bims-stacyt 2023-09-10 papers

bims-stacyt

Biomed News

on Metabolism and the paracrine crosstalk between cancer and the organism

Issue of 2023–09–10
nine papers selected by
Cristina Muñoz Pinedo, L’Institut d’Investigació Biomèdica de Bellvitge

eIF3d controls the persistent integrated stress response.
Vascular Endothelial Growth Factor-D (VEGF-D): An Angiogenesis Bypass in Malignant Tumors.
Metabolic barriers in non-small cell lung cancer with LKB1 and/or KEAP1 mutations for immunotherapeutic strategies.
Glycolysis regulation in tumor-associated macrophages: Its role in tumor development and cancer treatment.
Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation.
Role of Leptin and Adiponectin in Carcinogenesis.
Exploring the crosstalk between endothelial cells, immune cells, and immune checkpoints in the tumor microenvironment: new insights and therapeutic implications.
Activation of the integrated stress response by inhibitors of its kinases.
Loss of attachment promotes proline accumulation and excretion in cancer cells.

Mol Cell. 2023 Aug 30. pii: S1097-2765(23)00643-3. [Epub ahead of print]

eIF3d controls the persistent integrated stress response.

Shaoni Mukhopadhyay, Maria E Amodeo, Amy S Y Lee.

  Cells respond to intrinsic and extrinsic stresses by reducing global protein synthesis and activating gene programs necessary for survival. Here, we show that the integrated stress response (ISR) is driven by the non-canonical cap-binding protein eIF3d that acts as a critical effector to control core stress response orchestrators, the translation factor eIF2α and the transcription factor ATF4. We find that during persistent stress, eIF3d activates the translation of the kinase GCN2, inducing eIF2α phosphorylation and inhibiting general protein synthesis. In parallel, eIF3d upregulates the m6A demethylase ALKBH5 to drive 5' UTR-specific demethylation of stress response genes, including ATF4. Ultimately, this cascade converges on ATF4 expression by increasing mRNA engagement of translation machinery and enhancing ribosome bypass of upstream open reading frames (uORFs). Our results reveal that eIF3d acts in a life-or-death decision point during chronic stress and uncover a synergistic signaling mechanism in which translational cascades complement transcriptional amplification to control essential cellular processes.

Keywords:  ATF4; GCN2; RNA methylation; eIF3d; integrated stress response; m(6)A; translation regulation

DOI:  https://doi.org/10.1016/j.molcel.2023.08.008
Int J Mol Sci. 2023 Aug 28. pii: 13317. [Epub ahead of print]24(17):

Vascular Endothelial Growth Factor-D (VEGF-D): An Angiogenesis Bypass in Malignant Tumors.

Syeda Mahak Zahra Bokhari, Peter Hamar.

  Vascular endothelial growth factors (VEGFs) are the key regulators of vasculogenesis in normal and oncological development. VEGF-A is the most studied angiogenic factor secreted by malignant tumor cells under hypoxic and inflammatory stress, which made VEGF-A a rational target for anticancer therapy. However, inhibition of VEGF-A by monoclonal antibody drugs led to the upregulation of VEGF-D. VEGF-D was primarily described as a lymphangiogenic factor; however, VEGF-D's blood angiogenic potential comparable to VEGF-A has already been demonstrated in glioblastoma and colorectal carcinoma. These findings suggested a role for VEGF-D in facilitating malignant tumor growth by bypassing the anti-VEGF-A antiangiogenic therapy. Owing to its high mitogenic ability, higher affinity for VEGFR-2, and higher expression in cancer, VEGF-D might even be a stronger angiogenic driver and, hence, a better therapeutic target than VEGF-A. In this review, we summarized the angiogenic role of VEGF-D in blood vasculogenesis and its targetability as an antiangiogenic therapy in cancer.

Keywords:  FIGF; VEGF-D; angiogenesis; growth factors; lymphangiogenesis

DOI:  https://doi.org/10.3390/ijms241713317
Front Oncol. 2023 ;13 1249237

Metabolic barriers in non-small cell lung cancer with LKB1 and/or KEAP1 mutations for immunotherapeutic strategies.

Ichidai Tanaka, Junji Koyama, Hideyuki Itoigawa, Shunsaku Hayai, Masahiro Morise.

  Currently, immune checkpoint inhibitors (ICIs) are widely considered the standard initial treatment for advanced non-small cell lung cancer (NSCLC) when there are no targetable driver oncogenic alternations. NSCLC tumors that have two alterations in tumor suppressor genes, such as liver kinase B1 (LKB1) and/or Kelch-like ECH-associated protein 1 (KEAP1), have been found to exhibit reduced responsiveness to these therapeutic strategies, as revealed by multiomics analyses identifying immunosuppressed phenotypes. Recent advancements in various biological approaches have gradually unveiled the molecular mechanisms underlying intrinsic reprogrammed metabolism in tumor cells, which contribute to the evasion of immune responses by the tumor. Notably, metabolic alterations in glycolysis and glutaminolysis have a significant impact on tumor aggressiveness and the remodeling of the tumor microenvironment. Since glucose and glutamine are essential for the proliferation and activation of effector T cells, heightened consumption of these nutrients by tumor cells results in immunosuppression and resistance to ICI therapies. This review provides a comprehensive summary of the clinical efficacies of current therapeutic strategies against NSCLC harboring LKB1 and/or KEAP1 mutations, along with the metabolic alterations in glycolysis and glutaminolysis observed in these cancer cells. Furthermore, ongoing trials targeting these metabolic alterations are discussed as potential approaches to overcome the extremely poor prognosis associated with this type of cancer.

