bims-scepro Biomed News
on Stem cell proteostasis
Issue of 2025–10–05
fourteen papers selected by
William Grey, University of York
  1. Asrij/OCIAD1 expression delineates functionally distinct hematopoietic stem cells in the bone marrow.
  2. Regulation of metabolic adaptation and leukemia progression by MUSASHI2-DEPTOR-KIF11 axis.
  3. Regulation of Hematopoietic Stem Cell Dormancy and Quiescence: Insights into Regeneration and Disease.
  4. Fetal context conveys heritable protection against MLL-rearranged AML that depends on MLL3.
  5. Secreted Frizzled-Related Protein 1a regulates hematopoietic development in a dose-dependent manner.
  6. MRC2 expression modulates metabolism in acute myeloid leukemia stem cells.
  7. Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation.
  8. Influence of the protein corona on hematopoietic stem and progenitor cell uptake and macrophage clearance of membrane-wrapped nanoparticles.
  9. FLT3-ITD Induces CMTM6 and Enhances Immune Escape in Acute Myeloid Leukemia.
  10. JAK2V617F Myeloproliferative Neoplasms Support Parallel Evolution of Independent Leukemic Clones.
  11. Aberrant expression of SLAMF6 constitutes a targetable immune escape mechanism in acute myeloid leukemia.
  12. RPS19 and RPL5 Haploinsufficient Models Reveal Divergent Ribosomal Subunit Controls of Fetal Hematopoiesis.
  13. USP9X is a mechanosensitive deubiquitinase that controls tumor cell invasiveness and drug response through YAP stabilization.
  14. Proteotoxic stress response drives T cell exhaustion and immune evasion.
  1. Exp Hematol. 2025 Oct 01. pii: S0301-472X(25)00555-7. [Epub ahead of print] 105266
    Asrij/OCIAD1 expression delineates functionally distinct hematopoietic stem cells in the bone marrow.
    Aishwarya Prakash, Souvik Halder, Maneesha S Inamdar.
      Hematopoietic stem cells (HSCs) within the bone marrow (BM) display significant molecular and functional heterogeneity. Deciphering intrinsic factors that govern HSC diversity is key to enriching specific HSC subtypes for predictable and clinically relevant differentiation outcomes. Here, we show that the mitochondrial protein Asrij/OCIAD1, a conserved regulator of hematopoietic homeostasis, contributes to HSC heterogeneity. Asrij depletion is known to cause loss of quiescence, myeloid bias and aging-like changes in mouse BM HSCs. Interestingly, Asrij expression is inherently heterogeneous and enriched in only 47% of the HSC population. To investigate whether Asrij expression levels influence HSC fate, we generated a novel Asrij-mNeonGreen knock-in reporter mouse using CRISPR-Cas9 technology. We show that the Asrij reporter faithfully recapitulates its heterogeneous expression in the BM HSCs, allowing isolation of live cells based on Asrij expression levels. Ex-vivo culture of HSCs demonstrated that Asrijlow HSCs exhibit enhanced self-renewal capacity, whereas Asrijhigh HSCs are primed for differentiation. Transplantation assays further revealed that Asrijlow HSCs have enhanced reconstitution in the BM hematopoietic stem and progenitor cell (HSPC) and myeloid cell compartments. Transcriptomic analysis uncovered signatures of quiescence in Asrijlow HSCs, while Asrijhigh HSCs exhibit hallmarks of HSC activation. In summary, we show that Asrij levels impact the quiescence, self-renewal, and differentiation potential of HSCs, thereby contributing to the functional diversity of the HSC pool. Further, the Asrij-mNeonGreen reporter mouse provides a powerful and versatile model for investigating the molecular underpinnings of functional diversity within the HSC compartment. TEASER ABSTRACT: Our study addresses the complexities of hematopoietic stem cell (HSC) heterogeneity and uncovers novel determinants that govern long-term (LT) reconstituting HSC function. Using a novel Asrij-mNeonGreen fluorescent reporter mouse, we show that the mitochondrial protein Asrij/OCIAD1 regulates HSC heterogeneity. We show that low Asrij expression marks quiescent HSCs with robust self-renewal capacity, whereas high Asrij expression identifies activated, differentiation-primed HSCs. These findings position Asrij as a novel determinant of HSC heterogeneity and introduce the Asrij-mNeonGreen reporter as a versatile tool for dissecting stem cell fate decisions in-vivo.
