bims-iorami 2024-01-14 papers

bims-iorami

Biomed News

on Ionising Radiation and Mitochondria

Issue of 2024–01–14
nine papers selected by
Chenxiao Yu, Soochow University

cGAS-STING, inflammasomes and pyroptosis: an overview of crosstalk mechanism of activation and regulation.
Dose-Dependent Effects of Radiation on Mitochondrial Morphology and Clonogenic Cell Survival in Human Microvascular Endothelial Cells.
DNA sensing and repair systems unexpectedly team up against cancer.
Nrf2 and mitochondria form a mutually regulating circuit in the prevention and treatment of metabolic syndrome.
Antitumour effect of the mitochondrial complex III inhibitor Atovaquone in combination with anti-PD-L1 therapy in mouse cancer models.
MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis.
Rectal Cancer and Radiation in Colitis.
Single-cell and spatial profiling identify three response trajectories to pembrolizumab and radiation therapy in triple negative breast cancer.
Immunotherapy and Radiation therapy Sequencing in Breast Cancer: A Systematic Review.

Cell Commun Signal. 2024 Jan 09. 22(1): 22

cGAS-STING, inflammasomes and pyroptosis: an overview of crosstalk mechanism of activation and regulation.

Jingwen Liu, Jing Zhou, Yuling Luan, Xiaoying Li, Xiangrui Meng, Wenhao Liao, Jianyuan Tang, Zheilei Wang.

   BACKGROUND: Intracellular DNA-sensing pathway cGAS-STING, inflammasomes and pyroptosis act as critical natural immune signaling axes for microbial infection, chronic inflammation, cancer progression and organ degeneration, but the mechanism and regulation of the crosstalk network remain unclear. Cellular stress disrupts mitochondrial homeostasis, facilitates the opening of mitochondrial permeability transition pore and the leakage of mitochondrial DNA to cell membrane, triggers inflammatory responses by activating cGAS-STING signaling, and subsequently induces inflammasomes activation and the onset of pyroptosis. Meanwhile, the inflammasome-associated protein caspase-1, Gasdermin D, the CARD domain of ASC and the potassium channel are involved in regulating cGAS-STING pathway. Importantly, this crosstalk network has a cascade amplification effect that exacerbates the immuno-inflammatory response, worsening the pathological process of inflammatory and autoimmune diseases. Given the importance of this crosstalk network of cGAS-STING, inflammasomes and pyroptosis in the regulation of innate immunity, it is emerging as a new avenue to explore the mechanisms of multiple disease pathogenesis. Therefore, efforts to define strategies to selectively modulate cGAS-STING, inflammasomes and pyroptosis in different disease settings have been or are ongoing. In this review, we will describe how this mechanistic understanding is driving possible therapeutics targeting this crosstalk network, focusing on the interacting or regulatory proteins, pathways, and a regulatory mitochondrial hub between cGAS-STING, inflammasomes, and pyroptosis.
SHORT CONCLUSION: This review aims to provide insight into the critical roles and regulatory mechanisms of the crosstalk network of cGAS-STING, inflammasomes and pyroptosis, and to highlight some promising directions for future research and intervention.

Keywords:  Crosstalk network; Diseases; Inflammasome; Inflammation; Pyroptosis; cGAS-STING

DOI:  https://doi.org/10.1186/s12964-023-01466-w
Cells. 2023 Dec 23. pii: 39. [Epub ahead of print]13(1):

Dose-Dependent Effects of Radiation on Mitochondrial Morphology and Clonogenic Cell Survival in Human Microvascular Endothelial Cells.

Li Wang, Rafael Rivas, Angelo Wilson, Yu Min Park, Shannon Walls, Tianzheng Yu, Alexandra C Miller.

