bims-stacyt 2023-12-03 papers

Semin Cancer Biol. 2023 Nov 28. pii: S1044-579X(23)00147-5. [Epub ahead of print]97 104-123

Hypoxia as a potential inducer of immune tolerance, tumor plasticity and a driver of tumor mutational burden: Impact on cancer immunotherapy.

Raefa Abou Khouzam, Bassam Janji, Jerome Thiery, Rania Faouzi Zaarour, Ali N Chamseddine, Hemma Mayr, Pierre Savagner, Claudine Kieda, Sophie Gad, Stéphanie Buart, Jean-Marie Lehn, Perparim Limani, Salem Chouaib.

In cancer patients, immune cells are often functionally compromised due to the immunosuppressive features of the tumor microenvironment (TME) which contribute to the failures in cancer therapies. Clinical and experimental evidence indicates that developing tumors adapt to the immunological environment and create a local microenvironment that impairs immune function by inducing immune tolerance and invasion. In this context, microenvironmental hypoxia, which is an established hallmark of solid tumors, significantly contributes to tumor aggressiveness and therapy resistance through the induction of tumor plasticity/heterogeneity and, more importantly, through the differentiation and expansion of immune-suppressive stromal cells. We and others have provided evidence indicating that hypoxia also drives genomic instability in cancer cells and interferes with DNA damage response and repair suggesting that hypoxia could be a potential driver of tumor mutational burden. Here, we reviewed the current knowledge on how hypoxic stress in the TME impacts tumor angiogenesis, heterogeneity, plasticity, and immune resistance, with a special interest in tumor immunogenicity and hypoxia targeting. An integrated understanding of the complexity of the effect of hypoxia on the immune and microenvironmental components could lead to the identification of better adapted and more effective combinational strategies in cancer immunotherapy. Clearly, the discovery and validation of therapeutic targets derived from the hypoxic tumor microenvironment is of major importance and the identification of critical hypoxia-associated pathways could generate targets that are undeniably attractive for combined cancer immunotherapy approaches.

Keywords: Hypoxia; Immune tolerance; Immunotherapy; Plasticity; Tumor microenvironment

DOI: https://doi.org/10.1016/j.semcancer.2023.11.008

Front Immunol. 2023 ;14 1207746

The impact of inflammation and acute phase activation in cancer cachexia.

Tyler P Robinson, Tewfik Hamidi, Brittany Counts, Denis C Guttridge, Michael C Ostrowski, Teresa A Zimmers, Leonidas G Koniaris.

The development of cachexia in the setting of cancer or other chronic diseases is a significant detriment for patients. Cachexia is associated with a decreased ability to tolerate therapies, reduction in ambulation, reduced quality of life, and increased mortality. Cachexia appears intricately linked to the activation of the acute phase response and is a drain on metabolic resources. Work has begun to focus on the important inflammatory factors associated with the acute phase response and their role in the immune activation of cachexia. Furthermore, data supporting the liver, lung, skeletal muscle, and tumor as all playing a role in activation of the acute phase are emerging. Although the acute phase is increasingly being recognized as being involved in cachexia, work in understanding underlying mechanisms of cachexia associated with the acute phase response remains an active area of investigation and still lack a holistic understanding and a clear causal link. Studies to date are largely correlative in nature, nonetheless suggesting the possibility for a role for various acute phase reactants. Herein, we examine the current literature regarding the acute phase response proteins, the evidence these proteins play in the promotion and exacerbation of cachexia, and current evidence of a therapeutic potential for patients.

Keywords: acute phase reactant; acute phase response; cachexia; cancer; chronic disease; negative acute phase reactant; positive acute phase reactant

DOI: https://doi.org/10.3389/fimmu.2023.1207746

Curr Mol Med. 2023 Nov 27.

Hypoxia Affects Mitochondrial Stress and Facilitates Tumor Metastasis of Colorectal Cancer Through Slug SUMOylation.

Jin-Bao Wang, Shi-Lin Ding, Xiao-Song Liu, Tianren Yu, Zeng-An Wu, Yu-Xiang Li.

BACKGROUND: Colorectal cancer (CRC) is a malignant tumor. Slug has been found to display a key role in diversified cancers, but its relevant regulatory mechanisms in CRC development are not fully explored.
OBJECTIVE: Hence, exploring the function and regulatory mechanisms of Slug is critical for the treatment of CRC.
METHODS: Protein expressions of Slug, N-cadherin, E-cadherin, Snail, HIF-1α, SUMO1, Drp1, Opa1, Mfn1/2, PGC-1α, NRF1, and TFAM were measured through western blot. To evaluate the protein expression of Slug and SUMO-1, an immunofluorescence assay was used. Cell migration ability was tested through transwell assay. The SUMOylation of Slug was examined through CO-IP assay.
RESULTS: Slug displayed higher expression and facilitated tumor metastasis in CRC. In addition, hypoxia treatment was discovered to upregulate HIF-1α, Slug, and SUMO-1 levels, as well as induce Slug SUMOylation. Slug SUMOylation markedly affected mitochondrial biosynthesis, fusion, and mitogen-related protein expression levels to trigger mitochondrial stress. Additionally, the induced mitochondrial stress by hypoxia could be rescued by Slug inhibition and TAK-981 treatment.
CONCLUSION: Our study expounded that hypoxia affects mitochondrial stress and facilitates tumor metastasis of CRC through Slug SUMOylation.

