Abstract Background Cancer-associated fibroblasts (CAFs) play multiple roles in regulating tumor metastasis and treatment response. Current clinical indicators are insufficient to accurately assess disease risk and radiotherapy response, emphasizing the urgent need for additional molecular prognostic markers. Methods In order to investigate CAF-related genes associated with radiotherapy and construct prognostic CAF-related gene signatures for prostate cancer, we firstly established a radio-resistant prostate CAF cell subline (referred to as CAFR) from Mus-CAF (referred to as CAF) through fractionated irradiation using X-rays. Transcriptome sequencing for CAF and CAFR was conducted, and 2626 CAF-related differentially expressed genes (DEGs) associated with radiotherapy were identified. Human homologous genes of mouse CAF-related DEGs were then obtained. Results Functional enrichment analysis revealed that these CAF-related DEGs were significantly enriched ECM- and immune-related functions and pathways. Based on GSE116918 dataset, 186 CAF-related DEGs were correlated with biochemical recurrence-free survival (BCRFS) of prostate cancer patients, 16 of which were selected to construct a BCRFS-related CAF signature, such as ACPP , THBS2 , and KCTD14 ; 142 CAF-related DEGs were correlated with metastasis-free survival (MFS), 16 of which were used to construct a MFS-related CAF signature, such as HOPX , TMEM132A , and ZNF467 . Both Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) datasets confirmed that the two CAF signatures accurately predicted BCRFS and MFS of prostate cancer patients. The risk scores were higher in patients with higher gleason grades and higher clinical T stages. Moreover, the BCRFS-related CAF signature was an independent prognostic factor and a nomogram consisting of BCRFS-related CAF signature and various clinical factors accurately predicted 2-, 3-, and 5-year survival time of prostate cancer patients. Furthermore, the risk score was positively correlated with multiple immune checkpoints. Conclusions Our established CAF signatures could accurately predict BCRFS and MFS in prostate cancer patients undergoing radiotherapy. 

/pdf/cancer-associated-fibroblast-derived-gene-signatures-predict-2u8a6ys5.pdf

Cancer-associated fibroblast-derived gene signatures predict radiotherapeutic survival in prostate cancer patients

The role of Numb, a protein that is important for cell fate and development and that, in human muscle, is expressed at reduced levels with advanced age, was investigated; adult mice skeletal muscle and its localization and function within myofibres were determined.Numb expression was evaluated by western blot. Numb localization was determined by confocal microscopy. The effects of conditional knock out (cKO) of Numb and the closely related gene Numb-like in skeletal muscle fibres were evaluated by in situ physiology, transmission and focused ion beam scanning electron microscopy, three-dimensional reconstruction of mitochondria, lipidomics, and bulk RNA sequencing. Additional studies using primary mouse myotubes investigated the effects of Numb knockdown on cell fusion, mitochondrial function, and calcium transients.Numb protein expression was reduced by ~70% (P < 0.01) at 24 as compared with 3 months of age in gastrocnemius and tibialis anterior muscle. Numb was localized within muscle fibres as bands traversing fibres at regularly spaced intervals in close proximity to dihydropyridine receptors. The cKO of Numb and Numb-like reduced specific tetanic force by 36% (P < 0.01), altered mitochondrial spatial relationships to sarcomeric structures, increased Z-line spacing by 30% (P < 0.0001), perturbed sarcoplasmic reticulum organization and reduced mitochondrial volume by over 80% (P < 0.01). Only six genes were differentially expressed in cKO mice: Itga4, Sema7a, Irgm2, Vezf1, Mib1, and Tmem132a. Several lipid mediators derived from polyunsaturated fatty acids through lipoxygenases were up-regulated in Numb cKO skeletal muscle: 12-HEPE was increased by ~250% (P < 0.05) and 17,18-EpETE by ~240% (P < 0.05). In mouse primary myotubes, Numb knockdown reduced cell fusion (~20%, P < 0.01) and delayed the caffeine-induced rise in cytosolic calcium concentrations by more than 100% (P < 0.01).These findings implicate Numb as a critical factor in skeletal muscle structure and function and suggest that Numb is critical for calcium release. We therefore speculate that Numb plays critical roles in excitation-contraction coupling, one of the putative targets of aged skeletal muscles. These findings provide new insights into the molecular underpinnings of the loss of muscle function observed with sarcopenia. 

