bims-almceb 2021-08-22 papers

Nat Rev Cancer. 2021 Aug 20.

Tumour fatty acid metabolism in the context of therapy resistance and obesity.

Andrew J Hoy, Shilpa R Nagarajan, Lisa M Butler.

Fatty acid metabolism is known to support tumorigenesis and disease progression as well as treatment resistance through enhanced lipid synthesis, storage and catabolism. More recently, the role of membrane fatty acid composition, for example, ratios of saturated, monounsaturated and polyunsaturated fatty acids, in promoting cell survival while limiting lipotoxicity and ferroptosis has been increasingly appreciated. Alongside these insights, it has become clear that tumour cells exhibit plasticity with respect to fatty acid metabolism, responding to extratumoural and systemic metabolic signals, such as obesity and cancer therapeutics, to promote the development of aggressive, treatment-resistant disease. Here, we describe cellular fatty acid metabolic changes that are connected to therapy resistance and contextualize obesity-associated changes in host fatty acid metabolism that likely influence the local tumour microenvironment to further modify cancer cell behaviour while simultaneously creating potential new vulnerabilities.

DOI: https://doi.org/10.1038/s41568-021-00388-4

J Cancer. 2021 ;12(18): 5519-5529

Suppression Of Aberrant Activation Of NF-κB Pathway In Drug-resistant Leukemia Stem Cells Contributes To Parthenolide-potentiated Reversal Of Drug Resistance In Leukemia.

Juan Yi, Li Wang, Xiao-Yan Wang, Jing Sun, Xiao-Yang Yin, Jin-Xia Hou, Jing Chen, Bei Xie, Hu-Lai Wei.

Although many drugs that targeted the specific features of leukemia stem cells (LSCs) have substantial application in the clinical treatment of leukemia, the LSCs relapsed and caused drug-resistant leukemia. Therefore, it is necessary to identify the unique features of LSCs in relapsing and drug-resistant leukemia and also to explore the drugs that directed at these features. Our clinical data have indicated that relapsed patients with acute myeloid leukemia have more abundant proportion of LSCs with enhanced breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) expression when compared to the untreated patients. The results showed that compared with LSCs derived from sensitive K562 cells, LSCs from drug-resistant K562/ADM cells have much higher chemotherapeutic resistance, and so we termed these cells as "drug-resistant LSCs". Subsequently, aberrant activation of NF-κB pathway in drug-resistant LSCs was further using gene chip analysis. Also, parthenolide (PTL), which is a specific NF-κB inhibitor, effectively eliminated drug-resistant LSCs and enhanced the sensitivity of K562/ADM cells to doxorubicin-induced apoptosis by down-regulating NF-κB pathway-mediated P-gp expression. These findings make the research area of LSCs more abundant and provide a potential therapeutic strategy for the treatment of refractory and relapsed leukemia.

Keywords: Drug-resistant leukemia stem cells; MDR; NF-κB signaling pathway; PTL; aberrant activation

DOI: https://doi.org/10.7150/jca.52641

Leuk Lymphoma. 2021 Aug 18. 1-10

Prognostic significance of TIM-3 expression pattern at diagnosis in patients with t(8;21) acute myeloid leukemia.

Jun Wang, Lu Yang, Feng-Ting Dao, Ya-Zhe Wang, Yan Chang, Nan Xu, Wen-Min Chen, Qian Jiang, Hao Jiang, Yan-Rong Liu, Ya-Zhen Qin.

Acute myeloid leukemia (AML) with t(8;21) is a heterogeneous disease and needs to be stratified. Both, cancer cells and immune cells participate in tumor initiation, growth and progression and might affect clinical outcomes. TIM-3 (T cell immunoglobulin and mucin domain-containing protein 3), an immune checkpoint molecule, is expressed not only on immune cells but also on leukemic stem cells (LSCs) in AML. This prompted us to investigate the prognostic significance of TIM-3 in t(8;21) AML. A total of 47 t(8;21) AML patients were tested for TIM-3 expression by multi-parameter flow cytometry at diagnosis. 35 of these, who received chemotherapy alone or along with allogeneic hematopoietic stem cell transplantation were followed up. The expression pattern of TIM-3 on T-cells and NK (natural killer) cells as a whole (T + NK) and LSCs were evaluated independently. High percentage of T + NK - TIM-3+ and CD34+CD38-TIM-3+ cells were significantly associated with a high 2-year cumulative incidence of relapse (CIR) (p = 0.028, 0.016). Further, concurrent high frequencies of T + NK-TIM-3+ and CD34+CD38-TIM-3+ cells at diagnosis were significantly associated with a high 2-year CIR (p < 0.0001) and this together with c-KIT D816 mutation were the independent adverse prognostic factors for relapse (hazard ratio (HR)=2.5, [95% confidence interval (CI), 1.1-6.0], p = 0.04; HR = 46.5, [95% CI, 2.7-811.5], p = 0.009). In conclusion, the expression pattern of TIM-3 on both T and NK cells and LSCs at diagnosis had prognostic significance in t (8;21) AML.