    Keywords:  Cell fate; Fluorescent reporter mouse; HSC activation; Hematopoiesis; Hematopoietic Stem Cell heterogeneity; quiescence
    DOI:  https://doi.org/10.1016/j.exphem.2025.105266
  2. Leukemia. 2025 Oct 01.
    Regulation of metabolic adaptation and leukemia progression by MUSASHI2-DEPTOR-KIF11 axis.
    Tania Setiawan, Jabir Aliyu Muhammad, Nadya Marcellina, Lawrence Mario Wirawan, Nayoung Jun, Ita Novita Sari, Vivian G Oehler, Dong-Wook Kim, Hyog Young Kwon.
      Amino acid homeostasis is critical for leukemic cell survival, with the mTOR pathway playing a central role in sensing and responding to nutrient availability. DEPTOR, a component and negative regulator of mTOR complexes, has been extensively studied in solid tumors and multiple myeloma, but its role in acute myeloid leukemia (AML) remains unclear. Here, we identify DEPTOR as a key regulator of leukemia progression through its interaction with KIF11. DEPTOR expression is transcriptionally induced by ATF4 and post-transcriptionally stabilized by MSI2, which binds to DEPTOR mRNA and prevents its degradation. DEPTOR is highly expressed in leukemia stem cells (LSCs) and is associated with poor clinical outcomes. Functionally, DEPTOR loss impairs leukemogenesis in both AML and blast phase chronic myeloid leukemia (bpCML) models, without affecting normal hematopoietic stem cells. Mechanistically, DEPTOR stabilizes KIF11 by preventing its ubiquitination and proteasomal degradation, thereby ensuring proper mTORC1 localization and metabolic adaptation during nutrient stress. Collectively, our findings establish the MSI2/DEPTOR/KIF11 axis as a critical driver of leukemogenesis and a promising therapeutic target for aggressive myeloid leukemias.
    DOI:  https://doi.org/10.1038/s41375-025-02768-3
  3. Annu Rev Cell Dev Biol. 2025 Oct;41(1): 231-258
    Regulation of Hematopoietic Stem Cell Dormancy and Quiescence: Insights into Regeneration and Disease.
    Jasmin Rettkowski, Nina Cabezas-Wallscheid.
      Stem cells are undifferentiated cells capable of self-renewal and differentiation into specialized cell types, forming the foundation of tissue maintenance and repair. In the blood system, this process is known as hematopoiesis. Hematopoietic stem cells (HSCs), positioned at the apex of the hematopoietic hierarchy, have the unique ability to reconstitute the hematopoietic system long-term. HSC stemness is defined by multipotency, allowing differentiation into all blood lineages, and self-renewal, maintaining the stem cell pool. A fundamental property of HSCs is quiescence, which refers to a reversible inactive cell cycle state that preserves their self-renewal potential. Dormant HSCs represent a subset of quiescent stem cells with minimal division rates and the most potent stemness. Dysregulation of dormancy and quiescence is linked to HSC dysfunction. Here, we explore mechanisms regulating HSC dormancy and quiescence under homeostatic and stress conditions. Finally, we describe how factors such as aging, inflammation, and malignancies disrupt these states.
    Keywords:  dormancy; hematopoiesis; hematopoietic stem cells; molecular mechanisms regulating hematopoietic stem cells; quiescence; stem cell exhaustion
    DOI:  https://doi.org/10.1146/annurev-cellbio-101323-023806
  4. Blood. 2025 Oct 01. pii: blood.2025029686. [Epub ahead of print]
    Fetal context conveys heritable protection against MLL-rearranged AML that depends on MLL3.
    Jonny Mendoza-Castrejon, Wei Yang, Elisabeth D Denby, Helen C Wang, Emily B Casey, Rohini Muthukumar, Riddhi M Patel, Jihye Yoon, Yanan Li, J Michael White, Ran Chen, Luis Francisco Zirnberger Batista, Jeffrey A Magee.
