bims-scepro 2025-06-22 papers

bims-scepro

Biomed News

on Stem cell proteostasis

Issue of 2025–06–22
nineteen papers selected by
William Grey, University of York

The STAT3-VDAC1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cells.
Bivalent chromatin instructs lineage specification during hematopoiesis.
Structural basis for the midnolin-proteasome pathway and its role in suppressing myeloma.
Loss of BAP1 defines a unique subtype of TP53-mutated de novo AML and confers sensitivity to BCL-xL inhibitors.
Mer receptor expression promotes multiple myeloma disease development via a cell-extrinsic mechanism.
MARCH1, transcriptionally regulated by POU2F2, facilitates acute myeloid leukemia progression via inducing MYCT1 degradation.
KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia.
System-Wide Profiling of Ubiquitin E3 Ligase Activities with Quantitative Proteomics and Bioinformatics Analysis.
ATR promotes mTORC1 activity via de novo cholesterol synthesis.
Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia.
Human bone marrow organoids: emerging progress but persisting challenges.
N6-methyladenosine-modified GPX2 impacts cancer cell stemness and TKI resistance through regulating of redox metabolism.
STAMP: Single-cell transcriptomics analysis and multimodal profiling through imaging.
Establishing predictive machine learning models for drug responses in patient derived cell culture.
LZTS2 Negatively Regulates Centrosomal CEP135 Levels and Microtubule Nucleation.
The integrated stress response fine-tunes stem cell fate decisions upon serine deprivation and tissue injury.
Cell state-specific cytoplasmic density controls spindle architecture and scaling.
Blocking mutant IDH1 phosphorylation triggers APC/C CDH1-dependent ubiquitination in mitotic cells.
Proteostasis signatures in human diseases.

Haematologica. 2025 Jun 19.

The STAT3-VDAC1 axis modulates mitochondrial function and plays a critical role in the survival of acute myeloid leukemia cells.

Kellen B Gil, Jamie Borg, Rosana Moreira Pereira, Anagha Inguva-Sheth, Geovana Araujo, Jeremy Rahkola, William Showers, Abby Grier, Angelo D'Alessandro, Clayton Smith, Christine McMahon, Daniel A Pollyea, Austin E Gillen, Maria L Amaya.

Signal transducer and activator of transcription 3 (STAT3) is a well-described transcription factor that mediates oxidative phosphorylation and glutamine uptake in bulk acute myeloid leukemia (AML) cells and leukemic stem cells (LSCs). STAT3 has also been shown to translocate to the mitochondria in AML cells, and phosphorylation at the serine 727 (pSTAT3 S727) residue has been shown to be especially important for STAT3's mitochondrial functions. We demonstrate that inhibition of STAT3 results in impaired mitochondrial function and decreased leukemia cell viability. We discovered a novel interaction of STAT3 with voltage-dependent anion channel 1 (VDAC1) in the mitochondria which provides a mechanism through which STAT3 modulates mitochondrial function and cell survival. Through VDAC1, STAT3 regulates calcium and oxidative phosphorylation in the mitochondria. STAT3 and VDAC1 inhibition also result in significantly reduced engraftment potential of LSCs, including primary samples resistant to venetoclax. These results implicate STAT3 as a therapeutic target in AML.

DOI: https://doi.org/10.3324/haematol.2025.287352
Cell. 2025 Jun 12. pii: S0092-8674(25)00561-6. [Epub ahead of print]

Bivalent chromatin instructs lineage specification during hematopoiesis.

Masaki Yagi, Gracia Bonilla, Michael S Hoetker, Nikolaos Tsopoulidis, Joy E Horng, Chuck Haggerty, Alexander Meissner, Ruslan I Sadreyev, Hanno Hock, Konrad Hochedlinger.

  Developmental gene expression is regulated by the dynamic interplay of histone H3 lysine 4 (H3K4) and histone H3 lysine 27 (H3K27) methylation, yet the physiological roles of these epigenetic modifications remain incompletely understood. Here, we show that mice depleted for all forms of H3K4 methylation, using a dominant histone H3-lysine-4-to-methionine (H3K4M) mutation, succumb to a severe loss of all major blood cell types. H3K4M-expressing hematopoietic stem cells (HSCs) and committed progenitors are present at normal numbers, indicating that H3K4 methylation is dispensable for HSC maintenance and commitment but essential for progenitor cell maturation. Mechanistically, we reveal that H3K4 methylation opposes the deposition of repressive H3K27 methylation at differentiation-associated genes enriched for a bivalent (i.e., H3K4/H3K27-methylated) chromatin state in HSCs and progenitors. Indeed, by concomitantly suppressing H3K27 methylation in H3K4-methylation-depleted mice, we rescue the acute lethality, hematopoietic failure, and gene dysregulation. Our results provide functional evidence for the interaction between two crucial chromatin marks in mammalian tissue homeostasis.

