase the lactylation of histones at multiple sites including H3K9 and H3K18 sites, which resulted in epigenetic reprogramming to directly activate a variety of pathways that are essential for stemness. Hence, the study links α2δ1‐mediated calcium signaling to SIRT4‐mediated histone lactylation epigenetic reprogramming in promoting the stem cell‐like properties of pancreatic cancer, which holds significant potential for the development of novel therapeutic strategies by targeting TICs of pancreatic cancer. As a downstream target of α2δ1‐mediated calcium signaling, SIRT4 serves as an oncogene to promote the stemness of pancreatic cancer via deacetylating ENO1 directly at K358, leading to attenuated ENO1's RNA‐binding capacity, enhanced glycolytic substrate 2‐PG binding and robust glycolytic activity to increase the level of lactate that induce histone lactylation to epigenetically regulate signaling pathways essential for stemness.

Although tumor‐initiating cell (TIC) self‐renewal has been postulated to be essential in progression and metastasis formation of human pancreatic adenocarcinoma (PDAC), clonal dynamics of TICs within PDAC tumors are yet unknown. Here, we show that long‐term progression of PDAC in serial xenotransplantation is driven by a succession of transiently active TICs producing tumor cells in temporally restricted bursts. Clonal tracking of individual, genetically marked TICs revealed that individual tumors are generated by distinct sets of TICs with very little overlap between subsequent xenograft generations. An unexpected functional and phenotypic plasticity of pancreatic TICs in vivo underlies the recruitment of inactive TIC clones in serial xenografts. The observed clonal succession of TIC activity in serial xenotransplantation is in stark contrast to the continuous activity of limited numbers of self‐renewing TICs within a fixed cellular hierarchy observed in other epithelial cancers and emphasizes the need to target TIC activation, rather than a fixed TIC population, in PDAC. Synopsis Molecular tracking of single tumor initiating cells (TIC) of pancreatic ductal adenocarcinoma (PDAC) xenografts in vivo reveals the functional and phenotypic plasticity of transiently active TIC producing temporally restricted tumor cell bursts. PDAC TIC are functionally and phenotypically plastic. Transiently active PDAC TIC produce tumor cells in a succession of temporally restricted bursts. Long‐term progression of pancreatic cancer is driven by functional plasticity. Graphical Abstract Molecular tracking of single tumor initiating cells (TIC) of pancreatic ductal adenocarcinoma (PDAC) xenografts in vivo reveals the functional and phenotypic plasticity of transiently active TIC producing temporally restricted tumor cell bursts.

Principles of Stem Cell Biology and Cancer: Future Applications and Therapeutics Tarik Regad, The John van Geest Cancer Research Centre, Nottingham Trent University, UK, Thomas J. Sayers, Centre for Cancer Research, National Cancer Institute, Frederick, USA and Robert Rees The John van Geest Cancer Research Centre, Nottingham Trent University, UK The field of cancer stem cells is expanding rapidly, with many groups focusing on isolating and identifying cancer stem cell populations. Although some progress has been made developing efficient cancer therapies, targeting cancer stem cells remains one of the important challenges facing the growing stem cell research community. Principles of Stem Cell Biology and Cancer brings together original contributions from international experts in the field to present the very latest information linking stem cell biology and cancer. Divided into two parts, the book begins with a detailed introduction to stem cell biology with a focus on the characterization of these cells, progress that has been made in their identification, as well as future therapeutic applications of stem cells. The second part focuses on cancer stem cells and their role in cancer development, progression and chemo-resistance. This section of the book includes an overview of recent progress concerning therapies targeting cancer stem cells. Features: An authoritative introduction to the link between stem cell biology and cancer. Includes contributions from leading international experts in the field. Well-illustrated with full colour figures throughout. This book will prove an invaluable resource for basic and applied researchers and clinicians working on the development of new cancer treatments and therapies, providing a timely publication of high quality reviews outlining the current progress and exciting future possibilities for stem cell research.