  To better understand radiation-induced organ dysfunction at both high and low doses, it is critical to understand how endothelial cells (ECs) respond to radiation. The impact of irradiation (IR) on ECs varies depending on the dose administered. High doses can directly damage ECs, leading to EC impairment. In contrast, the effects of low doses on ECs are subtle but more complex. Low doses in this study refer to radiation exposure levels that are below those that cause immediate and necrotic damage. Mitochondria are the primary cellular components affected by IR, and this study explored their role in determining the effect of radiation on microvascular endothelial cells. Human dermal microvascular ECs (HMEC-1) were exposed to varying IR doses ranging from 0.1 Gy to 8 Gy (~0.4 Gy/min) in the AFRRI 60-Cobalt facility. Results indicated that high doses led to a dose-dependent reduction in cell survival, which can be attributed to factors such as DNA damage, oxidative stress, cell senescence, and mitochondrial dysfunction. However, low doses induced a small but significant increase in cell survival, and this was achieved without detectable DNA damage, oxidative stress, cell senescence, or mitochondrial dysfunction in HMEC-1. Moreover, the mitochondrial morphology was assessed, revealing that all doses increased the percentage of elongated mitochondria, with low doses (0.25 Gy and 0.5 Gy) having a greater effect than high doses. However, only high doses caused an increase in mitochondrial fragmentation/swelling. The study further revealed that low doses induced mitochondrial elongation, likely via an increase in mitochondrial fusion protein 1 (Mfn1), while high doses caused mitochondrial fragmentation via a decrease in optic atrophy protein 1 (Opa1). In conclusion, the study suggests, for the first time, that changes in mitochondrial morphology are likely involved in the mechanism for the radiation dose-dependent effect on the survival of microvascular endothelial cells. This research, by delineating the specific mechanisms through which radiation affects endothelial cells, offers invaluable insights into the potential impact of radiation exposure on cardiovascular health.

Keywords:  DNA damage; cell senescence; cell survival; dose-dependent effect; human microvascular endothelial cells; mitochondrial morphology and function; radiation exposure; reactive oxygen species

DOI:  https://doi.org/10.3390/cells13010039
Nature. 2024 Jan 10.

DNA sensing and repair systems unexpectedly team up against cancer.

Silvia Monticelli, Petr Cejka.



Keywords:  Cancer; Cell biology

DOI:  https://doi.org/10.1038/d41586-023-03994-4
Antioxid Redox Signal. 2024 Jan 06.

Nrf2 and mitochondria form a mutually regulating circuit in the prevention and treatment of metabolic syndrome.

Jiawei Zhang, Weiqiang Lv, Guanfei Zhang, Mengqi Zeng, Wenli Cao, Jiacan Su, Ke Cao, Jiankang Liu.

SIGNIFICANCE: Metabolic syndrome (MetS) has become a major global public health problem and there is an urgent need to elucidate its pathogenesis and find more effective targets and modalities for intervention.
RECENT ADVANCES: Oxidative stress and inflammation are two of the major causes of MetS-related symptoms such as insulin resistance and obesity. Nuclear factor erythroid 2 related factor 2 (Nrf2) is one of the important systems responding to oxidative stress and inflammation. As cells undergo stress, cysteines within Keap1 are oxidized or electrophilically modified, allowing Nrf2 to escape ubiquitination and be translocated from the cytoplasm to the nucleus, facilitating the initiation of the antioxidant transcriptional program. Meanwhile, a growing body of evidence points out a specific modulation of mitochondrial homeostasis by Nrf2. Following nuclear translocation, Nrf2 activates downstream genes involved in various aspects of mitochondrial homeostasis, including mitochondrial biogenesis and dynamics, mitophagy, aerobic respiration, and energy metabolism. In turn, mitochondria reciprocally activate Nrf2 by releasing reactive oxygen species and regulating antioxidant enzymes.
CRITICAL ISSUES: In this review, we firstly summarize the interactions between Nrf2 and mitochondria in the modulation of oxidative stress and inflammation to ameliorate MetS, then propose that Nrf2 and mitochondria form a mutually regulating circuit critical to maintaining homeostasis during MetS.
FUTURE DIRECTIONS: Targeting the Nrf2-mitochondrial circuit may be a promising strategy to ameliorate MetS, such as obesity, diabetes and cardiovascular diseases.

DOI: https://doi.org/10.1089/ars.2023.0339
Cell Death Dis. 2024 Jan 11. 15(1): 32

Antitumour effect of the mitochondrial complex III inhibitor Atovaquone in combination with anti-PD-L1 therapy in mouse cancer models.

Gonzalo Rodriguez-Berriguete, Rathi Puliyadi, Nicole Machado, Alessandro Barberis, Remko Prevo, Martin McLaughlin, Francesca M Buffa, Kevin J Harrington, Geoff S Higgins.

