bims-mibica Biomed News
on Mitochondrial bioenergetics in cancer
Issue of 2024–10–06
fourteen papers selected by
Kelsey Fisher-Wellman, Wake Forest University
  1. Cysteamine dioxygenase (ADO) governs cancer cell mitochondrial redox homeostasis through proline metabolism.
  2. Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity.
  3. De novo GTP synthesis is a metabolic vulnerability for the interception of brain metastases.
  4. Therapeutic modulation of ROCK overcomes metabolic adaptation of cancer cells to OXPHOS inhibition and drives synergistic anti-tumor activity.
  5. Selective translation of nuclear mitochondrial respiratory proteins reprograms succinate metabolism in AML development and chemoresistance.
  6. N6-methyladenosine modification of SLC38A7 promotes cell migration, invasion, oxidative phosphorylation, and mitochondrial function in gastric cancer.
  7. SIAH3 is frequently epigenetically silenced in cancer and regulates mitochondrial metabolism.
  8. SUMOylation of MFF coordinates fission complexes to promote stress-induced mitochondrial fragmentation.
  9. Mitotic ER-mitochondria contact enhances mitochondrial Ca2+ influx to promote cell division.
  10. Ex Vivo Venetoclax Sensitivity Predicts Clinical Response in Acute Myeloid Leukemia in the Prospective VenEx Trial.
  11. Mitochondrial Pyruvate Carrier 1 as a Novel Prognostic Biomarker in Non-Small Cell Lung Cancer.
  12. Single-cell transcriptomes identify patient-tailored therapies for selective co-inhibition of cancer clones.
  13. NIPSNAP3A regulates cellular homeostasis by modulating mitochondrial dynamics.
  14. Fructose: the sweet(er) side of the Warburg effect.
  1. Sci Adv. 2024 Oct 04. 10(40): eadq0355
    Cysteamine dioxygenase (ADO) governs cancer cell mitochondrial redox homeostasis through proline metabolism.
    Sandy Che-Eun S Lee, Andrea Hye An Pyo, Helia Mohammadi, Ji Zhang, Anna Dvorkin-Gheva, Lucie Malbeteau, Stephen Chung, Shahbaz Khan, M Teresa Ciudad, Vincent Rondeau, Rob A Cairns, Thomas Kislinger, Tracy L McGaha, Bradly G Wouters, Julie A Reisz, Rachel Culp-Hill, Angelo D'Alessandro, Courtney L Jones, Marianne Koritzinsky.
      2-Aminoethanethiol dioxygenase (ADO) is a thiol dioxygenase that sulfinylates cysteamine and amino-terminal cysteines in polypeptides. The pathophysiological roles of ADO remain largely unknown. Here, we demonstrate that ADO expression represents a vulnerability in cancer cells, as ADO depletion led to loss of proliferative capacity and survival in cancer cells and reduced xenograft growth. In contrast, generation of the ADO knockout mouse revealed high tolerance for ADO depletion in adult tissues. To understand the mechanism underlying ADO's essentiality in cancer cells, we characterized the cell proteome and metabolome following depletion of ADO. This revealed that ADO depletion leads to toxic levels of polyamines which can be driven by ADO's substrate cysteamine. Polyamine accumulation in turn stimulated expression of proline dehydrogenase (PRODH) which resulted in mitochondrial hyperactivity and ROS production, culminating in cell toxicity. This work identifies ADO as a unique vulnerability in cancer cells, due to its essential role in maintenance of redox homeostasis through restraining polyamine levels and proline catabolism.
    DOI:  https://doi.org/10.1126/sciadv.adq0355
  2. Cell Death Discov. 2024 Sep 30. 10(1): 417
    Fatty acid synthase (FASN) is a tumor-cell-intrinsic metabolic checkpoint restricting T-cell immunity.
    Elisabet Cuyàs, Stefano Pedarra, Sara Verdura, Miguel Angel Pardo, Roderic Espin Garcia, Eila Serrano-Hervás, Àngela Llop-Hernández, Eduard Teixidor, Joaquim Bosch-Barrera, Eugeni López-Bonet, Begoña Martin-Castillo, Ruth Lupu, Miguel Angel Pujana, Josep Sardanyès, Tomás Alarcón, Javier A Menendez.
