bims-stacyt 2022-10-23 papers

Nat Commun. 2022 Oct 20. 13(1): 6239

Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression.

Zhongchi Li, Vivien Low, Valbona Luga, Janet Sun, Ethan Earlie, Bobak Parang, Kripa Shobana Ganesh, Sungyun Cho, Jennifer Endress, Tanya Schild, Mengying Hu, David Lyden, Wenbing Jin, Chunjun Guo, Noah Dephoure, Lewis C Cantley, Ashley M Laughney, John Blenis.

The systemic metabolic shifts that occur during aging and the local metabolic alterations of a tumor, its stroma and their communication cooperate to establish a unique tumor microenvironment (TME) fostering cancer progression. Here, we show that methylmalonic acid (MMA), an aging-increased oncometabolite also produced by aggressive cancer cells, activates fibroblasts in the TME, which reciprocally secrete IL-6 loaded extracellular vesicles (EVs) that drive cancer progression, drug resistance and metastasis. The cancer-associated fibroblast (CAF)-released EV cargo is modified as a result of reactive oxygen species (ROS) generation and activation of the canonical and noncanonical TGFβ signaling pathways. EV-associated IL-6 functions as a stroma-tumor messenger, activating the JAK/STAT3 and TGFβ signaling pathways in tumor cells and promoting pro-aggressive behaviors. Our findings define the role of MMA in CAF activation to drive metastatic reprogramming, unveiling potential therapeutic avenues to target MMA at the nexus of aging, the tumor microenvironment and metastasis.

DOI: https://doi.org/10.1038/s41467-022-33862-0

Adv Biol (Weinh). 2022 Oct 20. e2200161

Macrophages in Tumor-Associated Adipose Microenvironment Accelerate Tumor Progression.

Bei Li, Siqing Liu, Qian Yang, Zhiyu Li, Juanjuan Li, Juan Wu, Shengrong Sun, Zhiliang Xu, Si Sun, Qi Wu.

Adipose-tissue macrophages (ATMs), a complex ensemble of diverse macrophage subtypes, are prevalent in the tumor-adipose microenvironment (TAME) and facilitate tumor growth. However, the mechanisms in which the tumor-adipocyte crosstalk may enable the properties and plasticity of macrophages remain unclear. The single-cell RNA-sequence profiling reveals that a subset of macrophages expressed CD163, CCL2, and CCL5 in TAME, exhibiting an immunosuppressive subtype. It is demonstrated that CD163+ macrophages aggregate to surround adipocytes in breast cancer tissues. The expressions of CCL2 and CCL5 are also elevated in TAME and enable the recruitment and polarize macrophages. Mechanically, the level of exosomal miRNA-155 increased in the coculture of tumor cells and adipocytes, and then it promoted the generation and release of CCL2 and CCL5 from adipocytes by targeting the SOCS6/STAT3 pathway. Inhibition of exosomal miRNA-155 in tumor cells reduced the CCL2 and CCL5 levels in tumor-adipocytes coculture and further retarded tumor growth. Finally, the deletion of macrophages partially inhibited adipocyte-induced tumor proliferation. Likewise, inhibiting chemokines and their receptors or suppressing the phosphorylation of STAT3 decreased tumor burden in preclinical models. These results demonstrate that the niche factors in TAME, such as exosomal miRNA-155, regulate the function and polarity of macrophages to facilitate tumor progression.

Keywords: adipocytes; cancer; exosomes; macrophages; obesity

DOI: https://doi.org/10.1002/adbi.202200161

Oncogenesis. 2022 Oct 16. 11(1): 62

Metabolic guidance and stress in tumors modulate antigen-presenting cells.

Jaeoh Park, Limei Wang, Ping-Chih Ho.

Successful antitumor immunity largely relies on efficient T cell priming by antigen-presenting cells (APCs); however, the capacity of APCs is found to be defective in many cancers. Metabolically reprogrammed cancer cells support the energetic and biosynthetic demands of their high proliferation rates by exploiting nutrients available in the tumor microenvironment (TME), which in turn limits proper metabolic reprogramming of APCs during recruitment, differentiation, activation and antigen presentation. Furthermore, some metabolites generated by the TME are unfavorable to antitumor immunity. This review summarizes recent studies on the metabolic features of APCs and their functionality in the TME. Particularly, we will describe how APCs respond to altered TME and how metabolic byproducts from cancer and immunomodulatory cells affect APCs. Finally, we introduce the current status of APC-oriented research and clinical trials targeting metabolic features to boost efficient immunotherapy.

DOI: https://doi.org/10.1038/s41389-022-00438-y

Cancer Biol Med. 2022 Oct 24. pii: j.issn.2095-3941.2022.0381. [Epub ahead of print]

Metabolic regulation of immune responses to cancer.

