bims-mecami Biomed News
on Metabolic interactions between cancer cells and their microenvironment
Issue of 2022‒12‒18
eleven papers selected by
Linda Chan
Yale University
  1. Opa1 and Drp1 reciprocally regulate cristae morphology, ETC function, and NAD+ regeneration in KRas-mutant lung adenocarcinoma.
  2. The rise of viperin: the emerging role of viperin in cancer progression.
  3. Targeting lactate metabolism for cancer immunotherapy - a matter of precision.
  4. LDHA: The Obstacle to T cell responses against tumor.
  5. Engineering amino acid uptake or catabolism promotes CAR-T cell adaption to the tumour environment.
  6. Fat Fuels the Fire in Cervical Cancer.
  7. Hyaluronan driven by epithelial aPKC deficiency remodels the microenvironment and creates a vulnerability in mesenchymal colorectal cancer.
  8. Regulation of epithelial-mesenchymal transition by tumor microenvironmental signals and its implication in cancer therapeutics.
  9. CSN6 mediates nucleotide metabolism to promote tumor development and chemoresistance in colorectal cancer.
  10. Mitochondria as a target of third row transition metal-based anticancer complexes.
  11. PARP inhibition induces synthetic lethality and adaptive immunity in LKB1-mutant lung cancer.
  1. Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01710-7. [Epub ahead of print]41(11): 111818
    Opa1 and Drp1 reciprocally regulate cristae morphology, ETC function, and NAD+ regeneration in KRas-mutant lung adenocarcinoma.
    Dane T Sessions, Kee-Beom Kim, Jennifer A Kashatus, Nikolas Churchill, Kwon-Sik Park, Marty W Mayo, Hiromi Sesaki, David F Kashatus.
      Oncogenic KRas activates mitochondrial fission through Erk-mediated phosphorylation of the mitochondrial fission GTPase Drp1. Drp1 deletion inhibits tumorigenesis of KRas-driven pancreatic cancer, but the role of mitochondrial dynamics in other Ras-driven malignancies is poorly defined. Here we show that in vitro and in vivo growth of KRas-driven lung adenocarcinoma is unaffected by deletion of Drp1 but is inhibited by deletion of Opa1, the GTPase that regulates inner membrane fusion and proper cristae morphology. Mechanistically, Opa1 knockout disrupts cristae morphology and inhibits electron transport chain (ETC) assembly and activity, which inhibits tumor cell proliferation through loss of NAD+ regeneration. Simultaneous inactivation of Drp1 and Opa1 restores cristae morphology, ETC activity, and cell proliferation indicating that mitochondrial fission activity drives ETC dysfunction induced by Opa1 knockout. Our results support a model in which mitochondrial fission events disrupt cristae structure, and tumor cells with hyperactive fission activity require Opa1 activity to maintain ETC function.
    Keywords:  CP: Cancer; Drp1; ETC; KRas; NAD; Opa1; cancer; cristae; fission; fusion; mitochondria
    DOI:  https://doi.org/10.1016/j.celrep.2022.111818
  2. J Clin Invest. 2022 Dec 15. pii: e165907. [Epub ahead of print]132(24):
    The rise of viperin: the emerging role of viperin in cancer progression.
    Alyssa G Weinstein, Inês Godet, Daniele M Gilkes.
      Viperin, an IFN-regulated gene product, is known to inhibit fatty acid β-oxidation in the mitochondria, which enhances glycolysis and lipogenesis during viral infections. Yet, its role in altering the phenotype of cancer cells has not been established. In this issue of the JCI, Choi, Kim, and co-authors report on a role of viperin in regulating metabolic alterations in cancer cells. The authors showed a correlation between clinical outcomes and viperin expression levels in multiple cancer tissues and proposed that viperin expression was upregulated in the tumor microenvironment via the JAK/STAT and PI3K/AKT/mTOR/HIF-1α pathways. Functionally, viperin increased lipogenesis and glycolysis in cancer cells by inhibiting fatty acid β-oxidation. Viperin expression also enhanced cancer stem cell properties, ultimately promoting tumor initiation in murine models. This study proposes a protumorigenic role for viperin and identifies HIF-1α as a transcription factor that increases viperin expression under serum starvation and hypoxia.
    DOI:  https://doi.org/10.1172/JCI165907
  3. Semin Cancer Biol. 2022 Dec 07. pii: S1044-579X(22)00255-3. [Epub ahead of print]88 32-45
    Targeting lactate metabolism for cancer immunotherapy - a matter of precision.
    Christoph Heuser, Kathrin Renner, Marina Kreutz, Luca Gattinoni.
