Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Май 19, 2023

Abstract The Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved mechanism transmembrane transduction that enables cells to communicate with the exterior environment. Various cytokines, interferons, growth factors, other specific molecules activate JAK-STAT signaling drive a series physiological pathological processes, including proliferation, metabolism, immune response, inflammation, malignancy. Dysregulated related genetic mutations are strongly associated activation cancer progression. Insights into structures functions have led development approval diverse drugs for clinical treatment diseases. Currently, been developed mainly target commonly divided three subtypes: cytokine or receptor antibodies, JAK inhibitors, STAT inhibitors. And novel agents also continue be tested in preclinical studies. effectiveness safety each kind drug warrant further scientific trials before put being applications. Here, we review current understanding fundamental composition function pathway. We discuss advancements JAK-STAT–related pathogenic mechanisms; targeted therapies various diseases, especially disorders, cancers; newly inhibitors; challenges directions field.

Язык: Английский

---

Macrophages Facilitate Interclonal Cooperation-Induced Tumor Malignancy by Hijacking the Innate Immune System

Опубликована: Янв. 1, 2025

Tumor heterogeneity is a common hallmark of cancer and considered major cause treatment failure relapse, yet it remains poorly understood how various types cells communicate within the tumor microenvironment to regulate progression in vivo. Here we establish novel model eye epithelium Drosophila melanogaster dissect vivo mechanisms underlying intercellular communication by combining sophisticated genetic techniques with single-cell RNA sequencing (scRNA-seq). Our results demonstrate that targeted mutation tricellular junction protein M6 surrounding RasV12 benign tumors promotes their malignant transformation. Mechanistically, loss activates JNK signaling, which propagates tumors, leading an increased recruitment macrophages site. Subsequently, tumor-associated secrete Spatzle (Spz) ligand activate Toll receptor tumors. Ultimately, pathway activation synergizes promote its transformation inactivating Hippo pathway. In summary, our study elucidates complex interplay among genetically distinct oncogenic cells, as well between macrophages, shedding light on exploit ancient innate immune system coordinate heterogeneity-mediated progression.

Язык: Английский

---

Fat body-derived cytokine Upd2 controls disciplined migration of tracheal stem cells in Drosophila

Опубликована: Фев. 7, 2025

Coordinated activation and directional migration of adult stem cells are essential for maintaining tissue homeostasis. Drosophila tracheal progenitors that migrate posteriorly along the dorsal trunk to replenish degenerating branches disperse FGF mitogen. However, it is currently unknown how overall anterior-to-posterior directionality such controlled. Here we show individual progenitor together in a concerted, disciplined manner, behavior dependent on neighboring fat body. We identify body-derived cytokine, Upd2, targeting inducing JAK/STAT signaling maintain their migration. Perturbation either Upd2 production body or trachea causes aberrant bidirectional progenitors. promotes expression genes involved planar cell polarity leading asymmetric localization Fat cells. provide evidence transport requires Rab5- Rab7-mediated endocytic sorting Lbm-dependent vesicle trafficking. Our study thus uncovers an inter-organ communication control cells, process vesicular trafficking cytokine signaling-mediated PCP genes.

Язык: Английский

---

Fat body-derived cytokine Upd2 controls disciplined migration of tracheal stem cells in Drosophila

Опубликована: Апрель 30, 2025

Coordinated activation and directional migration of adult stem cells are essential for maintaining tissue homeostasis. Drosophila tracheal progenitors that migrate posteriorly along the dorsal trunk to replenish degenerating branches disperse FGF mitogen. However, it is currently unknown how overall anterior-to-posterior directionality such controlled. Here we show individual progenitor together in a concerted, disciplined manner, behavior dependent on neighboring fat body. We identify body-derived cytokine, Upd2, targeting inducing JAK/STAT signaling maintain their migration. Perturbation either Upd2 production body or trachea causes aberrant bidirectional progenitors. promotes expression genes involved planar cell polarity leading asymmetric localization Fat cells. provide evidence transport requires Rab5- Rab7-mediated endocytic sorting Lbm-dependent vesicle trafficking. Our study thus uncovers an inter-organ communication control cells, process vesicular trafficking cytokine signaling-mediated PCP genes.

Язык: Английский

---

Oncogenic Ras, Yki and Notch signals converge to confer clone competitiveness through Upd2

Journal of genetics and genomics/Journal of Genetics and Genomics, Год журнала: 2025, Номер unknown

Опубликована: Май 1, 2025

Язык: Английский

---

JAK-STAT Signaling in Autoimmunity and Cancer

ImmunoTargets and Therapy, Год журнала: 2025, Номер Volume 14, С. 523 - 554

Опубликована: Май 1, 2025

The JAK-STAT pathway is an essential cell survival signaling that regulates gene expressions related to inflammation, immunity and cancer. Cytokine receptors, signal transducer activator of transcription (STAT) proteins, Janus kinases (JAKs) are the critical component this cascade. When JAKs stimulated by cytokines, STAT phosphorylation, dimerization, nuclear translocation occur, which eventually impacts transcription. Dysregulation linked with various autoimmune diseases, including rheumatoid arthritis, psoriasis, inflammatory bowel disease. This constitutively activated in human malignancies leads tumor survival, proliferation, immune evasion. Oncogenic mutations JAK genes have been found solid tumors, leukemia, lymphoma. Targeting a viable promising therapeutic strategy for treatment diseases cancers.

