bims-tumime 2024-07-07 papers

Issue of 2024–07–07
six papers selected by
Alex Muir, University of Chicago

J Immunother Cancer. 2024 Jul 04. pii: e008434. [Epub ahead of print]12(7):

Genetically engineering glycolysis in T cells increases their antitumor function.

Raphaëlle Toledano Zur, Orna Atar, Tilda Barliya, Shiran Hoogi, Ifat Abramovich, Eyal Gottlieb, Noga Ron-Harel, Cyrille J Cohen.

BACKGROUND: T cells play a central role in the antitumor response. However, they often face numerous hurdles in the tumor microenvironment, including the scarcity of available essential metabolites such as glucose and amino acids. Moreover, cancer cells can monopolize these resources to thrive and proliferate by upregulating metabolite transporters and maintaining a high metabolic rate, thereby outcompeting T cells.
METHODS: Herein, we sought to improve T-cell antitumor function in the tumor vicinity by enhancing their glycolytic capacity to better compete with tumor cells. To achieve this, we engineered human T cells to express a key glycolysis enzyme, phosphofructokinase, in conjunction with Glucose transporter 3, a glucose transporter. We co-expressed these, along with tumor-specific chimeric antigen or T-cell receptors.
RESULTS: Engineered cells demonstrated an increased cytokine secretion and upregulation of T-cell activation markers compared with control cells. Moreover, they displayed superior glycolytic capacity, which translated into an improved in vivo therapeutic potential in a xenograft model of human tumors.
CONCLUSION: In summary, these findings support the implementation of T-cell metabolic engineering to enhance the efficacy of cellular immunotherapies for cancer.

Keywords: Immunotherapy; Receptors, Antigen; T-Lymphocytes

DOI: https://doi.org/10.1136/jitc-2023-008434

Br J Cancer. 2024 Jul 05.

Metabolic adaptations in prostate cancer.

Mikel Pujana-Vaquerizo, Laura Bozal-Basterra, Arkaitz Carracedo.

Prostate cancer is one of the most commonly diagnosed cancers in men and is a major cause of cancer-related deaths worldwide. Among the molecular processes that contribute to this disease, the weight of metabolism has been placed under the limelight in recent years. Tumours exhibit metabolic adaptations to comply with their biosynthetic needs. However, metabolites also play an important role in supporting cell survival in challenging environments or remodelling the tumour microenvironment, thus being recognized as a hallmark in cancer. Prostate cancer is uniquely driven by androgen receptor signalling, and this knowledge has also influenced the paths of cancer metabolism research. This review provides a comprehensive perspective on the metabolic adaptations that support prostate cancer progression beyond androgen signalling, with a particular focus on tumour cell intrinsic and extrinsic pathways.

DOI: https://doi.org/10.1038/s41416-024-02762-z

J Cell Physiol. 2024 Jun 30.

Amino acid metabolic reprogramming in the tumor microenvironment and its implication for cancer therapy.

Jiarong Zhang, Mingjian Chen, Yuxin Yang, Ziqi Liu, Wanni Guo, Pingjuan Xiang, Zhaoyang Zeng, Dan Wang, Wei Xiong.

Amino acids are essential building blocks for proteins, crucial energy sources for cell survival, and key signaling molecules supporting the resistant growth of tumor cells. In tumor cells, amino acid metabolic reprogramming is characterized by the enhanced uptake of amino acids as well as their aberrant synthesis, breakdown, and transport, leading to immune evasion and malignant progression of tumor cells. This article reviews the altered amino acid metabolism in tumor cells and its impact on tumor microenvironment, and also provides an overview of the current clinical applications of amino acid metabolism. Innovative drugs targeting amino acid metabolism hold great promise for precision and personalized cancer therapy.

Keywords: amino acid metabolism; immune evasion; metabolic reprogramming; tumor microenvironment; tumor resistance

DOI: https://doi.org/10.1002/jcp.31349

Cancer Res. 2024 Jul 03.

Asparagine Dependency is a Targetable Metabolic Vulnerability in TP53-Altered Castration-Resistant Prostate Cancer.

Young A Yoo, Songhua Quan, William Yang, Qianyu Guo, Yara Rodríguez, Zachary R Chalmers, Mary F Dufficy, Barbara Lackie, Vinay Sagar, Kenji Unno, Mihai I Truica, Navdeep S Chandel, Sarki A Abdulkadir.

The TP53 tumor suppressor is frequently altered in lethal, castration-resistant prostate cancer (CRPC). However, to date there are no effective treatments that specifically target TP53 alterations. Using transcriptomic and metabolomic analyses, we showed here that TP53-altered prostate cancer (PCa) exhibits an increased dependency on asparagine and overexpresses asparagine synthetase (ASNS), the enzyme catalyzing the synthesis of asparagine. Mechanistically, loss or mutation of TP53 transcriptionally activated ASNS expression, directly as well as via mTORC1-mediated ATF4 induction, driving de novo asparagine biosynthesis to support CRPC growth. TP53-altered CRPC cells were sensitive to asparagine restriction by knockdown of ASNS or L-asparaginase treatment to deplete the intracellular and extracellular sources of asparagine, respectively, and cell viability was rescued by asparagine addition. Notably, pharmacological inhibition of intracellular asparagine biosynthesis using a glutaminase inhibitor and depletion of extracellular asparagine with L-asparaginase significantly reduced asparagine production and effectively impaired CRPC growth. This study highlights the significance of ASNS-mediated metabolic adaptation as a synthetic vulnerability in CRPC with TP53 alterations, providing a rationale for targeting asparagine production to treat these lethal prostate cancers.