      Fatty acid synthase (FASN)-catalyzed endogenous lipogenesis is a hallmark of cancer metabolism. However, whether FASN is an intrinsic mechanism of tumor cell defense against T cell immunity remains unexplored. To test this hypothesis, here we combined bioinformatic analysis of the FASN-related immune cell landscape, real-time assessment of cell-based immunotherapy efficacy in CRISPR/Cas9-based FASN gene knockout (FASN KO) cell models, and mathematical and mechanistic evaluation of FASN-driven immunoresistance. FASN expression negatively correlates with infiltrating immune cells associated with cancer suppression, cytolytic activity signatures, and HLA-I expression. Cancer cells engineered to carry a loss-of-function mutation in FASN exhibit an enhanced cytolytic response and an accelerated extinction kinetics upon interaction with cytokine-activated T cells. Depletion of FASN results in reduced carrying capacity, accompanied by the suppression of mitochondrial OXPHOS and strong downregulation of electron transport chain complexes. Targeted FASN depletion primes cancer cells for mitochondrial apoptosis as it synergizes with BCL-2/BCL-XL-targeting BH3 mimetics to render cancer cells more susceptible to T-cell-mediated killing. FASN depletion prevents adaptive induction of PD-L1 in response to interferon-gamma and reduces constitutive overexpression of PD-L1 by abolishing PD-L1 post-translational palmitoylation. FASN is a novel tumor cell-intrinsic metabolic checkpoint that restricts T cell immunity and may be exploited to improve the efficacy of T cell-based immunotherapy.
    DOI:  https://doi.org/10.1038/s41420-024-02184-z
  3. Cell Rep Med. 2024 Oct 03. pii: S2666-3791(24)00485-3. [Epub ahead of print] 101755
    De novo GTP synthesis is a metabolic vulnerability for the interception of brain metastases.
    Agata M Kieliszek, Daniel Mobilio, Blessing I Bassey-Archibong, Jarrod W Johnson, Mathew L Piotrowski, Elvin D de Araujo, Abootaleb Sedighi, Nikoo Aghaei, Laura Escudero, Patrick Ang, William D Gwynne, Cunjie Zhang, Andrew Quaile, Dillon McKenna, Minomi Subapanditha, Tomas Tokar, Muhammad Vaseem Shaikh, Kui Zhai, Shawn C Chafe, Patrick T Gunning, J Rafael Montenegro-Burke, Chitra Venugopal, Jakob Magolan, Sheila K Singh.
      Patients with brain metastases (BM) face a 90% mortality rate within one year of diagnosis and the current standard of care is palliative. Targeting BM-initiating cells (BMICs) is a feasible strategy to treat BM, but druggable targets are limited. Here, we apply Connectivity Map analysis to lung-, breast-, and melanoma-pre-metastatic BMIC gene expression signatures and identify inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the de novo GTP synthesis pathway, as a target for BM. We show that pharmacological and genetic perturbation of IMPDH attenuates BMIC proliferation in vitro and the formation of BM in vivo. Metabolomic analyses and CRISPR knockout studies confirm that de novo GTP synthesis is a potent metabolic vulnerability in BM. Overall, our work employs a phenotype-guided therapeutic strategy to uncover IMPDH as a relevant target for attenuating BM outgrowth, which may provide an alternative treatment strategy for patients who are otherwise limited to palliation.
    Keywords:  GTP synthesis; IMPDH; brain metastases; cancer stem cells
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101755
  4. bioRxiv. 2024 Sep 20. pii: 2024.09.16.613317. [Epub ahead of print]
    Therapeutic modulation of ROCK overcomes metabolic adaptation of cancer cells to OXPHOS inhibition and drives synergistic anti-tumor activity.
    Nicholas Blazanin, Xiaobing Liang, Iqbal Mahmud, Eiru Kim, Sara Martinez, Lin Tan, Waikin Chan, Nazanin Esmaeili Anvar, Min Jin Ha, Md Qudratullah, Rosalba Minelli, Michael Peoples, Philip Lorenzi, Traver Hart, Yonathan Lissanu.