Keywords:  H3K27 methylation; H3K27M; H3K4 methylation; H3K4M; bivalent genes; differentiation; hematopoiesis; hematopoietic stem and progenitor cells; histone methylation; lysine-to-methionine mutation

DOI:  https://doi.org/10.1016/j.cell.2025.05.011
Mol Cell. 2025 Jun 11. pii: S1097-2765(25)00469-1. [Epub ahead of print]

Structural basis for the midnolin-proteasome pathway and its role in suppressing myeloma.

Christopher Nardone, Jingjing Gao, Hyuk-Soo Seo, Julian Mintseris, Lucy Ort, Matthew C J Yip, Milen Negasi, Anna K Besschetnova, Nolan Kamitaki, Steven P Gygi, Sirano Dhe-Paganon, Nikhil C Munshi, Mariateresa Fulciniti, Michael E Greenberg, Sichen Shao, Stephen J Elledge, Xin Gu.

  The midnolin-proteasome pathway degrades many nuclear proteins without ubiquitination, but how it operates mechanistically remains unclear. Here, we present structures of the midnolin-proteasome complex, revealing how established proteasomal components are repurposed to enable a unique form of proteolysis. While the proteasomal subunit PSMD2/Rpn1 binds to ubiquitinated or ubiquitin-like (Ubl) proteins, we discover that it also interacts with the midnolin nuclear localization sequence, elucidating how midnolin's activity is confined to the nucleus. Likewise, PSMD14/Rpn11, an enzyme that normally cleaves ubiquitin chains, surprisingly functions non-enzymatically as a receptor for the midnolin Ubl domain, positioning the substrate-binding Catch domain directly above the proteasomal entry site to guide substrates into the proteasome. Moreover, we demonstrate that midnolin downregulation is critical for the survival of myeloma cells by stabilizing the transcription factor substrate IRF4. Our findings uncover the mechanisms underlying the midnolin-proteasome pathway and midnolin downregulation as a driver of multiple myeloma.

Keywords:  IRF4; PSMD14/Rpn11; PSMD2/Rpn1; midnolin; myeloma; proteasome; ubiquitin-independent

DOI:  https://doi.org/10.1016/j.molcel.2025.05.030
Blood. 2025 Jun 20. pii: blood.2024026417. [Epub ahead of print]

Loss of BAP1 defines a unique subtype of TP53-mutated de novo AML and confers sensitivity to BCL-xL inhibitors.

Jaclyn Andricovich, Coen Johannes Lap, Alexandros Tzatsos.

Mutations in TP53 are mutually exclusive with other known drivers of myeloid transformation and define a distinct molecular subtype within de novo Acute Myeloid Leukemia (AML) that is associated with a complex karyotype, resistance to chemotherapy, and poor prognosis. Although TP53 defects are rare in de novo AML, biallelic mutations are a defining molecular feature of erythroleukemia. The genetic alterations that cooperate with defective TP53 to transform erythroid progenitors remain unknown. We found that loss of BAP1 (BRCA1 Associated Protein-1) co-occurs in one-third of patients with TP53-mutated AML, is associated with an erythroid-primed gene expression signature, and confers an additional adverse effect on overall survival. BAP1 is a tumor suppressor involved in the DNA damage response as well as epigenetic regulation through histone H2AK119 de-ubiquitination. While Bap1KO mice develop myelodysplasia with prominent dyserythropoiesis, combined deletion of Bap1 and Trp53 caused transplantable erythroleukemia, and occasionally mixed AML, mirroring the heterogeneity of human disease. Bulk and single-cell RNA-seq coupled to ChIP-seq in hematopoietic progenitors revealed that Bap1 loss triggers a proinflammatory response and cooperates with Trp53 deficiency to transform erythroid-primed multipotent progenitors. Mechanistically, genomic instability led to the development of erythroleukemia, while epigenetic deregulation caused myelomonocytic skewing suggesting a dichotomous and context dependent role for BAP1. We also demonstrate that BAP1 deficient erythroleukemia is dependent on BCL2L1 expression and is sensitive to BCL-xL inhibitors in vivo.