In patients with triple‐negative breast cancer (TNBC), evidence suggests that tumor‐initiating cells (TIC) have stem cell‐like properties, leading to invasion and metastasis. HSP90 plays a critical role in the conformational maintenance of many client proteins in TIC development. Therefore, we hypothesize that the novel C‐terminal HSP90 inhibitors KU711 and KU758 can target TIC and represent a promising strategy for overcoming metastasis. Human breast cancer cells (MDA‐MB‐468LN, MDA‐MB‐231) treated with the HSP90 inhibitors KU711, KU758, and 17‐AAG showed a 50–80% decrease in TIC markers CD44 and aldehyde dehydrogenase (P < 0.01) as assessed by flow cytometry. A decrease in sphere formation, which was used to assess self‐renewal, was observed after the treatment of TNBC cells starting at 2.5 µm KU711 and 0.31 µm KU758. KU compounds also blocked the invasion and migration of TNBC cells in a dose‐dependent manner. The knockdown of HSP90 clients was observed without any change in prosurvival HSP70 levels. In vivo, in a murine orthotopic breast cancer model, treatment with KU758 and KU711 yielded an approximately twofold and a fourfold reduction in tumor volumes versus control, respectively, without demonstrated toxicity. In conclusion, C‐terminal HSP90 inhibitors are potent novel therapeutics against TNBC in vitro and in vivo as they target TICs and block invasion, EMT transition, and self‐renewal. C‐terminal HSP90 inhibitors KU711 and KU758 reduce tumor growth of triple‐negative breast cancer xenografts by targeting Akt/mTOR and MAPK/ERK pathways, cancer stem cells, migration, and EMT transition.

In liver cancer, leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) compartment represents an important tumor-initiating cell (TIC) population and served as a potential therapeutic target. Cancer-associated fibroblasts (CAFs) is a critical part of the tumor microenvironment, heavily influenced TIC function and fate. However, deeply investigations have been hindered by the lack of accurate preclinical models to investigate the interaction between CAFs and TIC. Organoids model have achieved major advancements as a precious research model for recapitulating the morphological aspects of organs, and thus also serving as a candidate model to investigate the mutual interaction between different cell types. Consequently, this study aimed to construct a three-dimensional (3D) co-culture organoid model of primary LGR5-expressing tumor stem cells from primary murine liver tumors with CAFs to investigate the impact of CAFs on LGR5 marked TICs in liver cancer. First, both of the transgenic LGR5-diphtheria toxin receptor (DTR)-GFP knock-in mice and transgenic Rosa26-mT mice developed primary liver tumors by diethylnitrosamine (DEN) administration. Tumor organoids and CAFs were generated from those primary liver cancer separately. Second, LGR5-expressing TICs organoid with CAFs were established ex vivo based on cell-cell contact or trans-well co-culture system, and the mutual influence between those two types of cells was further investigated. Subsequently, immunodeficient mouse-based xenograft model was further adopted to evaluate the influence of CAFs to LGR5 tumor stem cell, tumor formation, and metastasis. The co-culture organoid model composed of murine liver tumor LGR5+ tumor-initiating cells and CAFs in 3D co-culture was successfully established, with the intention to investigate their mutual interaction. The existence of CAFs upon engrafting tumor organoids resulted in dramatic higher number of LGR5+ cells in the neoplasia when compared with engrafting tumor organoids alone. Furthermore, ex vivo culture of isolated LGR5+ cells from tumors of co-engrafted mice formed significantly larger size of organoids than mono-engrafted. Our results also indicated significantly larger size and number of formed organoids, when LGR5+ cells co-cultured with CAF in both cell-cell contact and paracrine signaling in vitro, comparing to LGR5+ cells alone. Furthermore, we found that specific knockout of LGR5 expressing cells suppressed CAF-mediated promotion of tumor formation, growth, and metastasis in the experimental mice model. Altogether, in a 3D co-culture type of murine liver LGR5+ cells and cancer-associated fibroblasts, we have demonstrated robust effects of CAFs in the promotion of LGR5 marked liver TICs. We also further revealed the influence of tumor microenvironment on stem cell-related therapy, suggesting the possibility of combing CAF-targeted and tumor stem cell targeted therapy in treating liver cancer.