Jannis Wißfeld, Anke Werner, Xin Yan, Nora Ten Bosch, Guoliang Cui.

The tumor microenvironment is an ecosystem composed of multiple types of cells, such as tumor cells, immune cells, and cancer-associated fibroblasts. Cancer cells grow faster than non-cancerous cells and consume larger amounts of nutrients. The rapid growth characteristic of cancer cells fundamentally alters nutrient availability in the tumor microenvironment and results in reprogramming of immune cell metabolic pathways. Accumulating evidence suggests that cellular metabolism of nutrients, such as lipids and amino acids, beyond being essential to meet the bioenergetic and biosynthetic demands of immune cells, also regulates a broad spectrum of cellular signal transduction, and influences immune cell survival, differentiation, and anti-tumor effector function. The cancer immunometabolism research field is rapidly evolving, and exciting new discoveries are reported in high-profile journals nearly weekly. Therefore, all new findings in this field cannot be summarized within this short review. Instead, this review is intended to provide a brief introduction to this rapidly developing research field, with a focus on the metabolism of two classes of important nutrients-lipids and amino acids-in immune cells. We highlight recent research on the roles of lipids and amino acids in regulating the metabolic fitness and immunological functions of T cells, macrophages, and natural killer cells in the tumor microenvironment. Furthermore, we discuss the possibility of "editing" metabolic pathways in immune cells to act synergistically with currently available immunotherapies in enhancing anti-tumor immune responses.

Keywords: Lipids; NK cells; T cells; amino acids; anti-tumor immunity; cancer; immunometabolism; metabolism

DOI: https://doi.org/10.20892/j.issn.2095-3941.2022.0381

Mol Metab. 2022 Oct 13. pii: S2212-8778(22)00181-8. [Epub ahead of print] 101612

Lcn2 mediates adipocyte-muscle-tumor communication and hypothermia in pancreatic cancer cachexia.

Mengistu Lemecha, Jaya Chalise, Yuki Takamuku, Guoxiang Zhang, Takahiro Yamakawa, Garrett Larson, Keiichi Itakura.

OBJECTIVE: Adipose tissue is the largest endocrine organ. When activated by cancer cells, adipocytes secrete adipocytokines and release fatty acids, which are then transferred to cancer cells and used for structural and biochemical support. How this metabolic symbiosis between cancer cells and adipocytes affects skeletal muscle and thermogenesis during cancer cachexia is unknown. Cancer cachexia is a multiorgan syndrome and how the communication between tissues is established has yet to be determined. We investigated adipose tissue secretory factors and explored their role in crosstalk of adipocytes, muscle, and tumor during pancreatic cancer cachexia.METHODS: We used a pancreatic cancer cachexia mouse model generated by syngenic implantation of pancreatic ductal adenocarcinoma (PDAC) cells (KPC) intraperitoneally into C57BL/6 mice and Lcn2-knockout mice. For in vitro studies, adipocytes (3T3-L1 and primary adipocytes), cachectic cancer cells (Panc0203), non-cachectic cancer cells (Du145 cells), and skeletal muscle cells (C2C12 myoblasts) were used.
RESULTS: To identify molecules involved in the crosstalk of adipose tissue with muscle and tumors, we treated 3T3-L1 adipocytes with conditioned medium (CM) from cancer cells. Upon screening the secretomes from PDAC-induced adipocytes, several adipocytokines were identified, including lipocalin 2 (Lcn2). We investigated Lcn2 as a potential mediator of cachexia induced by adipocytes in response to PDAC. During tumor progression, mice exhibited a decline in body weight gain, which was accompanied by loss of adipose and muscle tissues. Tumor-harboring mice developed drastic hypothermia because of a dramatic loss of fat in brown adipose tissue (BAT) and suppression of the thermogenesis pathway. We inhibited Lcn2 with an anti-Lcn2 antibody neutralization or genomic ablation in mice. Lcn2 deficiency significantly improved body temperature in tumor-bearing mice, which was supported by the increased expression of Ucp1 and β3-adrenergic receptor in BAT. In addition, Lcn2 inhibition abrogated the loss of fat and muscle in tumor-bearing mice. In contrast to tumor-bearing WT mice, the corresponding Lcn2-knockout mice showed reduced ATGL expression in iWAT and decreased the expression of muscle atrophy molecular markers MuRF-1 and Fbx32.
CONCLUSIONS: This study showed that Lcn2 is causally involved in the dysregulation of adipose tissue-muscle-tumor crosstalk during pancreatic cancer cachexia. Therapeutic targets that suppress Lcn2 may minimize the progression of cachexia.

Keywords: BAT; Cachexia; Hypothermia; Lcn2; PDAC; Thermogenesis

DOI: https://doi.org/10.1016/j.molmet.2022.101612