DOI: https://doi.org/10.1182/blood.2024026417
Exp Hematol. 2025 Jun 14. pii: S0301-472X(25)00133-X. [Epub ahead of print] 104842

Mer receptor expression promotes multiple myeloma disease development via a cell-extrinsic mechanism.

Justine R Clark, Vasilios Panagopoulos, Jacqueline E Noll, Krzysztof M Mrozik, Alanah L Bradey, Peter I Croucher, Andrew C W Zannettino, Kate Vandyke, Duncan R Hewett.

  Multiple myeloma (MM) is an incurable haematological malignancy characterised by the uncontrolled proliferation of bone marrow resident plasma cells (PCs). Two members of the TAM (TYRO3, AXL and MER) receptor family have previously been implicated in distinct aspects of neoplastic PC biology. AXL expression in MM PCs has been associated with induction of a dormant, non-cycling state within the bone marrow, whereas expression of MER has been implicated in PC proliferation and survival. Here, generation of single TAM receptor expressing 5TGM1 murine MM cell lines enabled the individual functional assessment of the effects of Axl and Mer receptor expression on MM development. Axl expression did not affect proliferation, cell cycling, or stromal cell induced dormancy in vitro. Development of 5TGM1 tumours in C57BL/KaLwRij mice was also unaltered by Axl expression. By contrast, Mer expression conferred an increase in cell proliferation to 5TGM1 cells in vitro, and increased 5TGM1 tumour burden in C57BL/KaLwRij mice. The pro-tumourigenic properties of Mer were only observed following intravenous cell delivery into mice with an intact adaptive immune system. Thus, Axl is neither necessary nor sufficient for induction of MM cancer cell dormancy, whereas Mer remains a promising target for therapeutic intervention in MM patients. Teaser abstract: Multiple myeloma (MM) is an incurable haematological malignancy of plasma cells (PCs). Two members of the TAM (TYRO3, AXL and MER) receptor family have previously been implicated in distinct aspects of MM PC biology. AXL expression in MM PCs has been associated with induction of dormancy, whereas expression of MER has been implicated in PC proliferation and survival. Using mouse myeloma cell lines expressing single TAM receptors, we demonstrate that Axl is neither necessary nor sufficient for induction of MM cancer cell dormancy, whereas Mer promotes tumour development and remains a promising therapeutic target in MM patients.

Keywords:  5TGM1; Axl; C57BL/KaLwRij; Gas6; Mer; Multiple Myeloma; TAM receptor

DOI:  https://doi.org/10.1016/j.exphem.2025.104842
Oncogene. 2025 Jun 18.

MARCH1, transcriptionally regulated by POU2F2, facilitates acute myeloid leukemia progression via inducing MYCT1 degradation.

Jianing Liu, Jianan Xu, Rongcan Sun, Xiaohui Wang, Fang Chen, Yu Fu, Henan Zhang, Bin Wu, Ying Yang, Jihong Zhang, Shuang Fu.

Acute myeloid leukemia (AML) is a heterogeneous clonal disease. Membrane-associated ring-CH type finger 1 (MARCH1), a membrane-anchored E3 ubiquitin ligase, is highly expressed in AML. However, its role in AML remains unclear. Our study showed that MARCH1 expression was strongly associated with FAB classifications and the survival of patients with AML. Gain-of-function and loss-of-function experiments showed that MARCH1 promoted the proliferation of AML cells and inhibited apoptosis and differentiation. In vivo, MARCH1 knockdown inhibited the infiltration of AML cells, resulting in prolonged survival of AML mice. In order to illustrate what cause the high expression of MARCH1, we analyzed the promoter region of MARCH1 and found that POU2F2, a transcription factor with high levels in AML, positively regulated the transcription of MARCH1. Finally, we demonstrated that MARCH1 interacted with MYCT1, a candidate tumor suppressor, and accelerated its ubiquitination and degradation. Remarkably, MYCT1 knockdown abolished the inhibitory effects of MARCH1 knockdown on AML cell growth. Our findings indicate that MARCH1, whose transcription is positively modulated by POU2F2, facilitates the malignant behaviors of AML cells through interacting with MYCT1 and accelerating its ubiquitination and degradation. The results implied that targeting MARCH1 might be a promising therapeutic strategy for AML.

DOI: https://doi.org/10.1038/s41388-025-03464-3
Cancer Discov. 2025 Jun 19.