Keywords: T and NK cells; TIM-3; leukemic stem cells; t(8;21) acute myeloid leukemia

DOI: https://doi.org/10.1080/10428194.2021.1966785

Front Oncol. 2021 ;11 678343

MitoTracker Deep Red (MTDR) Is a Metabolic Inhibitor for Targeting Mitochondria and Eradicating Cancer Stem Cells (CSCs), With Anti-Tumor and Anti-Metastatic Activity In Vivo.

Camillo Sargiacomo, Sophie Stonehouse, Zahra Moftakhar, Federica Sotgia, Michael P Lisanti.

MitoTracker Deep Red (MTDR) is a relatively non-toxic, carbocyanine-based, far-red, fluorescent probe that is routinely used to chemically mark and visualize mitochondria in living cells. Previously, we used MTDR at low nano-molar concentrations to stain and metabolically fractionate breast cancer cells into Mito-high and Mito-low cell sub-populations, by flow-cytometry. Functionally, the Mito-high cell population was specifically enriched in cancer stem cell (CSC) activity, i) showing increased levels of ESA cell surface expression and ALDH activity, ii) elevated 3D anchorage-independent growth, iii) larger overall cell size (>12-μm) and iv) Paclitaxel-resistance. The Mito-high cell population also showed enhanced tumor-initiating activity, in an in vivo preclinical animal model. Here, we explored the hypothesis that higher nano-molar concentrations of MTDR could also be used to therapeutically target and eradicate CSCs. For this purpose, we employed an ER(+) cell line (MCF7) and two triple negative cell lines (MDA-MB-231 and MDA-MB-468), as model systems. Remarkably, MTDR inhibited 3D mammosphere formation in MCF7 and MDA-MB-468 cells, with an IC-50 between 50 to 100 nM; similar results were obtained in MDA-MB-231 cells. In addition, we now show that MTDR exhibited near complete inhibition of mitochondrial oxygen consumption rates (OCR) and ATP production, in all three breast cancer cell lines tested, at a level of 500 nM. However, basal glycolytic rates in MCF7 and MDA-MB-468 cells remained unaffected at levels of MTDR of up to 1 μM. We conclude that MTDR can be used to specifically target and eradicate CSCs, by selectively interfering with mitochondrial metabolism, by employing nano-molar concentrations of this chemical entity. In further support of this notion, MTDR significantly inhibited tumor growth and prevented metastasis in vivo, in a xenograft model employing MDA-MB-231 cells, with little or no toxicity observed. In contrast, Abemaciclib, an FDA-approved CDK4/6 inhibitor, failed to inhibit metastasis. Therefore, in the future, MTDR could be modified and optimized via medicinal chemistry, to further increase its potency and efficacy, for its ultimate clinical use in the metabolic targeting of CSCs for their eradication.

Keywords: MitoTracker Deep Red (MTDR); anti-metastatic activity; anti-tumor activity; cancer stem-like cells (CSCs); cancer therapy; mitochondria; near-infrared dyes (NIR)

DOI: https://doi.org/10.3389/fonc.2021.678343

Cancer Metab. 2021 Aug 16. 9(1): 31

Metabolic convergence on lipogenesis in RAS, BCR-ABL, and MYC-driven lymphoid malignancies.

Daniel F Liefwalker, Meital Ryan, Zhichao Wang, Khyatiben V Pathak, Seema Plaisier, Vidhi Shah, Bobby Babra, Gabrielle S Dewson, Ian K Lai, Adriane R Mosley, Patrick T Fueger, Stephanie C Casey, Lei Jiang, Patrick Pirrotte, Srividya Swaminathan, Rosalie C Sears.