      Genomic studies have identified frequent mutations in subunits of the SWI/SNF chromatin remodeling complex including SMARCA4 and ARID1A in non-small cell lung cancer. Previously, we and others have identified that SMARCA4 -mutant lung cancers are highly dependent on oxidative phosphorylation (OXPHOS). Despite initial excitements, therapeutics targeting metabolic pathways such as OXPHOS have largely been disappointing due to rapid adaptation of cancer cells to inhibition of single metabolic enzymes or pathways, suggesting novel combination strategies to overcome adaptive responses are urgently needed. Here, we performed a functional genomics screen using CRISPR-Cas9 library targeting genes with available FDA approved therapeutics and identified ROCK1/2 as a top hit that sensitizes cancer cells to OXPHOS inhibition. We validate these results by orthogonal genetic and pharmacologic approaches by demonstrating that KD025 (Belumosudil), an FDA approved ROCK inhibitor, has highly synergistic anti-cancer activity in vitro and in vivo in combination with OXPHOS inhibition. Mechanistically, we showed that this combination induced a rapid, profound energetic stress and cell cycle arrest that was in part due to ROCK inhibition-mediated suppression of the adaptive increase in glycolysis normally seen by OXPHOS inhibition. Furthermore, we applied global phosphoproteomics and kinase-motif enrichment analysis to uncover a dynamic regulatory kinome upon combination of OXPHOS and ROCK inhibition. Importantly, we found converging phosphorylation-dependent regulatory cross-talk by AMPK and ROCK kinases on key RHO GTPase signaling/ROCK-dependent substrates such as PPP1R12A, NUMA1 and PKMYT1 that are known regulators of cell cycle progression. Taken together, our study identified ROCK kinases as critical mediators of metabolic adaptation of cancer cells to OXPHOS inhibition and provides a strong rationale for pursuing ROCK inhibitors as novel combination partners to OXPHOS inhibitors in cancer treatment.
    DOI:  https://doi.org/10.1101/2024.09.16.613317
  5. Cell Stem Cell. 2024 Sep 26. pii: S1934-5909(24)00322-9. [Epub ahead of print]
    Selective translation of nuclear mitochondrial respiratory proteins reprograms succinate metabolism in AML development and chemoresistance.
    Guoqiang Han, Manman Cui, Pengbo Lu, Tiantian Zhang, Rong Yin, Jin Hu, Jihua Chai, Jing Wang, Kexin Gao, Weidong Liu, Shuxin Yao, Ziyan Cao, Yanbing Zheng, Wen Tian, Rongxia Guo, Min Shen, Zheming Liu, Weiming Li, Shanshan Zhao, Xiangpeng Lin, Yuhui Zhang, Kehan Song, Yan Sun, Fuling Zhou, Haojian Zhang.
      Mitochondrial adaptations dynamically reprogram cellular bioenergetics and metabolism and confer key properties for human cancers. However, the selective regulation of these mitochondrial responses remains largely elusive. Here, inspired by a genetic screening in acute myeloid leukemia (AML), we identify RAS effector RREB1 as a translational regulator and uncover a unique translation control system for nuclear-encoded mitochondrial proteins in human cancers. RREB1 deletion reduces mitochondrial activities and succinate metabolism, thereby damaging leukemia stem cell (LSC) function and AML development. Replenishing complex II subunit SDHD rectifies these deficiencies. Notably, inhibition of complex II re-sensitizes AML cells to venetoclax treatment. Mechanistically, a short RREB1 variant binds to a conserved motif in the 3' UTRs and cooperates with elongation factor eEF1A1 to enhance protein translation of nuclear-encoded mitochondrial mRNAs. Overall, our findings reveal a unique translation control mechanism for mitochondrial adaptations in AML pathogenesis and provide a potential strategy for targeting this vulnerability of LSCs.
