bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2023–06–04
eight papers selected by
Oltea Sampetrean, Keio University
  1. Uptake of tumor-derived microparticles induces metabolic reprogramming of macrophages in the early metastatic lung.
  2. Lipid droplets are a metabolic vulnerability in melanoma.
  3. Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer.
  4. Tumor microenvironment interactions with cancer stem cells in pancreatic ductal adenocarcinoma.
  5. Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity.
  6. Cholesterol atlas of tumor microenvironment provides route to improved CAR-T therapy.
  7. LXR Signaling-Mediated Cholesterol Metabolism Reprogramming Regulates Cancer Cell Metastasis.
  8. Adipocytes promote pancreatic cancer migration and invasion through fatty acid metabolic reprogramming.
  1. Cell Rep. 2023 May 30. pii: S2211-1247(23)00593-4. [Epub ahead of print]42(6): 112582
    Uptake of tumor-derived microparticles induces metabolic reprogramming of macrophages in the early metastatic lung.
    Kelly Kersten, Ran You, Sophia Liang, Kevin M Tharp, Joshua Pollack, Valerie M Weaver, Matthew F Krummel, Mark B Headley.
      Pre-metastatic niche formation is a critical step during the metastatic spread of cancer. One way by which primary tumors prime host cells at future metastatic sites is through the shedding of tumor-derived microparticles as a consequence of vascular sheer flow. However, it remains unclear how the uptake of such particles by resident immune cells affects their phenotype and function. Here, we show that ingestion of tumor-derived microparticles by macrophages induces a rapid metabolic and phenotypic switch that is characterized by enhanced mitochondrial mass and function, increased oxidative phosphorylation, and upregulation of adhesion molecules, resulting in reduced motility in the early metastatic lung. This reprogramming event is dependent on signaling through the mTORC1, but not the mTORC2, pathway and is induced by uptake of tumor-derived microparticles. Together, these data support a mechanism by which uptake of tumor-derived microparticles induces reprogramming of macrophages to shape their fate and function in the early metastatic lung.
    Keywords:  CP: Cancer; CP: Metabolism; infinity flow; lung; macrophages; metastasis
    DOI:  https://doi.org/10.1016/j.celrep.2023.112582
  2. Nat Commun. 2023 Jun 02. 14(1): 3192
    Lipid droplets are a metabolic vulnerability in melanoma.
    Dianne Lumaquin-Yin, Emily Montal, Eleanor Johns, Arianna Baggiolini, Ting-Hsiang Huang, Yilun Ma, Charlotte LaPlante, Shruthy Suresh, Lorenz Studer, Richard M White.
      Melanoma exhibits numerous transcriptional cell states including neural crest-like cells as well as pigmented melanocytic cells. How these different cell states relate to distinct tumorigenic phenotypes remains unclear. Here, we use a zebrafish melanoma model to identify a transcriptional program linking the melanocytic cell state to a dependence on lipid droplets, the specialized organelle responsible for lipid storage. Single-cell RNA-sequencing of these tumors show a concordance between genes regulating pigmentation and those involved in lipid and oxidative metabolism. This state is conserved across human melanoma cell lines and patient tumors. This melanocytic state demonstrates increased fatty acid uptake, an increased number of lipid droplets, and dependence upon fatty acid oxidative metabolism. Genetic and pharmacologic suppression of lipid droplet production is sufficient to disrupt cell cycle progression and slow melanoma growth in vivo. Because the melanocytic cell state is linked to poor outcomes in patients, these data indicate a metabolic vulnerability in melanoma that depends on the lipid droplet organelle.
    DOI:  https://doi.org/10.1038/s41467-023-38831-9
  3. Cancer Cell. 2023 May 26. pii: S1535-6108(23)00172-1. [Epub ahead of print]
    Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer.
    Scott Haston, Estela Gonzalez-Gualda, Samir Morsli, Jianfeng Ge, Virinder Reen, Alexander Calderwood, Ilias Moutsopoulos, Leonidas Panousopoulos, Polina Deletic, Gabriela Carreno, Romain Guiho, Saba Manshaei, Jose Mario Gonzalez-Meljem, Hui Yuan Lim, Daniel J Simpson, Jodie Birch, Husayn A Pallikonda, Tamir Chandra, David Macias, Gary J Doherty, Doris M Rassl, Robert C Rintoul, Massimo Signore, Irina Mohorianu, Arne N Akbar, Jesús Gil, Daniel Muñoz-Espín, Juan Pedro Martinez-Barbera.