Numb is required for optimal contraction of skeletal muscle

Wnts are a family of secreted, lipid-modified signaling glycoproteins that regulate a multiplicity of fundamental biological processes. Wnt signaling is essential for embryonic development, controlling body axis patterning, cell proliferation, cell migration and cell fate specification needed for proper tissue and organ formation. In adulthood, Wnt signaling controls tissue regeneration in a wide range of organs, and disturbance of this system is common in cancer and other diseases. A key feature of Wnt signaling is that it is a local process. Wnts signal via paracrine, cell-to-cell communication. Upon synthesis and transport to the plasma membrane in the "sending" cell, Wnts travel to nearby "receiving" cells. At the plasma membrane of these receiving cells, they interact with a variety of cell-surface receptors. This interaction triggers a diversity of different downstream signaling events, including the stabilization of β-catenin and tissue-specific changes in gene expression. Wnt signaling is a local event because as an indispensable step in their maturation, Wnts are palmitoleated immediately after synthesis. This lipid modification is essential for Wnts to be transported and biologically active, but it also renders them highly hydrophobic. This makes all Wnts highly dependent on carrier proteins and specialized cellular structures both for intra- and inter-cellular movement. How this complex machinery acts in concert to deliver its highly important payload from the place of synthesis to the correct site of delivery is under active investigation. Here, we review the current understanding of how lipid-modified Wnts are processed, transported, and guided to their place of action. 

An itch for things remote: The journey of Wnts.

Mechanistic insights into Wnt–β-catenin pathway activation and signal transduction

Coordinated migration of the mesoderm is essential for accurate organization of the body plan during embryogenesis. However, little is known about how mesoderm migration influences posterior neural tube closure in mammals. Here we show that spinal neural tube closure and lateral migration of the caudal paraxial mesoderm depend on Transmembrane protein 132A (TMEM132A), a single-pass type I transmembrane protein, the function of which is not fully understood. Our study in Tmem132a-null mice and cell models demonstrates that TMEM132A regulates several integrins and downstream integrin pathway activation as well as cell migration behaviors. Our data also implicates mesoderm migration in elevation of the caudal neural folds and successful closure of the caudal neural tube. These results suggest a requirement for paraxial mesodermal cell migration during spinal neural tube closure, disruption of which may lead to spinal bifida.

TMEM132A ensures mouse caudal neural tube closure and regulates integrin-based mesodermal migration.

Wnt signaling pathway plays indispensable roles in embryonic development and adult tissue homeostasis. However, the regulatory mechanisms involved in Wnt ligand trafficking within and secretion from the signal sending cells is still relatively uncharacterized. Here, we discover a novel regulator of Wnt signaling pathway called transmembrane protein 132A (TMEM132A). Our evidence shows a physical and functional interaction of TMEM132A with the Wnt ligand transporting protein Wntless (WLS). We show that TMEM132A stabilizes Wnt ligand, enhances WLS-Wnt ligand interaction, and activates the Wnt signaling pathway. Our results shed new light on the cellular mechanism underlying the fundamental aspect of WNT secretion from Wnt signal sending cells.

/pdf/tmem132a-a-novel-wnt-signaling-pathway-regulator-through-1engd2g9di.pdf

TMEM132A, a Novel Wnt Signaling Pathway Regulator Through Wntless (WLS) Interaction.

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TMEM132A, a Novel Wnt Signaling Pathway Regulator Through Wntless (WLS) Interaction.