      MLL rearrangements (MLLr) are the most common cause of congenital and infant leukemias. MLLr arise prior to birth and can transform fetal/neonatal progenitors with the help of only a few additional cooperating mutations. Despite the low threshold for transformation, infant leukemias are rare, and congenital leukemias, which arise before birth, are even less common. These observations raise the question of whether mechanisms exist to suppress leukemic transformation during fetal life, thereby protecting the developing fetus from malignancy during a period of rapid hematopoietic progenitor expansion. To test this possibility, we used a mouse model of temporally controlled MLL::ENL expression to show that fetal MLL::ENL exposure establishes a heritable, leukemia-resistant state within hematopoietic progenitors that persists after birth. When we induced MLL::ENL expression prior to birth and transplanted hematopoietic stem and progenitor cells, very few recipient mice developed acute myeloid leukemia (AML) despite robust engraftment. When we induced MLL::ENL expression shortly after birth, all recipient mice developed a highly penetrant AML. Fetal MLL::ENL expression imposed a negative selective pressure on hematopoietic progenitors before birth followed by loss of self-renewal gene expression and enhanced myeloid differentiation after birth that precluded transformation. These changes did not occur when MLL::ENL expression initiated shortly after birth. The fetal barrier to transformation was enforced by the histone methyltransferase MLL3, and it could be overcome by cooperating mutations, such as NrasG12D. Heritable fetal protection against leukemic transformation may contribute to the low incidence of congenital and infant leukemias in humans.
    DOI:  https://doi.org/10.1182/blood.2025029686
  5. Dev Biol. 2025 Sep 26. pii: S0012-1606(25)00277-5. [Epub ahead of print]
    Secreted Frizzled-Related Protein 1a regulates hematopoietic development in a dose-dependent manner.
    Amber D Ide, Kelsey A Carpenter, Mohamed T Elaswad, Katherine Opria, Kendersley Marcellin, Carla Gilliland, Stephanie Grainger.
      Hematopoietic stem and progenitor cells (HSPCs) are only generated during embryonic development, and their identity specification, emergence from the floor of the dorsal aorta, and proliferation are all tightly regulated by molecular mechanisms such as signaling cues. Among these, Wnt signaling is crucial for HSPC specification, differentiation, and self-renewal, requiring precise regulation for proper development and homeostasis. Wnt signaling begins when a Wnt ligand binds to cell surface receptors, such as those encoded by the frizzled gene family, activating intracellular pathways that regulate gene expression. Secreted frizzled-related proteins (Sfrps) are known to modulate Wnt signaling, acting as both agonists and antagonists. However, the in vivo roles of Sfrps in HSPC development are not fully understood. Here, we show that Sfrp1a influences zebrafish HSPC development and hematopoietic differentiation in a dose-dependent manner. Sfrp1a loss-of-function animals display an upregulation of canonical Wnt signaling, increased HSPC proliferation, and reduced differentiation into lymphoid and myeloid lineages. Conversely, low-dose overexpression of sfrp1a leads to decreased HSPC numbers and enhanced lymphoid differentiation. High-dose sfrp1a overexpression mimics the loss-of-function phenotype, with elevated canonical Wnt signaling, increased HSPCs, and decreased lymphoid and myeloid differentiation. These results emphasize the importance of dose-dependent Sfrp regulation, paralleling observations in hematopoietic cancers where SFRP1 variants can either promote or inhibit tumor development.
    Keywords:  Sfrp1a; Wnt; Wnt signaling; developmental biology; hematopoietic stem cell; zebrafish
    DOI:  https://doi.org/10.1016/j.ydbio.2025.09.019
  6. Cancer Lett. 2025 Sep 26. pii: S0304-3835(25)00640-8. [Epub ahead of print] 218068
    MRC2 expression modulates metabolism in acute myeloid leukemia stem cells.
    Taylor S Mills, Marlon Arnone, Elsa Görsch, Simone Poeschel, Stefan Winter, Jessica Kuebler, Lucca M Kimmich, Florian A Büttner, Jan Weller, Saskia S Rudat, Lucas Mix, Jan C Schroeder, Anna M Paczulla Stanger, Matthias Schwab, Claudia Lengerke.