Keywords:  KEAP1; LKB1; NSCLC; PD-1/PD-L1 inhibitors; glutaminolysis; glycolysis; immune checkpoint blockade; metabolic barriers

DOI:  https://doi.org/10.3389/fonc.2023.1249237
Int J Cancer. 2023 Sep 08.

Glycolysis regulation in tumor-associated macrophages: Its role in tumor development and cancer treatment.

Guangyi Jiang, Junjie Hong, Lu Sun, Haibin Wei, Wangang Gong, Shu Wang, Jianqing Zhu.

  Tumor-associated macrophages constitute the main cell population in the tumor microenvironment and play a crucial role in regulating the microenvironment composition. Emerging evidence has revealed that the metabolic profile determines the tumor-associated macrophage phenotype. Tumor-associated macrophage function is highly dependent on glucose metabolism, with glycolysis being the major metabolic pathway. Recent reports have demonstrated diversity in glucose flux of tumor-associated macrophages and complex substance communication with cancer cells. However, how the glucose flux in tumor-associated macrophages connects with glycolysis to influence tumor progression and the tumor microenvironment is still obscure. Moreover, while the development of single-cell sequencing technology allows a clearer and more accurate classification of tumor-associated macrophages, the metabolic profiles of tumor-associated macrophages from the perspective of single-cell omics has not been well summarized. Here, we review the current state of knowledge on glucose metabolism in tumor-associated macrophages and summarize the metabolic profiles of different tumor-associated macrophage subtypes from the perspective of single-cell omics. Additionally, we describe the current strategies targeting glycolysis in tumor-associated macrophages for cancer therapy.

Keywords:  glucose metabolism; single-cell omics; targeted cancer therapy; tumor microenvironment; tumor-associated macrophage

DOI:  https://doi.org/10.1002/ijc.34711
Cell Discov. 2023 Sep 07. 9(1): 92

Lysosomes mediate the mitochondrial UPR via mTORC1-dependent ATF4 phosphorylation.

Terytty Yang Li, Qi Wang, Arwen W Gao, Xiaoxu Li, Yu Sun, Adrienne Mottis, Minho Shong, Johan Auwerx.

Lysosomes are central platforms for not only the degradation of macromolecules but also the integration of multiple signaling pathways. However, whether and how lysosomes mediate the mitochondrial stress response (MSR) remain largely unknown. Here, we demonstrate that lysosomal acidification via the vacuolar H+-ATPase (v-ATPase) is essential for the transcriptional activation of the mitochondrial unfolded protein response (UPRmt). Mitochondrial stress stimulates v-ATPase-mediated lysosomal activation of the mechanistic target of rapamycin complex 1 (mTORC1), which then directly phosphorylates the MSR transcription factor, activating transcription factor 4 (ATF4). Disruption of mTORC1-dependent ATF4 phosphorylation blocks the UPRmt, but not other similar stress responses, such as the UPRER. Finally, ATF4 phosphorylation downstream of the v-ATPase/mTORC1 signaling is indispensable for sustaining mitochondrial redox homeostasis and protecting cells from ROS-associated cell death upon mitochondrial stress. Thus, v-ATPase/mTORC1-mediated ATF4 phosphorylation via lysosomes links mitochondrial stress to UPRmt activation and mitochondrial function resilience.

DOI: https://doi.org/10.1038/s41421-023-00589-1
Cancers (Basel). 2023 Aug 24. pii: 4250. [Epub ahead of print]15(17):

Role of Leptin and Adiponectin in Carcinogenesis.

Agnes Bocian-Jastrzębska, Anna Malczewska-Herman, Beata Kos-Kudła.

  Hormones produced by adipocytes, leptin and adiponectin, are associated with the process of carcinogenesis. Both of these adipokines have well-proven oncologic potential and can affect many aspects of tumorigenesis, from initiation and primary tumor growth to metastatic progression. Involvement in the formation of cancer includes interactions with the tumor microenvironment and its components, such as tumor-associated macrophages, cancer-associated fibroblasts, extracellular matrix and matrix metalloproteinases. Furthermore, these adipokines participate in the epithelial-mesenchymal transition and connect to angiogenesis, which is critical for cancer invasiveness and cancer cell migration. In addition, an enormous amount of evidence has demonstrated that altered concentrations of these adipocyte-derived hormones and the expression of their receptors in tumors are associated with poor prognosis in various types of cancer. Therefore, leptin and adiponectin dysfunction play a prominent role in cancer and impact tumor invasion and metastasis in different ways. This review clearly and comprehensively summarizes the recent findings and presents the role of leptin and adiponectin in cancer initiation, promotion and progression, focusing on associations with the tumor microenvironment and its components as well as roles in the epithelial-mesenchymal transition and angiogenesis.