Язык: Английский

---

Polyploid Cancer Cell Models in Drosophila

Genes, Год журнала: 2024, Номер 15(1), С. 96 - 96

Опубликована: Янв. 14, 2024

Cells with an abnormal number of chromosomes have been found in more than 90% solid tumors, and among these, polyploidy accounts for about 40%. Polyploidized cells most often duplicate centrosomes as well genomes, thus their mitosis tends to promote merotelic spindle attachments chromosomal instability, which produces a variety aneuploid daughter cells. Polyploid highly resistant various stress anticancer therapies, such radiation mitogenic inhibitors. In other words, common cancer therapies kill proliferative diploid cells, make up the majority tissues, while polyploid lurk smaller numbers, may survive. The surviving prompted by acute environmental changes, begin mitose leading explosion genetic heterogeneity concomitant cell competition adaptive evolution. result is recurrence during tenacious that survived treatment express malignant traits. Although presence tissues has observed 150 years, function exact role these progression remained elusive. For this reason, there currently no effective therapeutic directed against This due part lack suitable experimental models, but recently several models become available study vivo. We propose

Язык: Английский

---

Survival, Movement, and Lifespan: Decoding the Roles of Patched-Related (Ptr) inDrosophila melanogaster

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Май 8, 2024

Abstract Patched-related (Ptr) is a transmembrane protein implicated in developmental processes Drosophila melanogaster , yet its precise role remains incompletely understood. Here, we use Ptr 23c null mutants to investigate the functional significance of through entire life cycle monitoring survival during embryonic, larval, pupal and adult development, studying larval locomotion muscle structure. We report that larvae displayed impaired hatching, indicative defective embryonic development. Moreover, mutant exhibited reduced mobility lethargy, suggesting potential involvement neuromuscular function. Morphological analysis somatic muscles revealed enlarged cell nuclei. Despite high pre-adult mortality, subset adults display an unexpected extension lifespan compared controls, implicating regulation longevity. Our findings provide critical insights into multifaceted highlighting contributions post-embryonic survival, function, regulation. This study underscores exploring broader genetic networks unravel complexities processes.

Язык: Английский

---

Macrophages facilitate interclonal cooperation-induced tumor heterogeneity and malignancy by activating the innate immune signaling

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июнь 30, 2024

Abstract Tumor heterogeneity is a common hallmark of cancer and considered major cause treatment failure relapse, yet it remains poorly understood how various types cells communicate within the tumor microenvironment (TME) to regulate progression in vivo . Here we establish model Drosophila eye epithelium by mutating tricellular junction protein M6 surrounding Ras V12 benign tumors dissect mechanisms underlying interclonal cooperation-induced malignancy utilizing sophisticated genetic techniques conjunction with single-cell RNA sequencing (scRNA-seq). Our findings reveal that loss facilitates malignant transformation neighboring activating Toll signaling, innate immune response pathway. Notably, inhibiting signaling impedes progression, whereas its activation synergistically promotes inactivating Hippo Mechanistically, surrounded mutant clones lead increased recruitment hemocytes, which are equivalent macrophages , JNK pathway-dependent manner. Consequently, these tumor-associated secrete Spatzle (Spz) ligand, subsequently activates receptor tumors, thereby triggering tumorigenesis. In summary, our study elucidates complex interactions between genetically distinct oncogenic macrophages, shedding light on exploit promote progression. Significance statement Intratumoral profoundly affects development human tumors. The intricate nature presence diverse cell pose challenges uncovering responsible for heterogeneity. reveals fruit fly both malignancy. Following cells, ligand Spz activate pathway inactivates drive highlights crucial role hemocytes as intermediaries coordinating facilitating intercellular communication different TME.

Язык: Английский

---

Fat body-derived cytokine Upd2 controls disciplined migration of tracheal stem cells inDrosophila

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Июль 5, 2024

Coordinated activation and directional migration of adult stem cells are essential for maintaining tissue homeostasis. Drosophila tracheal progenitors that migrate posteriorly along the dorsal trunk to replenish degenerating branches disperse FGF mitogen. However, it is currently unknown how overall anterior-to-posterior directionality such controlled. Here we show individual progenitor together in a concerted, disciplined manner, behavior dependent on neighboring fat body. We identify body-derived cytokine, Upd2, targeting inducing JAK/STAT signaling maintain their migration. Perturbation either Upd2 production body or trachea causes aberrant bidirectional progenitors. promotes expression genes involved planar cell polarity leading asymmetric localization Fat cells. provide evidence transport requires Rab5- Rab7-mediated endocytic sorting Lbm-dependent vesicle trafficking. Our study thus uncovers an inter-organ communication control cells, process vesicular trafficking cytokine signaling-mediated PCP genes.

Язык: Английский

---