      Leukemic stem cells (LSC) are well recognized for their essential roles in acute myeloid leukemia (AML) initiation and relapse. LSC can be distinguished from non-LSC AML cells by the expression of specific cell surface markers, but there is considerable phenotypic heterogeneity among LSC in AML. Here, using primary patient samples, we report that mannose receptor C-type 2 (MRC2) can be used to enrich for LSC across various AML subtypes. When compared to MRC2- AML cells isolated from the same patient samples, MRC2+ leukemic subpopulations show increased in vitro clonogenic capacity, a stemness transcriptomic signature, and enhanced leukemic capacity in mouse xenograft models. Further, we find that MRC2 is functional on AML cells, and enables their robust uptake of collagen, which supports their glycolytic metabolism. In sum these data highlight the use of functional surface markers to distinguish LSC in AML, and how they can yield insight into their unique characteristics.
    Keywords:  MRC2; acute myeloid leukemia; glycolysis; leukemia stem cells; mannose receptor c-type2; metabolism
    DOI:  https://doi.org/10.1016/j.canlet.2025.218068
  7. Cell Rep. 2025 Sep 30. pii: S2211-1247(25)01150-7. [Epub ahead of print]44(10): 116379
    Retinoic acid and ascorbate synergize to suppress myeloid leukemia via TET2 activation.
    Tiffany E Leesang, John P Brabson, Yoon Sing Yap, Daniela A Barbieri, Abigail S Klimas, Joey Pinzone, Emily L Ahearn, Minh Q Lam, Peter D Lyon, Anna Swirski, Nicholas B Wolfe, Yuichiro Nakata, Helena Gomes Dos Santos, Ramin Shiekhattar, Lluis Morey, Panayiotis I Vlantis, Maria E Figueroa, Namrata Chandhok, Felipe Beckedorff, Aristeidis G Telonis, Luisa Cimmino.
      Enhancing ten-eleven translocation 2 (TET2) activity through genetic or pharmacologic approaches, such as ascorbate supplementation, can slow myeloid malignancy progression. However, ascorbate alone may be insufficient to fully activate TET2 in malignant cells due to pharmacokinetic constraints and the need for chromatin remodeling to enable effective cellular reprogramming. Here, we identify a novel mechanism to enhance TET2 activity via all-trans retinoic acid (ATRA), which induces retinoic acid receptor alpha (RARA)-mediated TET2 transcription in myeloid leukemia cells and synergizes with ascorbate to promote DNA hydroxymethylation and chromatin remodeling at key myeloid differentiation loci. Using Tet1/2/3-deficient mice and primary human acute myeloid leukemia (AML) models, we show that ATRA plus ascorbate more effectively induces differentiation, inhibits leukemia stem cell self-renewal in a TET2-dependent manner, and sensitizes AML cells to targeted therapies in vivo, leading to improved survival. These findings support the combined use of ATRA and ascorbate as a strategy to enhance TET2 activity for the treatment of myeloid malignancies.
    Keywords:  5hmC; CP: Cancer; CP: Genomics; TET2; ascorbate; differentiation therapy; myeloid leukemia; retinoic acid
    DOI:  https://doi.org/10.1016/j.celrep.2025.116379
  8. Proc Natl Acad Sci U S A. 2025 Oct 07. 122(40): e2507922122
    Influence of the protein corona on hematopoietic stem and progenitor cell uptake and macrophage clearance of membrane-wrapped nanoparticles.
    Eric H Sterin, Laura A Weinstein, Ashish Tiwari, George C Kramarenko, Chitran Roy Chowdhury, Kejian Li, Emily S Day.
      The ideal delivery of therapeutic nanoparticles (NPs) to specific sites requires evading immune clearance and selectively binding target cells. Wrapping NPs in cell-derived membranes has shown promise in improving targeted delivery, but the mechanisms underlying this phenomenon are not fully understood. Protein corona (PC) formation on NPs can significantly alter their biological identity to influence biodistribution, making its characterization on membrane-wrapped NPs (MWNPs) and unwrapped NPs crucial. In this study, we compared MWNPs incorporating membranes derived from megakaryoblastic CHRF-288-11 cells, which can accumulate in bone marrow (BM) and preferentially bind hematopoietic stem and progenitor cells (HSPCs), with unwrapped NPs. We investigated differences in PC composition, macrophage uptake, target cell uptake, and biodistribution in wild type (WT) mice and knockout mice that have low or absent expression of different opsonin proteins. In vitro, MWNPs with a PC exhibited increased target cell uptake and decreased macrophage uptake compared to unwrapped NPs with a PC. Proteomics revealed apolipoprotein B as the dominant opsonin on both NP types after incubation in mouse, bovine, or human serum, with other proteins like complement, immunoglobulins, and apolipoproteins also being present. Biodistribution studies indicated a complex interplay between the PC and targeting/clearance, where complement component 3 and immunoglobulin G adsorption on MWNPs led to macrophage clearance but also enabled HSPC targeting. Meanwhile, apolipoprotein E adsorption facilitated hepatocyte clearance but reduced immune cell uptake in the liver. Future research on PCs could determine whether these mechanisms are generalizable to other types of MWNPs, potentially revealing strategies to enhance their effectiveness as delivery systems.
