bims-almceb 2021-10-10 papers

Blood. 2021 Oct 05. pii: blood.2021011563. [Epub ahead of print]

Proton export alkalinizes intracellular pH and reprograms carbon metabolism to drive hematopoietic progenitor growth.

Cheuk Him Man, Francois Emile Mercier, Nian Liu, Wentao Dong, Gregory Stephanopoulos, Li Jiang, Yookyung Jung, Charles Lin, Anskar Yh Leung, David T Scadden.

Proton export is often considered a detoxifying process in animal cells with monocarboxylate symporters co-exporting excessive lactate and protons during glycolysis or the Warburg effect. Here we report a novel mechanism by which lactate/H+ export is sufficient to induce cell growth. Increased lactate/proton export induces intracellular alkalization that selectively activates catalysis by key metabolic gatekeeper enzymes, HK1/PKM2/G6PDH, thereby enhancing glycolytic and pentose phosphate pathway carbon flux. The result is increased nucleotide levels, NADPH/NADP+ ratio and cell proliferation. Simply increasing the lactate/proton symporter, MCT4, or sodium-proton antiporter, NHE1 was sufficient to increase intracellular-pH (pHi) and give normal hematopoietic cells a significant competitive growth advantage in vivo. This process does not require additional cytokine triggers and is exploited in malignancy where leukemogenic mutations epigenetically increase MCT4. Inhibiting MCT4 decreased intracellular pH, carbon flux and eliminated acute myeloid leukemia-initiating-cells without cytotoxic chemotherapy. Intracellular alkalization is a primitive mechanism by which proton partitioning can directly reprogram carbon metabolism for cell growth.

DOI: https://doi.org/10.1182/blood.2021011563

Trends Immunol. 2021 Oct 02. pii: S1471-4906(21)00178-2. [Epub ahead of print]

Metabolic regulation of the cancer-immunity cycle.

Luis F Somarribas Patterson, Santosha A Vardhana.

The cancer-immunity cycle (CIC) comprises a series of events that are required for immune-mediated control of tumor growth. Interruption of one or more steps of the CIC enables tumors to evade immunosurveillance. However, attempts to restore antitumor immunity by reactivating the CIC have had limited success thus far. Recently, numerous studies have implicated metabolic reprogramming of tumor and immune cells within the tumor microenvironment (TME) as key contributors to immune evasion. In this opinion, we propose that alterations in cellular metabolism during tumorigenesis promote both initiation and disruption of the CIC. We also provide a rationale for metabolically targeting the TME, which may assist in improving tumor responsiveness to chimeric antigen receptor (CAR)-transduced T cells or immune checkpoint blockade (ICB) therapies.

Keywords: CAR-T cells; PD-1; glycolysis; immunotherapy; lactate; metabolism; tumor immunology

DOI: https://doi.org/10.1016/j.it.2021.09.002

Front Pharmacol. 2021 ;12 730751

Role of Intra- and Extracellular Lipid Signals in Cancer Stemness and Potential Therapeutic Strategy.

Jianming Hu, Leyi Zhang, Wuzhen Chen, Lesang Shen, Jingxin Jiang, Shanshan Sun, Zhigang Chen.

Accumulating evidence showed that cancer stem cells (CSCs) play significant roles in cancer initiation, resistance to therapy, recurrence and metastasis. Cancer stem cells possess the ability of self-renewal and can initiate tumor growth and avoid lethal factors through flexible metabolic reprogramming. Abnormal lipid metabolism has been reported to be involved in the cancer stemness and promote the development of cancer. Lipid metabolism includes lipid uptake, lipolysis, fatty acid oxidation, de novo lipogenesis, and lipid desaturation. Abnormal lipid metabolism leads to ferroptosis of CSCs. In this review, we comprehensively summarized the role of intra- and extracellular lipid signals in cancer stemness, and explored the feasibility of using lipid metabolism-related treatment strategies for future cancer.

Keywords: cancer stem cell; ferroptosis; lipid metabolism; therapeutic target; tumor environment

DOI: https://doi.org/10.3389/fphar.2021.730751

Clin Lymphoma Myeloma Leuk. 2021 Sep 04. pii: S2152-2650(21)02018-8. [Epub ahead of print]

Harnessing Apoptosis in AML.

Kapil Saxena, Courtney DiNardo, Naval Daver, Marina Konopleva.

The treatment landscape for acute myeloid leukemia has expanded significantly in the past 5 years with the approval of several therapeutic small molecules. While agents such as FLT3 inhibitors and IDH inhibitors are restricted for patients with specific mutations, the selective BCL-2 inhibitor venetoclax combined with a hypomethylating agent or low-dose cytarabine was approved after demonstrating frontline efficacy across a molecularly heterogenous group of patients. Currently, venetoclax is being investigated in combination with multiple other therapies as the role of the intrinsic apoptotic pathway in acute myeloid leukemia continues to be explored.

Keywords: BCL-2; BCL-XL; MCL-1; Synergy; Venetoclax

DOI: https://doi.org/10.1016/j.clml.2021.08.015