      Immune checkpoint inhibitors and adoptive T cell therapies have been valuable additions to the toolbox in the fight against cancer. These treatments have profoundly increased the number of patients with a realistic perspective toward a return to a cancer-free life. Yet, in a number of patients and tumor entities, cancer immunotherapies have been ineffective so far. In solid tumors, immune exclusion and the immunosuppressive tumor microenvironment represent substantial roadblocks to successful therapeutic outcomes. A major contributing factor to the depressed anti-tumor activity of immune cells in tumors is the harsh metabolic environment. Hypoxia, nutrient competition with tumor and stromal cells, and accumulating noxious waste products, including lactic acid, pose massive constraints to anti-tumor immune cells. Numerous strategies are being developed to exploit the metabolic vulnerabilities of tumor cells in the hope that these would also alleviate metabolism-inflicted immune suppression. While promising in principle, especially in combination with immunotherapies, these strategies need to be scrutinized for their effect on tumor-fighting immune cells, which share some of their key metabolic properties with tumor cells. Here, we provide an overview of strategies that seek to tackle lactate metabolism in tumor or immune cells to unleash anti-tumor immune responses, thereby opening therapeutic options for patients whose tumors are currently not treatable.
    Keywords:  Acidification; Adoptive cell transfer; Checkpoint inhibition; Glycolysis; Immunotherapy; Lactate; Metabolism
    DOI:  https://doi.org/10.1016/j.semcancer.2022.12.001
  4. Front Oncol. 2022 ;12 1036477
    LDHA: The Obstacle to T cell responses against tumor.
    Yu Tang, Shuangshuang Gu, Liqun Zhu, Yujiao Wu, Wei Zhang, Chuanxiang Zhao.
      Immunotherapy has become a successful therapeutic strategy in certain solid tumors and hematological malignancies. However, this efficacy of immunotherapy is impeded by limited success rates. Cellular metabolic reprogramming determines the functionality and viability in both cancer cells and immune cells. Extensive research has unraveled that the limited success of immunotherapy is related to immune evasive metabolic reprogramming in tumor cells and immune cells. As an enzyme that catalyzes the final step of glycolysis, lactate dehydrogenase A (LDHA) has become a major focus of research. Here, we have addressed the structure, localization, and biological features of LDHA. Furthermore, we have discussed the various aspects of epigenetic regulation of LDHA expression, such as histone modification, DNA methylation, N6-methyladenosine (m6A) RNA methylation, and transcriptional control by noncoding RNA. With a focus on the extrinsic (tumor cells) and intrinsic (T cells) functions of LDHA in T-cell responses against tumors, in this article, we have reviewed the current status of LDHA inhibitors and their combination with T cell-mediated immunotherapies and postulated different strategies for future therapeutic regimens.
    Keywords:  LDHA; T cell responses; lactate; metabolic reprogramming; tumor
    DOI:  https://doi.org/10.3389/fonc.2022.1036477
  5. Blood Adv. 2022 Dec 15. pii: bloodadvances.2022008272. [Epub ahead of print]
    Engineering amino acid uptake or catabolism promotes CAR-T cell adaption to the tumour environment.
    Silvia Panetti, Nicola Jane McJannett, Livingstone Fultang, Sarah Booth, Luciana Gneo, Ugo Scarpa, Charles Smith, Ashley Vardon, Lisa Vettore, Celina Whalley, Yi Pan, Csilla Varnai, Hitoshi Endou, Jonathan Barlow, Daniel A Tennant, Andrew D Beggs, Francis Jay Mussai, Carmela De Santo.
      Cancer cells take up amino acids from the extracellular space to drive cell proliferation and viability. Similar mechanisms are employed by immune cells. The result is competition between conventional T cells, or indeed CAR-T cells, and tumour cells for limited availability of amino acids within the environment. We demonstrate that T cells can be re-engineered to express SLC7A5 or SLC7A11 transmembrane amino acid transporters alongside chimeric antigen receptors (CAR). Transporter modifications increase CAR-T cell proliferation under low tryptophan or cystine conditions with no loss of CAR cytotoxicity or increased exhaustion. Transcriptomic and phenotypic analysis reveals that downstream, SLC7A5/SLC7A11 modified CAR-T cells upregulate intracellular Arginase expression and activity. In turn we engineer and phenotype a further generation of CAR-T cells which express functional Arginase I/Arginase II enzymes, and have enhanced CAR-T cell proliferation and anti-tumour activity. Thus CAR-T cells can be adapted to the amino acid metabolic microenvironment of cancer, a hitherto recognised but unaddressed barrier to successful CAR-T therapy.