    Keywords:  RREB1; SDHD; acute myeloid leukemia; leukemia stem cell; mitochondria; succinate; translation; venetoclax
    DOI:  https://doi.org/10.1016/j.stem.2024.09.008
  6. J Biol Chem. 2024 Sep 30. pii: S0021-9258(24)02345-7. [Epub ahead of print] 107843
    N6-methyladenosine modification of SLC38A7 promotes cell migration, invasion, oxidative phosphorylation, and mitochondrial function in gastric cancer.
    Yi Hua, Wei-Jun Hua, Cun-Cheng Feng, Qiu-Wei Zhu.
      Solute carrier (SLC) 38 family responsible for trans-membrane transport of neutral amino acids, plays a role in the proliferation, invasion, and metastasis of cancer cells, but its role in gastric cancer (GC) progression remains unclear. This study aimed to explore the biological effects of SLC38A7 and its regulatory mechanisms in GC. RNA expression data, tumor tissue specimens, and GC cell lines were used for bioinformatics and experimental analyses. Cell Counting Kit-8 assay, wound healing assay, and Transwell invasion assay were used to evaluate cell viability, migration, and invasion, respectively. Oxidative phosphorylation, mitochondrial membrane potential and expression of the critical proteins in the mitochondrial respiratory chain were assayed using extracellular flux analysis, flow cytometry, and Western blot, respectively. RNA immunoprecipitation assay was used to explore the mechanisms of N6-methyladenosine (m6A) methylation. SLC38A7 was upregulated in GC tissue and cell lines. SLC38A7 silencing suppressed cell viability, migration, invasion, oxidative phosphorylation, and mitochondrial function in cancer cells. SLC38A7 overexpression had the opposite biological effects. Interactions between SLC38A7 and methyltransferase like 3 (METTL3) or insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) were detected. SLC38A7 mRNA stability was maintained by METTL3/IGF2BP2 axis in an m6A-dependent manner. Our results suggest that SLC38A7, stabilized by METTL3 and IGF2BP2-mediated m6A methylation, enhances cell viability, migration, invasion, oxidative phosphorylation, and mitochondrial function in GC, highlighting its role as a potential therapeutic target for GC.
    Keywords:  gastric cancer; m(6)A methylation; metastasis; oxidative phosphorylation; solute carrier family
    DOI:  https://doi.org/10.1016/j.jbc.2024.107843
  7. Int J Cancer. 2024 Sep 30.
    SIAH3 is frequently epigenetically silenced in cancer and regulates mitochondrial metabolism.
    Verena E Deutschmeyer, Nico A Schlaudraff, Sara K Walesch, Janine Moyer, Anna M Sokol, Johannes Graumann, Wolfgang Meissner, Marc Schneider, Thomas Muley, Peter Helmbold, Markus Schwinn, Antje M Richter, M Lienhard Schmitz, Reinhard H Dammann.
      Of the seven in absentia homologue (SIAH) family, three members have been identified in the human genome. In contrast to the E3 ubiquitin ligase encoding SIAH1 and SIAH2, little is known on the regulation and function of SIAH3 in tumorigenesis. In this study, we reveal that SIAH3 is frequently epigenetically silenced in different cancer entities, including cutaneous melanoma, lung adenocarcinoma and head and neck cancer. Low SIAH3 levels correlate with an impaired survival of cancer patients. Additionally, induced expression of SIAH3 reduces cell proliferation and induces cell death. Functionally, SIAH3 negatively affects cellular metabolism by shifting cells form aerobic oxidative phosphorylation to glycolysis. SIAH3 is localized in the mitochondrion and interacts with proteins involved in mitochondrial ribosome biogenesis and translation. We also report that SIAH3 interacts with ubiquitin ligases, including SIAH1 or SIAH2, and is degraded by them. These results suggest that SIAH3 acts as an epigenetically controlled tumor suppressor by regulating cellular metabolism through the inhibition of oxidative phosphorylation.
    Keywords:  SIAH; cancer; epigenetics; hypermethylation; metabolism
    DOI:  https://doi.org/10.1002/ijc.35202
  8. Sci Adv. 2024 Oct 04. 10(40): eadq6223
    SUMOylation of MFF coordinates fission complexes to promote stress-induced mitochondrial fragmentation.
