Yun Zhao

The Hedgehog (Hh) signaling pathway plays an essential role in embryonic development, and its aberrant activation is associated with pancreatic cancer progression. However, the function of Suppressor of Fused (SUFU), a critical negative regulator of the Hh pathway, in pancreatic cancer has been poorly studied. In this study, we found that SUFU knockdown significantly inhibits pancreatic cancer cell growth, migration, and proliferation while inducing apoptosis. We identified a direct interaction between JOSD1 and SUFU, whereby JOSD1 stabilizes SUFU protein by inhibiting its ubiquitination and proteasomal degradation. Public database analyses revealed a positive correlation between JOSD1 and SUFU expression in pancreatic cancer tissues, and immunofluorescence staining of clinical samples further showed that JOSD1 and SUFU are co-localized and expressed at higher levels in pancreatic cancer tissues compared with normal pancreatic tissues. Notably, SUFU regulates pancreatic cancer cell behavior through a non-canonical, Hh-independent mechanism. Depletion of either JOSD1 or SUFU downregulated proliferation-related genes and upregulated apoptosis-related genes, thereby suppressing pancreatic cancer cell growth and promoting apoptosis, with these effects reversed by SUFU restoration. Consistently, silencing of JOSD1 or SUFU significantly attenuates tumor growth and reduces Ki67 expression in vivo, whereas re-expression of SUFU in JOSD1-deficient tumors restores tumor growth and proliferation. Collectively, these findings highlight the functional importance of JOSD1-mediated SUFU stabilization in pancreatic cancer and suggest potential therapeutic strategies targeting this axis.

Cytotoxic lymphocytes use perforin to form plasma membrane (PM) pores in tumor cells, thereby enabling granzyme-mediated cell death. However, whether and how tumor metabolism enables PM repair to evade immunity is unclear. In this study, using a functional screen targeting 111 metabolic enzymes, we identified hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) as critical for repairing perforin-induced PM damage. HMGCS1 promotes PM repair by initiating de novo cholesterol synthesis, enhancing tumor cell resistance to lymphocyte-mediated killing and impairing the efficacy of NK, CAR-T, and anti-PD-1-based immunotherapies. Beyond its structural role, cholesterol directly binds charged multivesicular body protein 4b (CHMP4B) to enhance its PM localization, facilitating PM repair. Furthermore, oncogenic activation, cytokine, and hypoxia induce c-Jun activation, up-regulating HMGCS1 expression. In lung cancer patients, elevated c-Jun activation, HMGCS1 expression, cholesterol content and PM CHMP4B correlate with reduced anti-PD-1 immunotherapy efficacy. Our findings reveal a tumor immune evasion mechanism wherein HMGCS1 drives cholesterol-dependent PM repair by activating the cholesterol synthesis. Targeting HMGCS1 enhances the effectiveness of immunotherapies.

Metastasis, responsible for > 90% of cancer-related mortality, represents the most lethal yet least mechanistically understood phase of cancer progression. A critical bottleneck is tumor cell migration through physically confined environments, including dense extracellular matrix, narrow capillaries and endothelial gaps. Although tumor cells reprogram their metabolism to facilitate cancer progression, it remains unclear how specific metabolic adaptations enable them to overcome the unique physical challenges posed by these confined spaces, thereby promoting distant metastasis. We conducted a CRISPR screen targeting 1685 metabolic enzymes and identified dihydrolipoamide dehydrogenase (DLD), a mitochondrial enzyme involved in energy metabolism, as essential for confined migration of tumor cells. Depletion or pharmacological inhibition of DLD suppressed CRC metastasis by impairing tumor cell migration through capillaries and endothelial gaps. Upon mechanical compression, heterogeneous nuclear ribonucleoprotein A0 (hnRNPA0) binds to the adenylate uridylate-rich element (ARE) in the 3′UTR of DLD, enhancing its mRNA stability and upregulating DLD expression in tumor cells during confined migration. Elevated DLD expression enhances tricarboxylic acid (TCA) cycle metabolism, increasing malate levels. Malate interacts with tubulin alpha-1B chain (TUBA1B) to promote microtubule assembly, facilitating confined migration and metastasis. Knock-in of an ARE-deleted DLD mutant (DLD ΔARE) or disruption of the malate–TUBA1B interaction significantly suppressed tumor metastasis. In CRC patients, DLD expression was upregulated in tumor cells within capillaries of primary tumors and correlated with metastatic recurrence. Our findings reveal that compressive forces drive metastatic dissemination by epigenetically reprogramming mitochondrial metabolism, which in turn fuels cytoskeletal remodeling.

The immunosuppressive tumor microenvironment remains a major obstacle to successful immunotherapy. Pathologically activated neutrophils, alternatively termed polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), drive tumor immune evasion primarily by inducing CD8⁺ T cell tolerance. While direct intercellular contact between neutrophils and CD8⁺ T cells is essential for immunosuppressive activity, the mechanisms mediating this interaction need deeper understanding. We previously reported that CD300ld is required for recruiting PMN-MDSCs into tumors, suppressing T cell activation. Here we show that CD300ld mediates neutrophil-driven contact-dependent suppression of cytotoxic CD8⁺ T cells by binding to phosphatidylserine (PS). Mice with mutant CD300ld lacking PS-binding capacity exhibit reduced immunosuppressive activity. Blockade of the CD300ld-PS interaction by neutralizing antibodies demonstrates therapeutic efficacy against established tumors and synergizes with anti-PD1. Our findings establish CD300ld-PS-mediated cell contact as a critical mechanism of neutrophil-driven immune evasion, revealing a targetable checkpoint pathway to overcome tumor immune resistance and improve immunotherapy outcomes.