      The accumulation of senescent cells in the tumor microenvironment can drive tumorigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse line, we show that macrophages and endothelial cells are the predominant senescent cell types in murine KRAS-driven lung tumors. Through single cell transcriptomics, we identify a population of tumor-associated macrophages that express a unique array of pro-tumorigenic SASP factors and surface proteins and are also present in normal aged lungs. Genetic or senolytic ablation of senescent cells, or macrophage depletion, result in a significant decrease in tumor burden and increased survival in KRAS-driven lung cancer models. Moreover, we reveal the presence of macrophages with senescent features in human lung pre-malignant lesions, but not in adenocarcinomas. Taken together, our results have uncovered the important role of senescent macrophages in the initiation and progression of lung cancer, highlighting potential therapeutic avenues and cancer preventative strategies.
    Keywords:  ABT-737; NSCLC; aging; cancer; endothelial cells; immunosuppression; macrophages; p16INK4a; senescence; senolytic
    DOI:  https://doi.org/10.1016/j.ccell.2023.05.004
  4. Adv Cancer Res. 2023 ;pii: S0065-230X(23)00021-0. [Epub ahead of print]159 343-372
    Tumor microenvironment interactions with cancer stem cells in pancreatic ductal adenocarcinoma.
    António M Palma, Grace G Bushnell, Max S Wicha, Rajan Gogna.
      Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer in the United States. Additionally, the low survival rate makes PDAC the third-leading cause of cancer-related mortality in the United States, and it is projected that by 2030, it will become the second-leading cause of cancer mortality. Several biological factors contribute to PDAC aggressiveness, and their understanding will narrow the gap from biology to clinical care of PDAC, leading to earlier diagnoses and the development of better treatment options. In this review, we describe the origins of PDAC highlighting the role of cancer stem cells (CSC). CSC, also known as tumor initiating cells, which exhibit a unique metabolism that allows them to maintain a highly plastic, quiescent, immune- and therapy-evasive state. However, CSCs can exit quiescence during proliferation and differentiation, with the capacity to form tumors while constituting a small population in tumor tissues. Tumorigenesis depends on the interactions between CSCs and other cellular and non-cellular components in the microenvironment. These interactions are fundamental to support CSC stemness and are maintained throughout tumor development and metastasis. PDAC is characterized by a massive desmoplastic reaction, which result from the deposition of high amounts of extracellular matrix components by stromal cells. Here we review how this generates a favorable environment for tumor growth by protecting tumor cells from immune responses and chemotherapy and inducing tumor cell proliferation and migration, leading to metastasis formation ultimately leading to death. We emphasize the interactions between CSCs and the tumor microenvironment leading to metastasis formation and posit that better understanding and targeting of these interactions will improve patient outcomes.
    Keywords:  Cancer stem cells; Extracellular matrix; Metastasis; Pancreatic ductal adenocarcinoma; Tumor microenvironment
    DOI:  https://doi.org/10.1016/bs.acr.2023.02.007
  5. Cancer Cell. 2023 May 23. pii: S1535-6108(23)00142-3. [Epub ahead of print]
    Exhaustion-associated cholesterol deficiency dampens the cytotoxic arm of antitumor immunity.
    Chengsong Yan, Lin Zheng, Shutan Jiang, Haochen Yang, Jun Guo, Lu-Yi Jiang, Tongzhou Li, Haosong Zhang, Yibing Bai, Yu Lou, Qi Zhang, Tingbo Liang, Wolfgang Schamel, Haopeng Wang, Weiwei Yang, Guangchuan Wang, Zheng-Jiang Zhu, Bao-Liang Song, Chenqi Xu.
      The concept of targeting cholesterol metabolism to treat cancer has been widely tested in clinics, but the benefits are modest, calling for a complete understanding of cholesterol metabolism in intratumoral cells. We analyze the cholesterol atlas in the tumor microenvironment and find that intratumoral T cells have cholesterol deficiency, while immunosuppressive myeloid cells and tumor cells display cholesterol abundance. Low cholesterol levels inhibit T cell proliferation and cause autophagy-mediated apoptosis, particularly for cytotoxic T cells. In the tumor microenvironment, oxysterols mediate reciprocal alterations in the LXR and SREBP2 pathways to cause cholesterol deficiency of T cells, subsequently leading to aberrant metabolic and signaling pathways that drive T cell exhaustion/dysfunction. LXRβ depletion in chimeric antigen receptor T (CAR-T) cells leads to improved antitumor function against solid tumors. Since T cell cholesterol metabolism and oxysterols are generally linked to other diseases, the new mechanism and cholesterol-normalization strategy might have potential applications elsewhere.