    Richard Seager, Nitheyaa Shree Ramesh, Stephen Cross, Chun Guo, Kevin A Wilkinson, Jeremy M Henley.
      Mitochondria undergo fragmentation in response to bioenergetic stress, mediated by dynamin-related protein 1 (DRP1) recruitment to the mitochondria. The major pro-fission DRP1 receptor is mitochondrial fission factor (MFF), and mitochondrial dynamics proteins of 49 and 51 kilodaltons (MiD49/51), which can sequester inactive DRP1. Together, they form a trimeric DRP1-MiD-MFF complex. Adenosine monophosphate-activated protein kinase (AMPK)-mediated phosphorylation of MFF is necessary for mitochondrial fragmentation, but the molecular mechanisms are unclear. Here, we identify MFF as a target of small ubiquitin-like modifier (SUMO) at Lys151, MFF SUMOylation is enhanced following AMPK-mediated phosphorylation and that MFF SUMOylation regulates the level of MiD binding to MFF. The mitochondrial stressor carbonyl cyanide 3-chlorophenylhydrazone (CCCP) promotes MFF SUMOylation and mitochondrial fragmentation. However, CCCP-induced fragmentation is impaired in MFF-knockout mouse embryonic fibroblasts expressing non-SUMOylatable MFF K151R. These data suggest that the AMPK-MFF SUMOylation axis dynamically controls stress-induced mitochondrial fragmentation by regulating the levels of MiD in trimeric fission complexes.
    DOI:  https://doi.org/10.1126/sciadv.adq6223
  9. Cell Rep. 2024 Sep 28. pii: S2211-1247(24)01145-8. [Epub ahead of print]43(10): 114794
    Mitotic ER-mitochondria contact enhances mitochondrial Ca2+ influx to promote cell division.
    Gan Zhao, Mingkang Jia, Shicong Zhu, He Ren, Guopeng Wang, Guangwei Xin, Mengjie Sun, Xiangyang Wang, Qiaoyu Lin, Qing Jiang, Chuanmao Zhang.
      Cell division is tightly regulated and requires an expanded energy supply. However, how this energy is generated remains unclear. Here, we establish a correlation between two mitochondrial Ca2+ influx events and ATP production during mitosis. While both events promote ATP production during mitosis, the second event, the Ca2+ influx surge, is substantial. To facilitate this Ca2+ influx surge, the lamin B receptor (LBR) organizes a mitosis-specific endoplasmic reticulum (ER)-mitochondrial contact site (ERMCS), creating a rapid Ca2+ transport pathway. LBR acts as a tether, connecting the ER Ca2+ release channel IP3R with the mitochondrial VDAC2. Depletion of LBR disrupts the Ca2+ influx surge, reduces ATP production, and postpones the metaphase-anaphase transition and subsequent cell division. These findings provide insight into the mechanisms underlying mitotic energy production and supply required for cell proliferation.
    Keywords:  CP: Cell biology; CP: Metabolism; Ca(2+); ER-mitochondrial contact; LBR; VDAC2; cell cycle; cell division; energy generation; metaphase-anaphase transition; mitochondria; mitosis
    DOI:  https://doi.org/10.1016/j.celrep.2024.114794
  10. Blood. 2024 Oct 02. pii: blood.2024024968. [Epub ahead of print]
    Ex Vivo Venetoclax Sensitivity Predicts Clinical Response in Acute Myeloid Leukemia in the Prospective VenEx Trial.
    Sari Kytölä, Ida Maria Vänttinen, Tanja Ruokoranta, Anu Partanen, Annasofia Holopainen, Joseph Saad, Milla E L Kuusisto, Sirpa Koskela, Riikka Katariina Räty, Maija Itälä-Remes, Imre Västrik, Minna Suvela, Alun Owen Parsons, Kimmo Porkka, Krister Wennerberg, Caroline A Heckman, Tero Jalkanen, Teppo Huttunen, Pia Ettala, Johanna Rimpiläinen, Timo Siitonen, Marja Pyörälä, Heikki Kuusanmäki, Mika Kontro.