KAT6A and KAT7 Histone Acetyltransferase Complexes Are Molecular Dependencies and Therapeutic Targets in NUP98-Rearranged Acute Myeloid Leukemia.

Nicole L Michmerhuizen, Emily B Heikamp, Ilaria Iacobucci, Masayuki Umeda, Bright Arthur, Vibhor Mishra, Chun Shik Park, Danika Di Giacomo, Ryan Hiltenbrand, Qingsong Gao, Sandi Radko-Juettner, Josi Lott, Cynthia Martucci, Varsha Subramanyam, Charlie Hatton, Daniela V Wenge, Pradyuamna Baviskar, Pablo Portola, Aurelie Claquin, Bappaditya Chandra, David W Baggett, Ali Khalighifar, Hongling Huang, Peipei Zhou, Lingyun Long, Hao Shi, Yu Sun, Evangelia K Papachristou, Chandra Sekhar Reddy Chilamakuri, Francisca N de Luna Vitorino, Joanna M Gongora, Huiyun Wu, Stanley B Pounds, Laura J Janke, Alex Kentsis, Clive S D'Santos, Benjamin A Garcia, Richard W Kriwacki, Hongbo Chi, Jeffery M Klco, Scott A Armstrong, Charles G Mullighan.

NUP98 fusion oncoproteins (FOs) are a hallmark of childhood acute myeloid leukemia (AML). NUP98 FOs drive leukemogenesis through phase-separated condensate formation and maintenance of an active chromatin landscape at stem cell-associated genes in cooperation with epigenetic regulators. Here we show that MYST family histone acetyltransferase (HAT) complex proteins including KAT6A/MOZ, KAT7/HBO1, and the common KAT6A/7 complex subunit BRPF1 associate with NUP98 FOs on chromatin and within condensates. MYST HATs are molecular dependencies in NUP98-rearranged (NUP98-r) leukemia, and genetic inactivation or pharmacologic inhibition of Kat6a and Kat7 impairs NUP98-r cell fitness. KAT6A/7 inhibition decreased global H3K23ac levels, displaced NUP98::HOXA9 from chromatin at the Meis1 locus, and led to myeloid cell differentiation. Additionally, KAT6A/7 inhibition decreased leukemic burden in multiple NUP98-r leukemia xenograft mouse models, synergized with Menin inhibitor treatment, and was efficacious in Menin inhibitor-resistant cells. In summary, we show that MYST family HATs are therapeutically actionable dependencies in NUP98-r AML.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1772
Methods Mol Biol. 2025 ;2921 345-359

System-Wide Profiling of Ubiquitin E3 Ligase Activities with Quantitative Proteomics and Bioinformatics Analysis.

Yue Chen, Yao Gong.

  Ubiquitination is an essential protein posttranslational modification in eukaryotes governing protein homeostasis and ubiquitin-mediated cellular signaling. In human cells, the dynamics and substrate-specificity of ubiquitination are mediated by over 600 genetically encoded E3 ligases. Dysregulation of E3 ligase activities could disrupt protein turnover, gene expression, and signal transduction, which is widely implicated in diseases such as cancer and aging-related diseases. In this report, we presented a computational workflow, UbE3-APA, to profile E3 ligase activities based on quantitative proteomics data and bioinformatics analysis. We validated the strategy with published datasets from the analysis of cells and tissues with genetic knockout or knockdown of specific E3 ligases and demonstrated that the strategy can be applied to both data-dependent or data-independent quantitative proteomics datasets.

Keywords:  Activity-based profiling; E3 ligase; Quantitative proteomics; UbE3-APA; Ubiquitination

DOI:  https://doi.org/10.1007/978-1-0716-4502-4_19
EMBO Rep. 2025 Jun 13.

ATR promotes mTORC1 activity via de novo cholesterol synthesis.

Naveen Kumar Tangudu, Alexandra N Grumet, Richard Fang, Raquel Buj, Aidan R Cole, Apoorva Uboveja, Amandine Amalric, Baixue Yang, Zhentai Huang, Cassandra Happe, Mai Sun, Stacy L Gelhaus, Matthew L MacDonald, Nadine Hempel, Nathaniel W Snyder, Katarzyna M Kedziora, Alexander J Valvezan, Katherine M Aird.