    Keywords:  CAR-T cells; Intratumoral T cells; autophagy-mediated apoptosis; cholesterol deficiency; cholesterol normalization; oxysterols
    DOI:  https://doi.org/10.1016/j.ccell.2023.04.016
  6. Cancer Cell. 2023 May 22. pii: S1535-6108(23)00180-0. [Epub ahead of print]
    Cholesterol atlas of tumor microenvironment provides route to improved CAR-T therapy.
    Adriano B Chaves-Filho, Almut Schulze.
      Cholesterol is essential for the ability of cytotoxic T cells to eliminate cancer cells. In this issue of Cancer Cell, Yan et al. reveal how intra-tumoral cholesterol deficiency contributes to T cell exhaustion by inhibiting mTORC1 signaling. Moreover, they demonstrate that increasing cholesterol levels in chimeric antigen receptor (CAR)-T cells by blocking liver X receptor (LXR) leads to improved anti-tumor function.
    DOI:  https://doi.org/10.1016/j.ccell.2023.05.013
  7. Cancer Res. 2023 Jun 02. 83(11): 1759-1761
    LXR Signaling-Mediated Cholesterol Metabolism Reprogramming Regulates Cancer Cell Metastasis.
    Pankaj K Singh, Kamiya Mehla.
      Metastasis is a key contributor to mortality in patients with cancer. While many regulators of metastasis have been identified, critical targets to prevent and inhibit metastatic tumor growth remain elusive. A recent study in this issue of Cancer Research by Deng and colleagues compared gene expression signatures between primary esophageal squamous cell carcinoma tumors and metastatic tumors and combined the analysis with genes induced in metastatic cancer cell lines, which identified anoctamin 1 (ANO1) as a key driver of metastasis. ANO1 caused cholesterol accumulation by inhibiting LXR signaling and decreased cholesterol hydroxylation by downregulating the expression of cholesterol hydroxylase CYP27A1. ANO1 also regulated tumor cell-fibroblast cross-talk that contributed to inflammatory cytokine signaling (IL1β) and metastasis. Through in silico analysis, the study identified a novel small-molecule inhibitor of ANO1 that decreased tumor burden at a metastatic site. These studies provide novel insights into the role of ANO1 in cellular cholesterol metabolism and associated signaling in mediating metastasis. See related article by Deng et al., p. 1851.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0624
  8. Oncol Rep. 2023 Jul;pii: 141. [Epub ahead of print]50(1):
    Adipocytes promote pancreatic cancer migration and invasion through fatty acid metabolic reprogramming.
    Zhiwei Cai, Yang Li, Mingjian Ma, Longxiang Wang, Hongwei Wang, Meng Liu, Chongyi Jiang.
      Locally advanced and metastatic pancreatic cancer (PC) frequently grows in adipose tissue and has a poor prognosis. Although adipose tissue is largely composed of adipocytes, the mechanisms by which adipocytes impact PC are poorly understood. Using an in vitro coculture model, it was shown that adipocytes promoted tumor progression, and an intricate metabolic network between PC cells and adipocytes was identified and elucidated. First, the proteome of Panc‑1 PC cells cultured with or without mature adipocytes was identified. This revealed activated hypoxia signaling in cocultured Panc‑1 cells, which was confirmed by the increased expression of factors downstream of hypoxia signaling, such as ANGPTL4 and glycolytic genes, as determined by reverse transcription‑quantitative PCR and western blot analysis. In addition, it was demonstrated that coculture with cancer cells activated STAT3 and induced an insulin‑resistant phenotype in adipocytes. Furthermore, enhanced fatty acid β‑oxidation and increased lipid droplets (LDs) were observed in the cocultured cancer cells. In contrast, downregulated lipid metabolism and a decrease in the size of LDs were found in cocultured adipocytes. Finally, it was shown that the increase in LDs contributed to the increased metastatic capacity of the cocultured PC cells. These data demonstrated that interrupting the mechanisms of lipid uptake from adipocytes in the microenvironment may offer a potential strategy for attenuating PC metastasis.
    Keywords:  adipocyte; fatty acid; metabolism; pancreatic cancer; tumor microenvironment
    DOI:  https://doi.org/10.3892/or.2023.8578
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