DOI: https://doi.org/10.1158/0008-5472.CAN-23-2910

Cell Signal. 2024 Jun 28. pii: S0898-6568(24)00249-3. [Epub ahead of print] 111281

Metabolic crosstalk: Extracellular ATP and the tumor microenvironment in cancer progression and therapy.

Sourav Shukla, Parameswar Dalai, Reena Agrawal-Rajput.

Adenosine 5'-triphosphate (ATP) is a vital element in energy information. It plays a critical role in transmitting signals inside the body, which is necessary for controlling the life activities of all cells, including tumor cells [1]. Its significance extends from intracellular signaling pathways to tumor regression. Purinergic signaling, a form of extracellular paracrine signaling, relies on purine nucleotides. Extracellular ectonucleotidases convert these purine nucleotides to their respective di and mono-phosphate nucleoside forms, contributing significantly to immune biology, cancer biology, and inflammation studies. ATP functions as a mighty damage-linked molecular pattern when released outside the cell, accumulating in inflammatory areas. In the tumor microenvironment (TME), purinergic receptors such as ATP-gated ion channels P2X1-5 and G protein-coupled receptors (GPCR) (P2Y) interact with ATP and other nucleotides, influencing diverse immune cell activities. CD39 and CD73-mediated extracellular ATP degradation contributes to immunosuppression by diminishing ATP-dependent activation and generating adenosine (ADO), potentially hindering antitumor immunity and promoting tumor development. Unraveling the complexities of extracellular ATP (e-ATP) and ADO effects on the TME poses challenges in identifying optimal treatment targets, yet ongoing investigations aim to devise strategies combating e-ATP/ADO-induced immunosuppression, ultimately enhancing anti-tumor immunity. This review explores e-ATP metabolism, its purinergic signaling, and therapeutic strategies targeting associated receptors and enzymes.

Keywords: Extracellular ATP (e-ATP); Immunosuppression; Purinergic receptors; Purinergic signaling; Therapeutic potential; Tumor microenvironment (TME)

DOI: https://doi.org/10.1016/j.cellsig.2024.111281

Cancer Metab. 2024 Jun 30. 12(1): 19

Long-acting Erwinia chrysanthemi, Pegcrisantaspase, induces alternate amino acid biosynthetic pathways in a preclinical model of pancreatic ductal adenocarcinoma.

Dominique Bollino, Kanwal Hameed, Anusha Bhat, Arveen Zarrabi, Andrea Casildo, Xinrong Ma, Kayla M Tighe, Brandon Carter-Cooper, Erin T Strovel, Rena G Lapidus, Ashkan Emadi.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease without meaningful therapeutic options beyond the first salvage therapy. Targeting PDAC metabolism through amino acid restriction has emerged as a promising new strategy, with asparaginases, enzymes that deplete plasma glutamine and asparagine, reaching clinical trials. In this study, we investigated the anti-PDAC activity of the asparaginase formulation Pegcrisantaspase (PegC) alone and in combination with standard-of-care chemotherapeutics.
METHODS: Using mouse and human PDAC cell lines, we assessed the impact of PegC on cell proliferation, cell death, and cell cycle progression. We further characterized the in vitro effect of PegC on protein synthesis as well as the generation of reactive oxygen species and levels of glutathione, a major cellular antioxidant. Additional cell line studies examined the effect of the combination of PegC with standard-of-care chemotherapeutics. In vivo, the tolerability and efficacy of PegC, as well as the impact on plasma amino acid levels, was assessed using the C57BL/6-derived KPC syngeneic mouse model.
RESULTS: Here we report that PegC demonstrated potent anti-proliferative activity in a panel of human and murine PDAC cell lines. This decrease in proliferation was accompanied by inhibited protein synthesis and decreased levels of glutathione. In vivo, PegC was tolerable and effectively reduced plasma levels of glutamine and asparagine, leading to a statistically significant inhibition of tumor growth in a syngeneic mouse model of PDAC. There was no observable in vitro or in vivo benefit to combining PegC with standard-of-care chemotherapeutics, including oxaliplatin, irinotecan, 5-fluorouracil, paclitaxel, and gemcitabine. Notably, PegC treatment increased tumor expression of asparagine and serine biosynthetic enzymes.
CONCLUSIONS: Taken together, our results demonstrate the potential therapeutic use of PegC in PDAC and highlight the importance of identifying candidates for combination regimens that could improve cytotoxicity and/or reduce the induction of resistance pathways.

Keywords: Asparaginase; Asparagine; Crisantaspase; Glutamine; KPC; Pancreatic cancer; Pegcrisantaspase

DOI: https://doi.org/10.1186/s40170-024-00346-2