  DNA damage and cellular metabolism exhibit a complex interplay characterized by bidirectional feedback. Key mediators of these pathways include ATR and mTORC1, respectively. Previous studies established ATR as a regulatory upstream factor of mTORC1 during replication stress; however, the precise mechanisms remain poorly defined. Additionally, the activity of this signaling axis in unperturbed cells has not been extensively investigated. We demonstrate that ATR promotes mTORC1 activity across various human cancer cells and both human and mouse normal cells under basal conditions. This effect is enhanced in human cancer cells (SKMEL28, RPMI-7951, HeLa) following knockdown of p16, a cell cycle inhibitor that we have previously found increases mTORC1 activity and here found increases ATR activity. Mechanistically, ATR promotes de novo cholesterol synthesis and mTORC1 activation through the phosphorylation and upregulation of lanosterol synthase (LSS), independently of both CHK1 and the TSC complex. Interestingly, this pathway is distinct from the regulation of mTORC1 by ATM and may be specific to cancer cells. Finally, ATR-mediated increased cholesterol correlates with enhanced localization of mTOR to lysosomes. Collectively, our findings demonstrate a novel connection linking ATR and mTORC1 signaling through the modulation of cholesterol metabolism.

Keywords:  Cholesterol; Lanosterol Synthase; Lysosome; Metabolism; p16

DOI:  https://doi.org/10.1038/s44319-025-00451-3
Cancer Discov. 2025 Jun 19.

Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia.

Shellaina J V Gordon, Florian Perner, Laura MacPherson, Katie A Fennell, Daniela V Wenge, Wallace Bourgeois, Tabea Klaus, Thomas Plenge, Anelya Murat, Jelena Petrovic, Jakub Horvath, Joan Q Cao, John D Lapek, Sean Uryu, Jeffrey R White, Enid Yn Lam, Xinmeng Jasmine Mu, Yih-Chih Chan, Andrea Gillespie, Benjamin J Blyth, Michelle A Camerino, Ylva E Bozikis, Henrietta Holze, Kathy Knezevic, Jesse Balic, Paul A Stupple, Ian P Street, Brendon J Monahan, Shikhar Sharma, Elanor N Wainwright, Dane Vassiliadis, Thomas A Paul, Scott A Armstrong, Mark A Dawson.

Targeting the MYST acetyltransferases are an exciting therapeutic opportunity in acute myeloid leukaemia (AML). Here we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in range of AML models showing that although KAT6A/B inhibition is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, markedly increases efficacy. KAT7 interacts with Menin and the MLL complex and is co-localised at chromatin to co-regulate oncogenic transcriptional programs. Focusing on MLL fusion oncoprotein (MLL-FP) AML, we show that inhibition of KAT6/KAT7 provides an orthogonal route to targeting Menin to disable the transcriptional activity of the MLL-FP. Combined inhibition rapidly evicts the MLL-FP from chromatin, potently represses oncogenic transcription and overcomes primary resistance to Menin inhibitors. Notably, KAT7 remains an important targetable dependency in acquired genetic/non-genetic resistance to Menin inhibition providing the molecular rationale for rapid clinical translation of combination therapy, particularly in MLL-FP AML.

DOI: https://doi.org/10.1158/2159-8290.CD-24-1517
Trends Biotechnol. 2025 Jun 19. pii: S0167-7799(25)00214-8. [Epub ahead of print]

Human bone marrow organoids: emerging progress but persisting challenges.

Paul E Bourgine.

  Organoid systems hold promise as miniaturized in vitro platforms that model developmental and pathological processes. However, the engineering of human bone marrow organoids (BMOs) has been a long-standing challenge. Recently, the field has witnessed the emergence of BMO-like systems, a potential paradigm shift for the study of human hematopoiesis and associated niche elements. Published protocols rely on the mesodermal induction of iPSCs, establishing mesenchymal-vascular-hematopoietic tissues exhibiting fetal compositional and functional features. However, concerns on their reliability to model adult bone marrow processes exist. Given the blood ontogeny complexity, leveraging developmentally inspired programs presents a significant challenge in establishing relevant BMO systems. While the importance of developing human BMO persists, the engineering modalities to achieve it remain cryptic.

Keywords:  bone marrow; hematopoiesis; mesenchymal stem/stromal cells; organoid; pluripotent stem cells

DOI:  https://doi.org/10.1016/j.tibtech.2025.05.028
Cell Death Dis. 2025 Jun 18. 16(1): 458

N6-methyladenosine-modified GPX2 impacts cancer cell stemness and TKI resistance through regulating of redox metabolism.