    DOI:  https://doi.org/10.1182/bloodadvances.2022008272
  6. Cancer Res. 2022 Dec 16. 82(24): 4513-4514
    Fat Fuels the Fire in Cervical Cancer.
    Kassidy M Jungles, Michael D Green.
      Cervical cancer is the second most common cause of cancer mortality among young women and disproportionately impacts underserved patient populations. An obesity paradox has been observed in cervical cancer wherein patients with higher body mass indices benefit more from standard-of-care chemoradiation. However, the molecular pathways through which obesity modulates treatment response are poorly defined. In exciting work in this issue of Cancer Research, Muhammad and colleagues have shown that monounsaturated and diunsaturated free fatty acids released by adipocytes activate β-oxidation within tumor cells, which potentiates radiotherapy. This work extends our understanding of the metabolic vulnerabilities of cervical cancer. See related article by Muhammad et al., p. 4515.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-3143
  7. Cancer Cell. 2022 Dec 06. pii: S1535-6108(22)00563-3. [Epub ahead of print]
    Hyaluronan driven by epithelial aPKC deficiency remodels the microenvironment and creates a vulnerability in mesenchymal colorectal cancer.
    Anxo Martinez-Ordoñez, Angeles Duran, Marc Ruiz-Martinez, Tania Cid-Diaz, Xiao Zhang, Qixiu Han, Hiroto Kinoshita, Yu Muta, Juan F Linares, Hiroaki Kasashima, Yuki Nakanishi, Mohamed Omar, Sadaaki Nishimura, Leandro Avila, Masakazu Yashiro, Kiyoshi Maeda, Tania Pannellini, Alessio Pigazzi, Giorgio Inghirami, Luigi Marchionni, Darren Sigal, Maria T Diaz-Meco, Jorge Moscat.
      Mesenchymal colorectal cancer (mCRC) is microsatellite stable (MSS), highly desmoplastic, with CD8+ T cells excluded to the stromal periphery, resistant to immunotherapy, and driven by low levels of the atypical protein kinase Cs (aPKCs) in the intestinal epithelium. We show here that a salient feature of these tumors is the accumulation of hyaluronan (HA) which, along with reduced aPKC levels, predicts poor survival. HA promotes epithelial heterogeneity and the emergence of a tumor fetal metaplastic cell (TFMC) population endowed with invasive cancer features through a network of interactions with activated fibroblasts. TFMCs are sensitive to HA deposition, and their metaplastic markers have prognostic value. We demonstrate that in vivo HA degradation with a clinical dose of hyaluronidase impairs mCRC tumorigenesis and liver metastasis and enables immune checkpoint blockade therapy by promoting the recruitment of B and CD8+ T cells, including a proportion with resident memory features, and by blocking immunosuppression.
    Keywords:  aPKC; colorectal cancer; hyaluronan; immune checkpoint therapy; immunosuppression; inflammation; liver metastasis; mesenchymal; stroma; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2022.11.016
  8. Semin Cancer Biol. 2022 Dec 13. pii: S1044-579X(22)00256-5. [Epub ahead of print]88 46-66
    Regulation of epithelial-mesenchymal transition by tumor microenvironmental signals and its implication in cancer therapeutics.
    Jing Zhang, Zhimin Hu, Calista A Horta, Jing Yang.
      Epithelial-mesenchymal transition (EMT) has been implicated in various aspects of tumor development, including tumor invasion and metastasis, cancer stemness, and therapy resistance. Diverse stroma cell types along with biochemical and biophysical factors in the tumor microenvironment impinge on the EMT program to impact tumor progression. Here we provide an in-depth review of various tumor microenvironmental signals that regulate EMT in cancer. We discuss the molecular mechanisms underlying the role of EMT in therapy resistance and highlight new therapeutic approaches targeting the tumor microenvironment to impact EMT and tumor progression.
    Keywords:  Epithelial-Mesenchymal Transition (EMT); Extracellular matrix (ECM); Hypoxia; Invasion and metastasis; Tumor stroma
    DOI:  https://doi.org/10.1016/j.semcancer.2022.12.002
  9. Cancer Res. 2022 Dec 13. pii: CAN-22-2145. [Epub ahead of print]
    CSN6 mediates nucleotide metabolism to promote tumor development and chemoresistance in colorectal cancer.
    Shaomin Zou, Baifu Qin, Ziqing Yang, Wencong Wang, Jieping Zhang, Yijing Zhang, Manqi Meng, Junyan Feng, Yunling Xie, Ling Fang, Lishi Xiao, Peng Zhang, Xiangqi Meng, Hyun Ho Choi, Weijie Wen, Qihao Pan, Bart Ghesquiere, Ping Lan, Mong-Hong Lee, Lekun Fang.