    Keywords:  biomimicry; immune clearance; in vivo targeting; nanoparticle biodistribution; opsonization
    DOI:  https://doi.org/10.1073/pnas.2507922122
  9. Cancer Res. 2025 Oct 03.
    FLT3-ITD Induces CMTM6 and Enhances Immune Escape in Acute Myeloid Leukemia.
    Melissa Zwick, Bastian Zinkel, Corinna Spohr, Tamina Rückert, Sebastian Halbach, Khalid Shoumariyeh, Jonas Scheid, Anna-Sophia Baur, Lukas M Braun, Moritz Angel, Elisa Michaeli, Abhijeet Todkar, Annika Nelde, Melanie Märklin, Samuel J Holzmayer, Severin Dicks, Melanie Boerries, Sandra Duquesne, Alexandra Emilia Schlaak, Patricia Otto-Mora, Bertram Bengsch, Marcel Schiff, Sandra Kissel, Michael Selle, Marie Follo, Heidi Altmann, Desiree Kunadt, Anna-Lena Illert, Juliane S Walz, Gerd Walz, Justus Duyster, Johannes Schetelig, Tilman Brummer, Robert Zeiser, Natalie Köhler.
      FMS-like tyrosine kinase-3 internal tandem duplication (FLT3-ITD) mutations are frequent in acute myeloid leukemia (AML) and are associated with a high risk of relapse. CKLF-like MARVEL transmembrane domain containing member 6 (CMTM6) stabilizes PD-L1 surface expression and modulates tumor immunity in solid cancer. In this study, we found a role for FLT3-induced CMTM6 in hematological malignancies. FLT3 drove CMTM6 and PD-L1 expression in AML cells, while FLT3 inhibition reduced expression of CMTM6 and PD-L1. In three distinct allogeneic hematopoietic cell transplantation mouse models, transplantation of Cmtm6 deficient FLT3-ITD+ leukemia cells resulted in prolonged survival, reduced leukemia burden, enhanced T cell effector function, and decreased expression of T cell exhaustion markers compared to Cmtm6 proficient FLT3-ITD+ leukemia cells. Furthermore, combination therapy with anti-PD-L1 and tandutinib significantly improved survival, suppressed leukemia cell expansion, and augmented the anti-leukemia T cell response in mice bearing FLT3-ITD+ leukemia. Mechanistically, protein-protein interaction of FLT3 and CMTM6 within their transmembrane domains, which was not phosphorylation dependent, enhanced CMTM6 stability in leukemia cells, while FLT3-ITD did not increase CMTM6 and PD-L1 expression at the RNA level. Furthermore, CMTM6 upregulation and protein interaction with FLT3 was validated in primary leukemia cells from two independent cohorts of patients with FLT3-ITD+ AML. Collectively, these findings uncover FLT3-mediated stabilization of CMTM6 in AML cells, which results in enhanced PD-L1 cell surface expression and leukemia immune escape.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-0349
  10. bioRxiv. 2025 Sep 25. pii: 2025.09.23.678057. [Epub ahead of print]
    JAK2V617F Myeloproliferative Neoplasms Support Parallel Evolution of Independent Leukemic Clones.
    Tyler M Parsons, Aishwarya Krishnan, Infencia Xavier Raj, Andrew L Young, David R O'Leary, Jason Arand, Maggie Cox, Stephen T Oh, Grant A Challen.