Xu Yang, Long Yu, Miaomiao Shao, Huiling Yang, Kangwei Qi, Gaofei He, Lanxin Wang, Di Kong, Jianxin Gu, Xiaolin Xu, Lan Wang.

As a predominant oncogenic driver in non-small cell lung cancer (NSCLC), EGFR frequently undergoes amplification or mutation, with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib constituting frontline therapy for advanced EGFR-mutant cases. However, both primary and acquired resistance significantly limit clinical efficacy. Here, we revealed that glutathione metabolic pathway controlled by glutathione peroxidase GPX2 was abnormally activated in gefitinib-resistant A549 and HCC827-GR cell lines. Mechanistically, GPX2 triggers Hedgehog signaling activation through releasing GLI transcriptional regulator, promoting cancer stem cell (CSC) characteristics and TKI resistance. Notably, N6-methyladenosine (m6A) modification on GPX2 mRNA mediated by METTL14 diminished its stability. In vivo, GPX2 deletion constrained glutathione metabolism and boosted the effectiveness of TKI in cell line-derived xenograft models. Collectively, these findings demonstrate that GPX2 serves as a positive regulator of both primary and acquired EGFR-TKI resistance and could be a promising therapeutic target for precise treatment of NSCLC.

DOI: https://doi.org/10.1038/s41419-025-07764-0
Cell. 2025 Jun 17. pii: S0092-8674(25)00577-X. [Epub ahead of print]

STAMP: Single-cell transcriptomics analysis and multimodal profiling through imaging.

Emanuele Pitino, Anna Pascual-Reguant, Felipe Segato-Dezem, Kellie Wise, Irepan Salvador-Martinez, Helena Lucia Crowell, Maycon Marção, Max Ruiz, Elise Courtois, William F Flynn, Santhosh Sivajothi, Emily Soja, Ginevra Caratù, German Atzin Mora-Roldan, B Kate Dredge, Yutian Liu, Hannah Chasteen, Monika Mohenska, Juan C Nieto, Raymond K H Yip, Ruvimbo D Mishi, José M Polo, Mohmed Abdalfttah, Adrienne E Sullivan, Jasmine T Plummer, Holger Heyn, Luciano G Martelotto.

  Single-cell RNA sequencing has revolutionized our understanding of cellular diversity but remains constrained by scalability, high costs, and the destruction of cells during analysis. To overcome these challenges, we developed STAMP (single-cell transcriptomics analysis and multimodal profiling), a highly scalable approach for the profiling of single cells. By leveraging transcriptomics and proteomics imaging platforms, STAMP eliminates sequencing costs, enabling cost-efficient single-cell genomics of millions of cells. Immobilizing (stamping) cells in suspension onto imaging slides, STAMP supports multimodal (RNA, protein, and H&E) profiling, while retaining cellular structure and morphology. We demonstrate STAMP's versatility by profiling peripheral blood mononuclear cells, cell lines, and stem cells. We highlight the capability of STAMP to identify ultra-rare cell populations, simulate clinical applications, and show its utility for large-scale perturbation studies. In total, we present data for 10,962,092 high-quality cells/nuclei and 6,030,429,954 transcripts. STAMP makes high-resolution cellular profiling more accessible, scalable, and affordable.

Keywords:  cell atlas; circulating tumor cells; genomics; imaging; multimodal; phenotyping; proteomics; single cell; stem cells; transcriptomics

DOI:  https://doi.org/10.1016/j.cell.2025.05.027
NPJ Precis Oncol. 2025 Jun 13. 9(1): 180

Establishing predictive machine learning models for drug responses in patient derived cell culture.

Abbi Abdel-Rehim, Oghenejokpeme Orhobor, Gareth Griffiths, Larisa Soldatova, Ross D King.

The concept of personalised medicine in cancer therapy is becoming increasingly important. There already exist drugs administered specifically for patients with tumours presenting well-defined genetic mutations. However, the field is still in its infancy, and personalised treatments are far from being standard of care. Personalised medicine is often associated with the utilisation of omics data. Yet, implementation of multi-omics data has proven difficult, due to the variety and scale of the information within the data, as well as the complexity behind the myriad of interactions taking place within the cell. An alternative approach to precision medicine is to employ a function-based profile of cells. This involves screening a range of drugs against patient-derived cells (or derivative organoids and xenograft models). Here we demonstrate a proof-of-concept, where a collection of drug screens against a highly diverse set of patient-derived cell lines, are leveraged to identify putative treatment options for a 'new patient'. We show that this methodology is highly efficient in ranking the drugs according to their activity towards the target cells. We argue that this approach offers great potential, as activities can be efficiently imputed from various subsets of the drug-treated cell lines that do not necessarily originate from the same tissue type.