Keywords: CRC; Slug SUMOylation; hypoxia; mitochondrial stress

DOI: https://doi.org/10.2174/0115665240271525231112121008

Front Mol Biosci. 2023 ;10 1281244

Lipidomic landscape of lipokines in adipose tissue derived extracellular vesicles.

Yan Zhang, Tingyan Dong, Muyao Wang.

Introduction: Adipose tissue-derived extracellular vesicles (EVs-AT) are recognized as critical mediators of metabolic alterations in obesity-related diseases. However, few studies have focused on the role of lipids within EVs-AT in the development of obesity-related diseases. Methods: In this study, we performed a targeted lipidomic analysis to compare the lipidome of EVs secreted by inguinal white adipose tissue (EVs-iWAT), epididymal white adipose tissue (EVs-eWAT), and interscapular brown adipose tissue (EVs-BAT) in lean and obese mice. Results: We uncovered a comprehensive lipidomic map, revealing the diversity and specific lipid sorting in EVs-iWAT, EVs-eWAT, and EVs-BAT in obesity. Biological function analyses suggested that lipids encapsulated within EVs-AT of obese individuals might correlate with metabolism, pro-inflammatory response, and insulin resistance. These effects were particularly pronounced in EVs-eWAT and EVs-BAT. Conclusion: Our findings indicated that EVs-AT serves as novel carriers for lipokines, thereby mediating the biological functions of EVs-AT. This study holds promise for the identification of new biomarkers for obesity-related diseases and the development of new strategies to combat metabolic diseases.

Keywords: adipose tissue; extracellular vesicles; lipidome; lipokines; obesity

DOI: https://doi.org/10.3389/fmolb.2023.1281244

Mol Metab. 2023 Nov 25. pii: S2212-8778(23)00179-5. [Epub ahead of print] 101845

Independent activation of CREB3L2 by glucose fills a regulatory gap in mouse β-cells by co-ordinating insulin biosynthesis with secretory granule formation.

Nancy Sue, Le May Thai, Atsushi Saito, Cierra K Boyer, Ashleigh M Fordham, Chenxu Yan, Aimee Davenport, Jiang Tao, Mohammed Bensellam, James Cantley, Yan-Chuan Shi, Samuel B Stephens, Kazunori Imaizumi, Trevor J Biden.

OBJECTIVE: Although individual steps have been characterized, there is little understanding of the overall process whereby glucose co-ordinates the biosynthesis of insulin with its export out of the endoplasmic reticulum (ER) and incorporation into insulin secretory granules (ISGs). Here we investigate a role for the transcription factor CREB3L2 in this context.
METHODS: MIN6 cells and mouse islets were analysed by immunoblotting after treatment with glucose, fatty acids, thapsigargin and various inhibitors. Knockdown of CREB3L2 was achieved using si or sh constructs by transfection, or viral delivery. In vivo metabolic phenotyping was conducted after deletion of CREB3L2 in β-cells of adult mice using Ins1-CreER+. Islets were isolated for RNAseq and assays of glucose-stimulated insulin secretion (GSIS). Trafficking was monitored in islet monolayers using a GFP-tagged proinsulin construct that allows for synchronised release from the ER.
RESULTS: With a Km ≈3.5mM, glucose rapidly (T1/2 0.9h) increased full length (FL) CREB3L2 followed by a slower rise (T1/2 2.5h) in its transcriptionally-active cleavage product, P60 CREB3L2. Glucose stimulation repressed the ER stress marker, CHOP, and this was partially reverted by knockdown of CREB3L2. Activation of CREB3L2 by glucose was not due to ER stress, however, but a combination of O-GlcNAcylation, which impaired proteasomal degradation of FL-CREB3L2, and mTORC1 stimulation, which enhanced its conversion to P60. cAMP generation also activated CREB3L2, but independently of glucose. Deletion of CREB3L2 inhibited GSIS ex vivo and, following a high-fat diet (HFD), impaired glucose tolerance and insulin secretion in vivo. RNAseq revealed that CREB3L2 regulated genes controlling trafficking to-and-from the Golgi, as well as a broader cohort associated with β-cell compensation during a HFD. Although post-Golgi trafficking appeared intact, knockdown of CREB3L2 impaired the generation of both nascent ISGs and proinsulin condensates in the Golgi, implying a defect in ER export of proinsulin and/or its processing in the Golgi.
CONCLUSION: The stimulation of CREB3L2 by glucose defines a novel, rapid and direct mechanism for co-ordinating the synthesis, packaging and storage of insulin, thereby minimizing ER overload and optimizing β-cell function under conditions of high secretory demand. Upregulation of CREB3L2 also potentially contributes to the benefits of GLP1 agonism and might in itself constitute a novel means of treating β-cell failure.

Keywords: ER stress; ER-to-Golgi trafficking; O-GlcNAcylation; Pancreatic β-cell; insulin biosynthesis; insulin secretion

DOI: https://doi.org/10.1016/j.molmet.2023.101845