      Metabolic reprogramming can contribute to colorectal cancer (CRC) progression and therapy resistance. Identification of key regulators of CRC metabolism could provide new approaches to improve treatment and reduce recurrence. Here, we demonstrate a critical role for the COP9 signalosome subunit CSN6 in rewiring nucleotide metabolism in CRC. Transcriptomic analysis of CRC patient samples revealed a correlation between CSN6 expression and purine and pyrimidine metabolism. A colitis-associated colorectal cancer model established that Csn6 intestinal conditional deletion decreased tumor development and altered nucleotide metabolism. CSN6 knockdown increased the chemosensitivity of CRC cells in vitro and in vivo, which could be partially reversed with nucleoside supplementation. Isotope metabolite tracing showed that CSN6 loss reduced de novo nucleotide synthesis. Mechanistically, CSN6 upregulated purine and pyrimidine biosynthesis by increasing expression of PHGDH, a key enzyme in the serine synthesis pathway. CSN6 inhibited β-Trcp-mediated DDX5 polyubiquitination and degradation, which in turn promoted DDX5-mediated PHGDH mRNA stabilization, leading to metabolic reprogramming and CRC progression. Butyrate treatment decreased CSN6 expression and improved chemotherapy efficacy. These findings unravel the oncogenic role of CSN6 in regulating nucleotide metabolism and chemosensitivity in CRC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-2145
  10. Curr Opin Chem Biol. 2022 Dec 12. pii: S1367-5931(22)00120-X. [Epub ahead of print]72 102235
    Mitochondria as a target of third row transition metal-based anticancer complexes.
    Chibuzor Olelewe, Samuel G Awuah.
      In pursuit of better treatment options for malignant tumors, metal-based complexes continue to show promise as attractive chemotherapeutics due to tunability, novel mechanisms, and potency exemplified by platinum agents. The metabolic character of tumors renders the mitochondria and other metabolism pathways fruitful targets for medicinal inorganic chemistry. Cumulative understanding of the role of mitochondria in tumorigenesis has ignited research in mitochondrial targeting metal-based complexes to overcome resistance and inhibit tumor growth with high potency and selectivity. Here, we discuss recent progress made in third row transition metal-based mitochondrial targeting agents with the goal of stimulating an active field of research toward new clinical anticancer agents and the elucidation of novel mechanisms of action.
    Keywords:  Gold; Iridium; Metabolism; Metal-based drugs; Mitochondria-targeting; Platinum; Rhenium
    DOI:  https://doi.org/10.1016/j.cbpa.2022.102235
  11. Cancer Res. 2022 Dec 13. pii: CAN-22-1740. [Epub ahead of print]
    PARP inhibition induces synthetic lethality and adaptive immunity in LKB1-mutant lung cancer.
    Li-Li Long, Si-Cong Ma, Ze-Qin Guo, Yan-Pei Zhang, Zhenzhen Fan, Li-Juan Liu, Li Liu, Duan-Duan Han, Meng-Xin Leng, Jian Wang, Xue-Jun Guo, Jia-Le Tan, Xiao-Ting Cai, Yan Lin, Xinghua Pan, De-Hua Wu, Xue Bai, Zhong-Yi Dong.
      Contradictory characteristics of elevated mutational burden and a "cold" tumor microenvironment (TME) coexist in LKB1-mutant non-small cell lung cancers (NSCLC). The molecular basis underlying this paradox and strategies tailored to these historically difficult-to-treat cancers are lacking. Here, by mapping the single-cell transcriptomic landscape of genetically engineered mouse models with Kras versus Kras/Lkb1 driven lung tumors, we detected impaired tumor-intrinsic IFNγ signaling in Kras/Lkb1 driven tumors that explains the inert immune context. Mechanistic analysis showed that mutant LKB1 led to deficiency in the DNA damage repair process and abnormally activated PARP1. Hyperactivated PARP1 attenuated the IFNγ pathway by physically interacting with and enhancing the poly(ADP-ribosyl)ation of STAT1, compromising its phosphorylation and activation. Abrogation of the PARP1-driven program triggered synthetic lethality in NSCLC on the basis of the LKB1 mutation-mediated DNA repair defect, while also restoring phosphorylated STAT1 to favor an immunologically "hot" TME. Accordingly, PARP1 inhibition restored the disrupted IFN-γ signaling and thus mounted an adaptive immune response to synergize with PD-1 blockade in multiple LKB1-deficient murine tumor models. Overall, this study reveals an unexplored interplay between the DNA repair process and adaptive immune response, providing a molecular basis for dual PARP1 and PD-1 inhibition in treating LKB1-mutant NSCLC.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-1740
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