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer‐related death worldwide and lacks biomarkers for personalized therapy. Herein, it is reported that MCB1 could be a novel oncofetal protein that is upregulated in the preneoplastic lesions and serum of early HCC patients. Functional studies reveal that MCB1 modulated p53 protein degradation to promote T‐IC generation and drive HCC initiation. Furthermore, the MCB1/p53 axis is shown to determine the responses of hepatoma cells to conventional chemotherapeutics and predict transcatheter arterial chemoembolization (TACE) benefits in patients. Importantly, MCB1 can mediate sorafenib/lenvatinib resistance by downregulating two essential drug targets fibroblast growth factor receptor 1 (FGFR1) and vascular endothelial growth factor receptor 3 (VEGFR3) expression in a proteasome‐dependent manner. Patient‐derived tumor organoids (PDOs), patient‐derived xenografts (PDXs), and patient cohorts analysis suggested that MCB1 levels in HCCs may determine the distinct responses to conventional therapeutics and targeted drugs. Furthermore, treatment of targeted drugs‐resistant HCC with adeno‐associated virus (AAV) targeting MCB1 or a proteasome inhibitor restores targeted drug response, suggesting their clinical significance in HCC combinational therapy. In conclusion, these findings demonstrate that MCB1 could act as a driver for HCC initiation, a contributor to drug resistance, and a biomarker for individualized HCC therapy. Oncofetal protein MCB1 promotes T‐IC generation and drives HCC initiation through accelerating p53 degradation, and MCB1/p53 axis determines the responses of HCC cells to conventional chemotherapeutics. MCB1 also mediates sorafenib/lenvatinib resistance by downregulating FGFR1 and VEGFR3 expression in a proteasome‐dependent manner and serves as a potential biomarker for individualized HCC therapy.

When PIWIL2 expression is restored via heterogeneous integration of human papillomavirus, cellular reprogramming is initiated to form tumor‐initiating cells (TICs), which triggers cervical squamous intraepithelial lesions (SIL). TIC stemness is critical for the prognosis of SIL. However, the mechanisms underlying TIC stemness maintenance and tumorigenicity remain unclear. Here, it is revealed that aberrant pyruvate dehydrogenase kinase 1 (PDK1) expression is closely related to aerobic glycolysis in SIL and poor survival in patients with cervical cancer. Mechanistically, that PIWIL2, which induced by stable transfection of either PIWIL2 or HPV16 oncogene E6 in human primary cervical basal epithelial cells and keratinocyte cell line HaCaT, upregulates PDK1 expression via the LIN28/let‐7 axis, hence reprogramming metabolism to activate glycolysis and synchronize with TIC formation. It is further demonstrate that PDK1 is critical for TIC stemness maintenance and tumorigenicity via the PI3K/AKT/mTOR pathway both in vitro and in vivo, revealing a previously unclear mechanism for SIL progression, regression or relapse. Therefore, this findings suggest a potential rationale for prognostic predictions and selecting targeted therapy for cervical lesions. Heterogeneous integration of HPV restores PIWIL2 expression to cause TIC formation via initiating cellular reprogram. This study is the first to verify that PIWIL2 upregulates PDK1 expression, hence reprogramming metabolism to maintain TIC stemness and tumorigenicity via the PI3K/AKT/mTOR pathway both in vitro and in vivo, highlighting a potential prognostic prediction and therapeutic target for cervical lesions.

Tumor‐initiating cells (TICs) resilience and an immunosuppressive microenvironment are aggressive oncogenic phenotypes that contribute to unsatisfactory long‐term outcomes in lung adenocarcinoma (LUAD) patients. The molecular mechanisms mediating the interaction between TICs and immune tolerance have not been elucidated. The role of Galectin‐9 in oncogenesis and immunosuppressive microenvironment is still unknown. This study explored the potential role of galectin‐9 in TIC regulation and immune modulation in LUAD. The results show that galectin‐9 supports TIC properties in LUAD. Co‐culture of patient‐derived organoids and matched peripheral blood mononuclear cells showed that tumor‐secreted galectin‐9 suppressed T cell cytotoxicity and induced regulatory T cells (Tregs). Clinically, galectin‐9 is upregulated in human LUAD. High expression of galectin‐9 predicted poor recurrence‐free survival and correlated with high levels of Treg infiltration. LGALS9, the gene encoding galectin‐9, is found to be transcriptionally regulated by the nuclear factor of activated T cells 2 (NFATc2), a previously reported TIC regulator, via in silico prediction and luciferase reporter assays. Overall, the results suggest that the NFATc2/galectin‐9 axis plays a dual role in TIC regulation and immune suppression. This study unveils the important role of NFATc2/galectin‐9 axis in modulating tumor‐initiating cell (TIC) phenotypes and immune suppression in lung cancer. Galectin‐9 secreted from tumor cells suppresses CD8+ T cell cytotoxicity and induces regulatory T cell fraction. The study illustrates galectin‐9 to be a promising prognostic marker and therapeutic target for targeting the TIC pool and immune‐suppressive microenvironment.