      The BCL2 inhibitor venetoclax has shown promise for treating acute myeloid leukemia (AML). However, identifying patients likely to respond remains a challenge, especially for those with relapsed/refractory (R/R) disease. We evaluated the utility of ex vivo venetoclax sensitivity testing to predict treatment responses to venetoclax-azacitidine in a prospective, multicenter, phase 2 trial conducted by the Finnish AML Group (VenEx, NCT04267081). The trial recruited 104 participants with previously untreated (n=48), R/R (n=39) or previously treated secondary AML (sAML) (n=17). The primary endpoint was complete remission or complete remission with incomplete hematologic recovery (CR/CRi) rate in ex vivo sensitive trial participants during the first three therapy cycles. The key secondary endpoints included the correlations between ex vivo drug sensitivity, responses, and survival. Venetoclax sensitivity was successfully assessed in 102/104 participants, with results available within a median of three days from sampling. In previously untreated AML, ex vivo sensitivity corresponded to an 85% (34/40) CR/CRi rate, with a median overall survival (OS) of 28.7 months, compared to 5.5 months for ex vivo resistant patients (p = 0.002). For R/R/sAML, ex vivo sensitivity resulted in a 62% CR/CRi rate (21/34) and median OS of 9.7 versus 3.3 months for ex vivo resistant patients (p < 0.001). In univariate and multivariate analysis, ex vivo venetoclax sensitivity was the strongest predictor for a favorable treatment response and survival. The VenEx trial demonstrates the feasibility of integrating ex vivo drug testing into clinical practice to identify AML patients, particularly in the R/R setting, who benefit from venetoclax.
    DOI:  https://doi.org/10.1182/blood.2024024968
  11. Technol Cancer Res Treat. 2024 Jan-Dec;23:23 15330338241282080
    Mitochondrial Pyruvate Carrier 1 as a Novel Prognostic Biomarker in Non-Small Cell Lung Cancer.
    Hongbo Zou, Yunfei Yin, Kai Xiong, Xuelian Luo, Zhongju Sun, Bijing Mao, Qichao Xie, Mei Tan, Rui Kong.
       BACKGROUND: Abnormal mitochondrial pyruvate carrier 1 (MPC1) expression plays a key role in tumor metabolic reprogramming and progression. Understanding its significance in non-small cell lung cancer (NSCLC) is crucial for identifying therapeutic targets.
    METHODS: TIMER 2.0 was utilized to assess the expression of MPC1 in both normal and cancer tissues in pan-cancer. Overall survival (OS) differences between high and low MPC1 expression were analyzed in NSCLC using the Cancer Genome Atlas (TCGA) datasets. We also examined the expression of MPC1 in NSCLC cell lines using western blotting and quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). In addition, the tissue samples and clinical information of 80 patients with NSCLC from our hospital were collected. Immunohistochemistry (IHC) was used to assess MPC1 expression, and OS was evaluated using Kaplan-Meier curves and the log-rank test. Univariate and multivariate Cox regression analyses were conducted to evaluate the prognostic values of the clinical characteristics and MPC1expression.
    RESULTS: Analysis of public databases suggested that MPC1 was downregulated in NSCLC compared to that in normal lung tissue and predicted poor prognosis. In addition, the expression of MPC1 in NSCLC cell lines was lower than that in human bronchial epithelial (HBE) cells at both protein and mRNA levels. Further clinical analysis suggested that MPC1 expression was correlated with age, tumor T stage, and TNM stage. Kaplan-Meier analysis revealed that NSCLC patients with high MPC1 expression had a better prognosis, particularly in lung adenocarcinoma (LUAD), whereas no survival benefit was observed in lung squamous cell carcinoma (LUSC). Univariate and multivariate analyses suggested that MPC1 was an independent prognostic factor for patients with NSCLC.
    CONCLUSIONS: MPC1 is poorly expressed in NSCLC, particularly in LUAD, which predicts a poor prognosis and may serve as an independent prognostic factor. Further studies on MPC1 may reveal new targets for the treatment of NSCLC.