      Myeloproliferative neoplasms (MPNs) are hematological diseases predominantly driven by the JAK2 V617F mutation. Progression from chronic-phase MPN to secondary acute myeloid leukemia (sAML) is a severe complication that dramatically worsens disease prognosis. While progression to sAML is classically linked to MPN clones acquiring additional mutations, the absence of JAK2 V617F in some cases of post-MPN sAML cases suggests alternative mechanisms of transformation. Utilizing patient samples and in vivo modeling, we establish that leukemic clones can emerge independently of JAK2 -mutant cells and undergo positive selection in the pro-inflammatory MPN environment, leading to parallel disease evolution. Genetic and pharmacological inhibition of IL-12 and TNFα mitigates this competitive advantage. Our data establish a new paradigm and show that disease progression in MPN can arise from parallel acute myeloid leukemia (pAML) clones.
    DOI:  https://doi.org/10.1101/2025.09.23.678057
  11. Nat Cancer. 2025 Oct 03.
    Aberrant expression of SLAMF6 constitutes a targetable immune escape mechanism in acute myeloid leukemia.
    Carl Sandén, Niklas Landberg, Pablo Peña-Martínez, Hanna Thorsson, Shruti Daga, Noelia Puente-Moncada, Maria Rodriguez-Zabala, Sofia von Palffy, Marianne Rissler, Vladimir Lazarevic, Gunnar Juliusson, Mats Ohlin, Axel Hyrenius-Wittsten, Christina Orsmark-Pietras, Henrik Lilljebjörn, Helena Ågerstam, Thoas Fioretos.
      Immunotherapy has shown limited success in acute myeloid leukemia (AML), indicating an incomplete understanding of the underlying immunoregulatory mechanisms. Here we identify an immune evasion mechanism present in 60% of AML cases, wherein primitive AML cells aberrantly express the lymphoid surface protein SLAMF6 (signaling lymphocyte activation molecule family member 6). Knockout of SLAMF6 in AML cells enables T cell activation and highly efficient killing of leukemia cells in coculture systems, demonstrating that SLAMF6 protects AML cells from recognition and elimination by the immune system in a mode analogous to the programmed cell death protein-ligand (PDL1/PD1) axis. Targeting SLAMF6 with an antibody against the SLAMF6 dimerization site inhibits the SLAMF6-SLAMF6 interaction and induces T cell activation and killing of AML cells both in vitro and in humanized in vivo models. In conclusion, we show that aberrant expression of SLAMF6 is a common and targetable immune escape mechanism that could pave the way for immunotherapy in AML.
    DOI:  https://doi.org/10.1038/s43018-025-01054-6
  12. Res Sq. 2025 Sep 26. pii: rs.3.rs-7563799. [Epub ahead of print]
    RPS19 and RPL5 Haploinsufficient Models Reveal Divergent Ribosomal Subunit Controls of Fetal Hematopoiesis.
    Lionel Blanc, Yuefeng Tang, Te Ling, Rashid Mehmood, Alexis Bertrand, Julien Papoin, Mushran Khan, Riaz Rao, Jianing Xu, Vincent Schulz, James Palis, Laurie Steiner, Betsy Barnes, YongRui Zou, Philippe Marambaud, Robert Signer, Irene Roberts, Deena Iskander, Leonard Zon, Senthil Bhoopalan, Mitchell Weiss, Jeffrey Lipton, Patrick Gallagher, Narla Mohandas, Naomi Taylor, Sebastien Durand, John Crispino.
      Diamond Blackfan anemia syndrome (DBAS) is a congenital ribosomopathy caused by haploinsufficiency of ribosomal proteins (RPs), but how RP stoichiometry and activity regulates erythroid development remains enigmatic. Using novel in vivo models, we uncover strikingly divergent functions for the small and large ribosomal subunit proteins RPS19 and RPL5 in fetal hematopoiesis. While RPL5 haploinsufficiency causes hematopoietic stem and progenitor cell (HSPC) accumulation and prenatal lethality via p53-mediated ferroptosis of mature erythroid progenitors, RPS19 haploinsufficiency leads to HSPC depletion and impaired erythroid expansion through p53-dependent apoptosis. The latter is accompanied by translational and transcriptional dysregulation, including the upregulation of RUNX1 , which is also observed in RPS- haploinsufficient DBAS patients. Importantly, Runx1 deletion in RPS19-haploinsufficient mice partially rescues HSPC numbers. These findings reveal subunit-specific RP functions in controlling fetal hematopoiesis and demonstrate how imbalanced RP stoichiometry disrupts developmental programs, providing crucial mechanistic insights into DBAS pathogenesis and the basis for its clinical heterogeneity.