DOI: https://doi.org/10.1038/s41698-025-00937-2
Cytoskeleton (Hoboken). 2025 Jun 16.

LZTS2 Negatively Regulates Centrosomal CEP135 Levels and Microtubule Nucleation.

Catarina Peneda, Joana N Bugalhao, Marco Antonio Dias Louro, Andreia Henriques-Soares, Monica Bettencourt-Dias.

  The microtubule cytoskeleton is a fundamental functional component of the cell. In vertebrate proliferating cells, centrosomes are the primary microtubule organizing center (MTOC), and their dysregulation has been linked to genomic instability and cancer. LZTS2, a known tumor suppressor, localizes to centrosomes and regulates microtubule severing. However, whether LZTS2 regulates centrosome structure and/or its function in microtubule organization or ciliation remains unknown. Here, we investigate the function of LZTS2 at the centrosome. Through fluorescence and electron microscopy assays, we observed that LZTS2 knockdown does not affect centriole biogenesis or structure, nor ciliation. Importantly, we show that LZTS2 depletion increases microtubule nucleation at the centrosome. Moreover, LZTS2 negatively regulates centrosomal levels of CEP135. Notably, depletion of LZTS2 can partially rescue the impaired centrosome microtubule nucleation caused by CEP135 knockdown. Taken together, our findings reveal a novel role for LZTS2 as a negative regulator of CEP135 and centrosomal microtubule nucleation, providing a potential mechanistic link to its tumor suppressor function.

Keywords:  centriole; centrosome; microtubules

DOI:  https://doi.org/10.1002/cm.22052
Cell Metab. 2025 Jun 12. pii: S1550-4131(25)00266-9. [Epub ahead of print]

The integrated stress response fine-tunes stem cell fate decisions upon serine deprivation and tissue injury.

Jesse S S Novak, Lisa Polak, Sanjeethan C Baksh, Douglas W Barrows, Marina Schernthanner, Benjamin T Jackson, Elizabeth A N Thompson, Anita Gola, M Deniz Abdusselamoglu, Alain R Bonny, Kevin A U Gonzales, Julia S Brunner, Anna E Bridgeman, Katie S Stewart, Lynette Hidalgo, June Dela Cruz-Racelis, Ji-Dung Luo, Shiri Gur-Cohen, H Amalia Pasolli, Thomas S Carroll, Lydia W S Finley, Elaine Fuchs.

  Epidermal stem cells produce the skin's barrier that excludes pathogens and prevents dehydration. Hair follicle stem cells (HFSCs) are dedicated to bursts of hair regeneration, but upon injury, they can also reconstruct, and thereafter maintain, the overlying epidermis. How HFSCs balance these fate choices to restore physiologic function to damaged tissue remains poorly understood. Here, we uncover serine as an unconventional, non-essential amino acid that impacts this process. When dietary serine dips, endogenous biosynthesis in HFSCs fails to meet demands (and vice versa), slowing hair cycle entry. Serine deprivation also alters wound repair, further delaying hair regeneration while accelerating re-epithelialization kinetics. Mechanistically, we show that HFSCs sense each fitness challenge by triggering the integrated stress response, which acts as a rheostat of epidermal-HF identity. As stress levels rise, skin barrier restoration kinetics accelerate while hair growth is delayed. Our findings offer potential for dietary and pharmacological intervention to accelerate wound healing.

Keywords:  dietary intervention; epidermal stem cells; fate selection; hair follicle stem cells; hair regrowth; integrated stress response; serine metabolism; tissue regeneration; tissue repair; wound healing

DOI:  https://doi.org/10.1016/j.cmet.2025.05.010
Nat Cell Biol. 2025 Jun;27(6): 959-971

Cell state-specific cytoplasmic density controls spindle architecture and scaling.

Tobias Kletter, Omar Muñoz, Sebastian Reusch, Abin Biswas, Aliaksandr Halavatyi, Beate Neumann, Benno Kuropka, Vasily Zaburdaev, Simone Reber.