Immune checkpoint blockade (ICB) provides effective and durable responses for several tumour types by unleashing an immune response directed against cancer cells. However, a substantial number of patients treated with ICB develop relapse or do not respond, which has been partly attributed to the immune-suppressive effect of tumour hypoxia. We have previously demonstrated that the mitochondrial complex III inhibitor atovaquone alleviates tumour hypoxia both in human xenografts and in cancer patients by decreasing oxygen consumption and consequently increasing oxygen availability in the tumour. Here, we show that atovaquone alleviates hypoxia and synergises with the ICB antibody anti-PD-L1, significantly improving the rates of tumour eradication in the syngeneic CT26 model of colorectal cancer. The synergistic effect between atovaquone and anti-PD-L1 relied on CD8+ T cells, resulted in the establishment of a tumour-specific memory immune response, and was not associated with any toxicity. We also tested atovaquone in combination with anti-PD-L1 in the LLC (lung) and MC38 (colorectal) cancer syngeneic models but, despite causing a considerable reduction in tumour hypoxia, atovaquone did not add any therapeutic benefit to ICB in these models. These results suggest that atovaquone has the potential to improve the outcomes of patients treated with ICB, but predictive biomarkers are required to identify individuals likely to benefit from this intervention.

DOI: https://doi.org/10.1038/s41419-023-06405-8
Nature. 2024 Jan 10.

MRE11 liberates cGAS from nucleosome sequestration during tumorigenesis.

Min-Guk Cho, Rashmi J Kumar, Chien-Chu Lin, Joshua A Boyer, Jamshaid A Shahir, Katerina Fagan-Solis, Dennis A Simpson, Cheng Fan, Christine E Foster, Anna M Goddard, Lynn M Lerner, Simon W Ellington, Qinhong Wang, Ying Wang, Alice Y Ho, Pengda Liu, Charles M Perou, Qi Zhang, Robert K McGinty, Jeremy E Purvis, Gaorav P Gupta.

Oncogene-induced replication stress generates endogenous DNA damage that activates cGAS-STING-mediated signalling and tumour suppression1-3. However, the precise mechanism of cGAS activation by endogenous DNA damage remains enigmatic, particularly given that high-affinity histone acidic patch (AP) binding constitutively inhibits cGAS by sterically hindering its activation by double-stranded DNA (dsDNA)4-10. Here we report that the DNA double-strand break sensor MRE11 suppresses mammary tumorigenesis through a pivotal role in regulating cGAS activation. We demonstrate that binding of the MRE11-RAD50-NBN complex to nucleosome fragments is necessary to displace cGAS from acidic-patch-mediated sequestration, which enables its mobilization and activation by dsDNA. MRE11 is therefore essential for cGAS activation in response to oncogenic stress, cytosolic dsDNA and ionizing radiation. Furthermore, MRE11-dependent cGAS activation promotes ZBP1-RIPK3-MLKL-mediated necroptosis, which is essential to suppress oncogenic proliferation and breast tumorigenesis. Notably, downregulation of ZBP1 in human triple-negative breast cancer is associated with increased genome instability, immune suppression and poor patient prognosis. These findings establish MRE11 as a crucial mediator that links DNA damage and cGAS activation, resulting in tumour suppression through ZBP1-dependent necroptosis.

DOI: https://doi.org/10.1038/s41586-023-06889-6
Clin Colon Rectal Surg. 2024 Jan;37(1): 30-36

Rectal Cancer and Radiation in Colitis.

Patricio B Lynn, Catherine Cronin, Sriram Rangarajan, Maria Widmar.

  Inflammatory bowel disease (IBD) is associated with an increased risk of colorectal cancer. When IBD patients develop a rectal cancer, this should be treated with the same oncological principles and guidelines as the general population. Rectal cancer treatment includes surgery, chemotherapy, and radiation therapy (RT). Many IBD patients will require a total proctocolectomy with an ileal-pouch anal anastomosis (IPAA) and others, restoration of intestinal continuity may not be feasible or advisable. The literature is scarce regarding outcomes of IPAA after RT. In the present review, we will summarize the evidence regarding RT toxicity in IBD patients and review surgical strategies and outcomes of IPAA after RT.

Keywords:  functional outcomes; ileal pouch-anal anastomosis; inflammatory bowel disease; radiation therapy; rectal cancer

DOI:  https://doi.org/10.1055/s-0043-1762561
Cancer Cell. 2024 Jan 08. pii: S1535-6108(23)00440-3. [Epub ahead of print]42(1): 70-84.e8

Single-cell and spatial profiling identify three response trajectories to pembrolizumab and radiation therapy in triple negative breast cancer.