    DOI:  https://doi.org/10.21203/rs.3.rs-7563799/v1
  13. Cell Rep. 2025 Oct 01. pii: S2211-1247(25)01143-X. [Epub ahead of print]44(10): 116372
    USP9X is a mechanosensitive deubiquitinase that controls tumor cell invasiveness and drug response through YAP stabilization.
    Pierric Biber, Alexandrine Carminati, Walaa Mohager, Mickael Ohanna, Christophe A Girard, Margaux Lecacheur, Mira Kahil, Océane Bouvet, Marie Irondelle, Stéphane Audebert, Mehdi Khaled, Sophie Tartare-Deckert, Marcel Deckert.
      Ubiquitin removal by deubiquitinases (DUBs) is crucial for protein activity and homeostasis. While tumor cells adapt to treatment and environmental stress, the role of DUBs in sensing mechanical signals from the extracellular matrix (ECM) remains an unexplored area. Using melanoma cells cultured on collagen matrices of varying stiffness and activity-based ubiquitin probe profiling combined with quantitative proteomics, we identify ubiquitin specific peptidase 9 X-linked (USP9X) as a stiffness-sensitive DUB acting through the discoidin domain receptor (DDR)/actomyosin signaling pathway. USP9X regulates levels of the mechanosensor YAP by preventing its proteasomal degradation via deubiquitination. Inhibition or knockdown of USP9X reduced YAP expression, impaired tumor cell migration, invasion, and ECM contraction, and decreased metastatic potential in vivo. Targeting USP9X also enhanced the effectiveness of BRAF-targeted therapies by limiting YAP-mediated mechanosensing, drug resistance, and tumor relapse. These findings establish USP9X as a mechanoresponsive DUB essential for cancer cell adaptation to mechanical cues, proposing it as a targetable mechanosensitive therapeutic target in cancer.
    Keywords:  CP: Cancer; CP: Cell biology; DUB; USP9X; YAP; extracellular matrix stiffness; invasion; mechanotransduction; therapy resistance; ubiquitin proteasome system
    DOI:  https://doi.org/10.1016/j.celrep.2025.116372
  14. Nature. 2025 Oct 01.
    Proteotoxic stress response drives T cell exhaustion and immune evasion.
    Yi Wang, Anjun Ma, No-Joon Song, Ariana E Shannon, Yaa S Amankwah, Xingyu Chen, Weidong Wu, Ziyu Wang, Abbey A Saadey, Amir Yousif, Gautam Ghosh, Jay K Mandula, Maria Velegraki, Tong Xiao, Haitao Wen, Stanley Ching-Cheng Huang, Ruoning Wang, Christian M Beusch, Abdelhameed S Dawood, David E Gordon, Mohamed S Abdel-Hakeem, Hazem E Ghoneim, Gang Xin, Brian C Searle, Zihai Li.
      Chronic infections and cancer cause T cell dysfunction known as exhaustion. This cell state is caused by persistent antigen exposure, suboptimal co-stimulation and a plethora of hostile factors that dampen protective immunity and limit the efficacy of immunotherapies1-4. The mechanisms that underlie T cell exhaustion remain poorly understood. Here we analyse the proteome of CD8+ exhausted T (Tex) cells across multiple states of exhaustion in the context of both chronic viral infections and cancer. We show that there is a non-stochastic pathway-specific discordance between mRNA and protein dynamics between T effector (Teff) and Tex cells. We identify a distinct proteotoxic stress response (PSR) in Tex cells, which we term Tex-PSR. Contrary to canonical stress responses that induce a reduction in protein synthesis5,6, Tex-PSR involves an increase in global translation activity and an upregulation of specialized chaperone proteins. Tex-PSR is further characterized by the accumulation of protein aggregates and stress granules and an increase in autophagy-dominant protein catabolism. We establish that disruption of proteostasis alone can convert Teff cells to Tex cells, and we link Tex-PSR mechanistically to persistent AKT signalling. Finally, disruption of Tex-PSR-associated chaperones in CD8+ T cells improves cancer immunotherapy in preclinical models. Moreover, a high Tex-PSR in T cells from patients with cancer confers poor responses to clinical immunotherapy. Collectively, our findings indicate that Tex-PSR is a hallmark and a mechanistic driver of T cell exhaustion, which raises the possibility of targeting proteostasis pathways as an approach for cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41586-025-09539-1
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