    Keywords:  lung adenocarcinoma (LUAD); mitochondrial pyruvate carrier 1 (MPC1); non-small cell lung cancer (NSCLC); overall survival (OS); prognosis
    DOI:  https://doi.org/10.1177/15330338241282080
  12. Nat Commun. 2024 Oct 03. 15(1): 8579
    Single-cell transcriptomes identify patient-tailored therapies for selective co-inhibition of cancer clones.
    Aleksandr Ianevski, Kristen Nader, Kyriaki Driva, Wojciech Senkowski, Daria Bulanova, Lidia Moyano-Galceran, Tanja Ruokoranta, Heikki Kuusanmäki, Nemo Ikonen, Philipp Sergeev, Markus Vähä-Koskela, Anil K Giri, Anna Vähärautio, Mika Kontro, Kimmo Porkka, Esa Pitkänen, Caroline A Heckman, Krister Wennerberg, Tero Aittokallio.
      Intratumoral cellular heterogeneity necessitates multi-targeting therapies for improved clinical benefits in advanced malignancies. However, systematic identification of patient-specific treatments that selectively co-inhibit cancerous cell populations poses a combinatorial challenge, since the number of possible drug-dose combinations vastly exceeds what could be tested in patient cells. Here, we describe a machine learning approach, scTherapy, which leverages single-cell transcriptomic profiles to prioritize multi-targeting treatment options for individual patients with hematological cancers or solid tumors. Patient-specific treatments reveal a wide spectrum of co-inhibitors of multiple biological pathways predicted for primary cells from heterogenous cohorts of patients with acute myeloid leukemia and high-grade serous ovarian carcinoma, each with unique resistance patterns and synergy mechanisms. Experimental validations confirm that 96% of the multi-targeting treatments exhibit selective efficacy or synergy, and 83% demonstrate low toxicity to normal cells, highlighting their potential for therapeutic efficacy and safety. In a pan-cancer analysis across five cancer types, 25% of the predicted treatments are shared among the patients of the same tumor type, while 19% of the treatments are patient-specific. Our approach provides a widely-applicable strategy to identify personalized treatment regimens that selectively co-inhibit malignant cells and avoid inhibition of non-cancerous cells, thereby increasing their likelihood for clinical success.
    DOI:  https://doi.org/10.1038/s41467-024-52980-5
  13. Gene. 2024 Oct 01. pii: S0378-1119(24)00857-6. [Epub ahead of print] 148976
    NIPSNAP3A regulates cellular homeostasis by modulating mitochondrial dynamics.
    Run Yan, Liting Chen, Zimu Cai, Jiyao Tang, Yanlin Zhu, Yanping Li, Xuemin Wang, Yu Ruan, Qi Han.
      Mitochondria are essential for cell metabolism and survival as they produce the majority of cellular ATP through oxidative phosphorylation as well as regulate critical processes such as cell proliferation and apoptosis. NIPSNAP family of proteins are predominantly mitochondrial matrix proteins. However, the molecular and cellular functions of the NIPSNAPs, particularly NIPSNAP3A, have remained elusive. Here, we demonstrated that NIPSNAP3A knockdown in HeLa cells inhibited their proliferation and migration and attenuated apoptosis induced by Actinomycin D (Act-D). These findings suggested a complex relationship between cellular processes and mitochondrial functions, mediated by NIPSNAP3A. Further investigations revealed that NIPSNAP3A knockdown not only inhibited mitochondrial fission through reduction of DRP1-S616, but also suppressed cytochrome c release in apoptosis. Collectively, our findings highlight the critical role of NIPSNAP3A in coordinating cellular processes, likely through its influence on mitochondrial dynamics.
    Keywords:  Apoptosis; Drp1; Fission; Mitochodnria; NIPSNAP3A; Proliferation
    DOI:  https://doi.org/10.1016/j.gene.2024.148976
  14. Cell Death Differ. 2024 Oct 05.
    Fructose: the sweet(er) side of the Warburg effect.
    Christian Frezza.
      
    DOI:  https://doi.org/10.1038/s41418-024-01395-2
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