Mitotic spindles are dynamically intertwined with the cytoplasm they assemble in. How the physicochemical properties of the cytoplasm affect spindle architecture and size remains largely unknown. Using quantitative biochemistry in combination with adaptive feedback microscopy, we investigated mitotic cell and spindle morphology during neural differentiation of embryonic stem cells. While tubulin biochemistry and microtubule dynamics remained unchanged, spindles changed their scaling behaviour; in differentiating cells, spindles were considerably smaller than those in equally sized undifferentiated stem cells. Integrating quantitative phase imaging, biophysical perturbations and theory, we found that as cells differentiated, their cytoplasm became more dilute. The concomitant decrease in free tubulin activated CPAP (centrosomal P4.1-associated protein) to enhance the centrosomal nucleation capacity. As a consequence, in differentiating cells, microtubule mass shifted towards spindle poles at the expense of the spindle bulk, explaining the differentiation-associated switch in spindle architecture. This study shows that cell state-specific cytoplasmic density tunes mitotic spindle architecture. Thus, we reveal physical properties of the cytoplasm as a major determinant in organelle size control.

DOI: https://doi.org/10.1038/s41556-025-01678-x
Biochim Biophys Acta Mol Cell Res. 2025 Jun 11. pii: S0167-4889(25)00107-7. [Epub ahead of print]1872(7): 120002

Blocking mutant IDH1 phosphorylation triggers APC/C CDH1-dependent ubiquitination in mitotic cells.

Sonam Swain, Nishant Jain.

  IDH1 mutation occurs early in glioma development; thus, mutant IDH1-specific inhibitors are being developed as glioma therapy. But, recent reports suggest that mutant IDH1 inhibitors treatments result in loss of therapeutic vulnerabilities and makes cells resistant to anticancer agents. To overcome resistance, the new paradigm in drug discovery is to develop molecules that can degrade oncogenes by harnessing cellular ubiquitination machinery. Therefore, it is imperative to identify strategies for degrading mutant IDH1 employing cellular ubiquitination machinery. To address this, we found that concerted action of the mitotic kinases Cdk1/Cyclin B1 and Plk1 increases mutant IDH1 enzyme activity. It is known that phosphorylation is linked to protein stability, phosphorylation of a short linear degron motif or phosphodegron can trigger target protein ubiquitination. By contrast, phosphorylation of constitutively active degron motifs can block target protein ubiquitination - phospho-inactivated degron. As phosphorylation can trigger or block ubiquitination, it is unknown if phosphorylation affects mutant IDH1 ubiquitination in mitosis. Therefore, in this study, we asked if phosphorylation of mutant IDH1 is linked to ubiquitination. To answer this question, we examined ubiquitination of phosphomutants and phosphomimetics of mutant IDH1 in mitosis. We found that blocking IDH1R132H phosphorylation is linked to ubiquitination. We observed that APC/C CDH1 ubiquitinates IDH1R132H-T77A-S94A. Further, we show that APC/C CDH1 ubiquitinates lysines 301 and 321 in C-terminal domain of IDH1R132H-T77A-S94A. Thus, blocking mutant IDH1 phosphorylation triggers APC/C CDH1-dependent ubiquitination in mitotic cells. We suggest employing mitotic inhibitors that also block phosphorylation of mutant IDH1 can ubiquitinate mutant IDH1 in cancer cells.

Keywords:  APC/C; CDC20; CDH1; IDH1(R132H-T77A-S94A); Mitosis; Ubiquitination

DOI:  https://doi.org/10.1016/j.bbamcr.2025.120002
PLoS Comput Biol. 2025 Jun;21(6): e1013155

Proteostasis signatures in human diseases.

Christine M Lim, Michele Vendruscolo.

The protein homeostasis (proteostasis) network maintains the proteome in a functional state. Although this network has been comprehensively mapped, its perturbations in disease remain incompletely characterised. To address this problem, here we define the proteostasis signatures, which represent the characteristic patterns of change in the proteostasis network associated with disease. We performed a large-scale, pan-disease analysis across 32 human diseases spanning 7 disease types. We first identified unique proteostasis perturbations in specific disease states. We then uncovered distinctive signatures differentiating disease types, pointing to a range of proteostasis mechanisms in disease development. Next, we tracked the temporal evolution of proteostasis signatures, revealing shifts in proteostasis disruption over the course of disease progression. Finally, we demonstrated how smoking, a major risk factor for many diseases, impairs proteostasis in a manner similar to disease, potentially creating a predisposed environment for disease onset. These results illustrate the opportunities offered by the study of human diseases from the perspective of proteostasis signatures.

DOI: https://doi.org/10.1371/journal.pcbi.1013155