Stephen L Shiao, Kenneth H Gouin, Nathan Ing, Alice Ho, Reva Basho, Aagam Shah, Richard H Mebane, David Zitser, Andrew Martinez, Natalie-Ya Mevises, Bassem Ben-Cheikh, Regina Henson, Monica Mita, Philomena McAndrew, Scott Karlan, Armando Giuliano, Alice Chung, Farin Amersi, Catherine Dang, Heather Richardson, Wonwoo Shon, Farnaz Dadmanesh, Michele Burnison, Amin Mirhadi, Zachary S Zumsteg, Rachel Choi, Madison Davis, Joseph Lee, Dustin Rollins, Cynthia Martin, Negin H Khameneh, Heather McArthur, Simon R V Knott.

  Strategies are needed to better identify patients that will benefit from immunotherapy alone or who may require additional therapies like chemotherapy or radiotherapy to overcome resistance. Here we employ single-cell transcriptomics and spatial proteomics to profile triple negative breast cancer biopsies taken at baseline, after one cycle of pembrolizumab, and after a second cycle of pembrolizumab given with radiotherapy. Non-responders lack immune infiltrate before and after therapy and exhibit minimal therapy-induced immune changes. Responding tumors form two groups that are distinguishable by a classifier prior to therapy, with one showing high major histocompatibility complex expression, evidence of tertiary lymphoid structures, and displaying anti-tumor immunity before treatment. The other responder group resembles non-responders at baseline and mounts a maximal immune response, characterized by cytotoxic T cell and antigen presenting myeloid cell interactions, only after combination therapy, which is mirrored in a murine model of triple negative breast cancer.

Keywords:  Breast cancer metastasis; CAR T cell; T cell; TCR T cell; disseminated tumor cells; immunotherapy; tumor dormancy; tumor microenvironment; vaccine

DOI:  https://doi.org/10.1016/j.ccell.2023.12.012
Int J Radiat Oncol Biol Phys. 2024 Jan 07. pii: S0360-3016(24)00006-3. [Epub ahead of print]

Immunotherapy and Radiation therapy Sequencing in Breast Cancer: A Systematic Review.

Saurav Verma, Sympascho Young, Gabriel Boldt, Phillip Blanchette, Michael Lock, Joelle Helou, Jacques Raphael.

   PURPOSE: In the past decade, immune checkpoint inhibitors (ICIs) have emerged as a treatment option for metastatic breast cancer (BC). More recently, ICIs have been approved in the perioperative setting. This has led to clinical scenarios where radiation therapy (RT) is given concurrently with ICIs. On the other hand, moderate- and ultra-hypofractionated (HF) schedules of RT are being widely adopted in the adjuvant setting, in addition to an increased use of metastasis-directed therapy. Furthermore, RT can modulate the tumor microenvironment and induce a systemic response at non-irradiated sites, 'abscopal effect'. The amplification of anti-tumor immune response is used as the rationale behind the concomitant use of ICIs and RT. To date, there is a lack of literature on the optimal sequence, timing, dose/fractionation schema and treated RT volumes with ICIs in patients with BC, especially in the era of HF.
METHODS AND MATERIALS: We conducted a systematic review to delineate the reported treatment details, safety and efficacy of combiningICI and RT in patients with BC. Pubmed, Embase and Cochrane CENTRAL were searched up between 2014-2023. Data was extracted to assess the details of ICIs/RT delivery, safety and efficacy.
RESULTS: Of the twelve eligible studies, nine involved patients with metastatic BC. Most studies were phase 1/2, had a small sample size (range 8-28) and were heterogenous in patients' population and reported outcomes. The combination was reported to be safe. We identified one study in the perioperative setting, which did a post-hoc analysis of safety/efficacy of ICIs in the adjuvant setting with receipt and pattern of RT.
CONCLUSIONS: In conclusion, there is limited data on the dose, timing, fractionation, volumes of RT in both the adjuvant and metastatic setting in BC. The ongoing/future trials should collect and report such data on RT details, whenever RT is used in combination with ICIs.

Keywords:  ICIs; Immunotherapy; RT; breast cancer; efficacy; immune checkpoint inhibitor; radiation; safety

DOI:  https://doi.org/10.1016/j.ijrobp.2024.01.001