Aberrant cholesterol biosynthesis is a notable hallmark of cancers, supporting unlimited cell proliferation. Previously, we delineated that cholesterol synthases FDFT1 and SQLE promoted colorectal cancer (CRC) cell proliferation, while how these enzymes influence CRC metastasis and stemness remains unclear. This study demonstrates that suppress of FDFT1 or SQLE enhances CRC metastasis and stemness through impairing ER stress and degrading PDIA4 or SYVN1 individually. Additionally, the function of FDFT1 and SQLE on CRC metastasis relies on tryptophan. Tryptophan augments PDIA4-ACLY and SYVN1-SCD1 co-complex association to drive CRC metastasis and stemness. Consequently, the specific inhibitor of ACLY or SCD1 blocks FDFT1 or SQLE deficiency induced CRC metastasis using Male BALB/c nude mice. Besides, sub-cytotoxic concentrations of inhibitors targeting FDFT1 or SQLE generate the invasive feature in CRC cells. Overall, these findings indicate that cholesterol synthases impact ER homeostasis and fatty acid synthesis to regulate CRC metastasis and stemness, offering potential for combined targeted therapies in CRC.

Mutations in the extracellular or intracellular domains of epidermal growth factor receptor (EGFR) are implicated in the development of various cancers. While the intracellular mutations of EGFR have been extensively studied, the function of extracellular mutations remains poorly understood. In this study, we identify an EGFR mutant (EGFR R252C) in a patient with multifocal lung cancer and glioma, in which arginine (R) 252 is mutated to cysteine (C) in the EGFR extracellular domain. This mutation promotes C252-C252 disulfide-mediated EGFR dimerization and induces a conformational change of EGFR, leading to absent autophosphorylation and enhanced direct interaction between EGFR and extracellular signal-regulated protein kinase 1/2 (ERK1/2). Importantly, EGFR directly phosphorylates ERK1/2 at threonine (T) 202 / tyrosine (Y) 204 and activates ERK1/2, thereby promoting tumor cell proliferation and tumor growth in vivo. Afatinib, a second-generation EGFR tyrosine kinase inhibitor, effectively suppresses primary tumor growth and extends progression-free survival in the patient with multifocal lung cancer and glioma driven by EGFR R252C. Our finding elucidates the activation mechanism of this extracellular EGFR mutation and demonstrates the efficacy of afatinib in treating lung cancer or glioma patients with this variant.

The Hedgehog (Hh) signaling pathway plays a pivotal role in tumorigenesis. SUFU (Suppressor of Fused), a key negative regulator of Hh signaling, also inter

Background: Beige adipocytes play a critical role in thermoregulation by upregulating uncoupling protein 1 (UCP1) upon stimulation. While the transcriptional regulation of UCP1 in adipose tissue has been extensively investigated, the mechanisms governing its translational control remain largely elusive.

Metastasis remains the primary cause of cancer-related mortality. During dissemination, cancer cells must navigate spatially confined microenvironments, yet the underlying metabolic adaptations that facilitate this process remain unclear. Here, through an in vivo CRISPR screen targeting metabolic enzymes, we identify aldehyde dehydrogenase 1 family member B1 (ALDH1B1) as essential for tumor cell survival in confining capillaries. Mechanistically, compressive force induces casein kinase 2 alpha 3 (CSK23) to phosphorylate kappa-B kinase subunit beta (IKKβ) at Ser177/181, which activates the nuclear factor kappa B (NF-κB) pathway and upregulates ALDH1B1. The upregulation of ALDH1B1 enhances aldehyde detoxification, which suppresses ferroptosis and promotes tumor cell survival during migration through the capillaries, thereby facilitating metastasis. Importantly, genetic or pharmacological inhibition of CSK23 or ALDH1B1 effectively impairs metastasis. In lung cancer patients, confined tumor cells exhibit higher levels of ALDH1B1 and NF-κB activation, which correlates with metastatic recurrence. Our findings reveal a mechano-metabolic pathway that promotes metastasis and suggest CSK23 and ALDH1B1 as potential therapeutic targets.

Gli1 is a critical marker of diverse stem cell populations across multiple tissues and is essential for tissue regeneration. However, its functional relevance in skeletal muscle has remained largely unexplored. Here, we demonstrate that Gli1 primarily expressed in muscle stem cells (MuSCs) and fibro/adipogenic progenitors (FAPs) in skeletal muscle. Utilizing conditional knockout mouse models, we found that systemic loss of Gli1 impairs muscle regeneration; however, this effect is not attributable to MuSC-dependent mechanisms. Rather, conditional deletion of Gli1 in FAPs lead to significant regenerative impairment, characterized by aberrant FAP expansion and their enhanced adipogenic potential. In vivo, Gli1-deficient FAPs contributed to increased intramuscular adipocyte accumulation, while in vitro assays confirmed enhanced lipid droplet formation under adipogenic conditions. Mechanistically, Gli1 directly activates the transcription of the key metabolic enzyme indoleamine 2,3-dioxygenase 1 (Ido1), and inhibition or knockdown of Ido1 phenocopied the effects of Gli1 loss. Together, these findings uncover a previously unrecognized role for Gli1 in orchestrating muscle regeneration by modulating FAP fate and function, providing new insights into the cellular and molecular framework governing muscle repair.