Keywords:  adiponectin; angiogenesis; epithelial–mesenchymal transition; leptin; tumor microenvironment

DOI:  https://doi.org/10.3390/cancers15174250
Cell Death Dis. 2023 09 04. 14(9): 586

Exploring the crosstalk between endothelial cells, immune cells, and immune checkpoints in the tumor microenvironment: new insights and therapeutic implications.

Jianwen Fang, Yue Lu, Jingyan Zheng, Xiaocong Jiang, Haixing Shen, Xi Shang, Yuexin Lu, Peifen Fu.

The tumor microenvironment (TME) is a highly intricate milieu, comprising a multitude of components, including immune cells and stromal cells, that exert a profound influence on tumor initiation and progression. Within the TME, angiogenesis is predominantly orchestrated by endothelial cells (ECs), which foster the proliferation and metastasis of malignant cells. The interplay between tumor and immune cells with ECs is complex and can either bolster or hinder the immune system. Thus, a comprehensive understanding of the intricate crosstalk between ECs and immune cells is essential to advance the development of immunotherapeutic interventions. Despite recent progress, the underlying molecular mechanisms that govern the interplay between ECs and immune cells remain elusive. Nevertheless, the immunomodulatory function of ECs has emerged as a pivotal determinant of the immune response. In light of this, the study of the relationship between ECs and immune checkpoints has garnered considerable attention in the field of immunotherapy. By targeting specific molecular pathways and signaling molecules associated with ECs in the TME, novel immunotherapeutic strategies may be devised to enhance the efficacy of current treatments. In this vein, we sought to elucidate the relationship between ECs, immune cells, and immune checkpoints in the TME, with the ultimate goal of identifying novel therapeutic targets and charting new avenues for immunotherapy.

DOI: https://doi.org/10.1038/s41419-023-06119-x
Nat Commun. 2023 Sep 08. 14(1): 5535

Activation of the integrated stress response by inhibitors of its kinases.

Maria Szaruga, Dino A Janssen, Claudia de Miguel, George Hodgson, Agnieszka Fatalska, Aleksandra P Pitera, Antonina Andreeva, Anne Bertolotti.

Phosphorylation of the translation initiation factor eIF2α to initiate the integrated stress response (ISR) is a vital signalling event. Protein kinases activating the ISR, including PERK and GCN2, have attracted considerable attention for drug development. Here we find that the widely used ATP-competitive inhibitors of PERK, GSK2656157, GSK2606414 and AMG44, inhibit PERK in the nanomolar range, but surprisingly activate the ISR via GCN2 at micromolar concentrations. Similarly, a PKR inhibitor, C16, also activates GCN2. Conversely, GCN2 inhibitor A92 silences its target but induces the ISR via PERK. These findings are pivotal for understanding ISR biology and its therapeutic manipulations because most preclinical studies used these inhibitors at micromolar concentrations. Reconstitution of ISR activation with recombinant proteins demonstrates that PERK and PKR inhibitors directly activate dimeric GCN2, following a Gaussian activation-inhibition curve, with activation driven by allosterically increasing GCN2 affinity for ATP. The tyrosine kinase inhibitors Neratinib and Dovitinib also activate GCN2 by increasing affinity of GCN2 for ATP. Thus, the mechanism uncovered here might be broadly relevant to ATP-competitive inhibitors and perhaps to other kinases.

DOI: https://doi.org/10.1038/s41467-023-40823-8
Sci Adv. 2023 Sep 08. 9(36): eadh2023

Loss of attachment promotes proline accumulation and excretion in cancer cells.

Steven E Pilley, Marc Hennequart, Anke Vandekeere, Julianna Blagih, Nathalie M Legrave, Sarah-Maria Fendt, Karen H Vousden, Christiaan F Labuschagne.

Previous studies have revealed a role for proline metabolism in supporting cancer development and metastasis. In this study, we show that many cancer cells respond to loss of attachment by accumulating and secreting proline. Detached cells display reduced proliferation accompanied by a general decrease in overall protein production and de novo amino acid synthesis compared to attached cells. However, proline synthesis was maintained under detached conditions. Furthermore, while overall proline incorporation into proteins was lower in detached cells compared to other amino acids, there was an increased production of the proline-rich protein collagen. The increased excretion of proline from detached cells was also shown to be used by macrophages, an abundant and important component of the tumor microenvironment. Our study suggests that detachment induced accumulation and secretion of proline may contribute to tumor progression by supporting increased production of extracellular matrix and providing proline to surrounding stromal cells.

DOI: https://doi.org/10.1126/sciadv.adh2023