BACKGROUND: Metabolic reprogramming is a central feature in many cancer subtypes and a hallmark of cancer. Many therapeutic strategies attempt to exploit this feature, often having unintended side effects on normal metabolic programs and limited efficacy due to integrative nature of metabolic substrate sourcing. Although the initiating oncogenic lesion may vary, tumor cells in lymphoid malignancies often share similar environments and potentially similar metabolic profiles. We examined cells from mouse models of MYC-, RAS-, and BCR-ABL-driven lymphoid malignancies and find a convergence on de novo lipogenesis. We explore the potential role of MYC in mediating lipogenesis by 13C glucose tracing and untargeted metabolic profiling. Inhibition of lipogenesis leads to cell death both in vitro and in vivo and does not induce cell death of normal splenocytes.
METHODS: We analyzed RNA-seq data sets for common metabolic convergence in lymphoma and leukemia. Using in vitro cell lines derived in from conditional MYC, RAS, and BCR-ABL transgenic murine models and oncogene-driven human cell lines, we determined gene regulation, metabolic profiles, and sensitivity to inhibition of lipogenesis in lymphoid malignancies. We utilize preclinical murine models and transgenic primary model of T-ALL to determine the effect of lipogenesis blockade across BCR-ABL-, RAS-, and c-MYC-driven lymphoid malignancies. Statistical significance was calculated using unpaired t-tests and one-way ANOVA.
RESULTS: This study illustrates that de novo lipid biogenesis is a shared feature of several lymphoma subtypes. Using cell lines derived from conditional MYC, RAS, and BCR-ABL transgenic murine models, we demonstrate shared responses to inhibition of lipogenesis by the acetyl-coA carboxylase inhibitor 5-(tetradecloxy)-2-furic acid (TOFA), and other lipogenesis inhibitors. We performed metabolic tracing studies to confirm the influence of c-MYC and TOFA on lipogenesis. We identify specific cell death responses to TOFA in vitro and in vivo and demonstrate delayed engraftment and progression in vivo in transplanted lymphoma cell lines. We also observe delayed progression of T-ALL in a primary transgenic mouse model upon TOFA administration. In a panel of human cell lines, we demonstrate sensitivity to TOFA treatment as a metabolic liability due to the general convergence on de novo lipogenesis in lymphoid malignancies driven by MYC, RAS, or BCR-ABL. Importantly, cell death was not significantly observed in non-malignant cells in vivo.
CONCLUSIONS: These studies suggest that de novo lipogenesis may be a common survival strategy for many lymphoid malignancies and may be a clinically exploitable metabolic liability.
TRIAL REGISTRATION: This study does not include any clinical interventions on human subjects.

Keywords: ACACA; BCR-ABL; Cancer metabolism; De novo lipogenesis; FASN; Fatty acid synthesis; Lipogenesis; Lymphoma; Oncogene addiction; RAS; T-ALL; c-MYC

DOI: https://doi.org/10.1186/s40170-021-00263-8

Blood Cancer J. 2021 Aug 14. 11(8): 144

Targeting of IL-10R on acute myeloid leukemia blasts with chimeric antigen receptor-expressing T cells.

Nianci Chen, Yingxi Xu, Junli Mou, Qing Rao, Haiyan Xing, Zheng Tian, Kejing Tang, Min Wang, Jiangxiang Wang.

Acute myeloid leukemia (AML) is a biologically and clinically heterogeneous disease with a dismal prognosis and limited treatment options. Chimeric antigen receptor (CAR) T cells have achieved unprecedented clinical responses in patients with B cell malignancies but a dismal consequences in AML. In our previous study, we found that interleukin-10 receptor (IL-10R) was overexpressed in most AML cells, and played an important role in promoting the stemness of leukemia cells. In this study, we developed a novel ligand-based CAR-T cell targeting IL-10R, which displayed striking cytotoxicity both in vitro and in vivo against AML cells. Except for monocytes, it had no significant adverse effects on the normal hematopoietic system, including CD34+ hematopoietic stem and progenitor cells (HSPCs). In addition, even though the incorporation of IL-10 in the CAR cassette led to phenotypes change, it had few adverse effects on the survival and biological activity of IL-10 CAR-T cells and did not cause excessive proliferation of leukemia cells. Therefore, we propose IL-10R is a novel promising therapeutic candidate for AML, and IL-10R targeted CAR-T therapy provides a new treatment strategy to improve the prognosis of AML.

DOI: https://doi.org/10.1038/s41408-021-00536-x

Cancer Manag Res. 2021 ;13 6291-6307

The Crucial Roles of Intermediate Metabolites in Cancer.

Sisi Huang, Zhiqin Wang, Liang Zhao.

Metabolic alteration, one of the hallmarks of cancer cells, is important for cancer initiation and development. To support their rapid growth, cancer cells alter their metabolism so as to obtain the necessary energy and building blocks for biosynthetic pathways, as well as to adjust their redox balance. Once thought to be merely byproducts of metabolic pathways, intermediate metabolites are now known to mediate epigenetic modifications and protein post-transcriptional modifications (PTM), as well as connect cellular metabolism with signal transduction. Consequently, they can affect a myriad of processes, including proliferation, apoptosis, and immunity. In this review, we summarize multiple representative metabolites involved in glycolysis, the pentose phosphate pathway (PPP), the tricarboxylic acid (TCA) cycle, lipid synthesis, ketogenesis, methionine metabolism, glutamine metabolism, and tryptophan metabolism, focusing on their roles in chromatin and protein modifications and as signal-transducing messengers.

Keywords: epigenetic modification; extra-metabolic functions; oncometabolites; post-transcriptional modifications; signaling transduction

DOI: https://doi.org/10.2147/CMAR.S321433