Coordinated Regulation of Palladin and α–Smooth Muscle Actin by Transforming Growth Factor–β in Human Corneal Fibroblasts

Morishige, Naoyuki; Murata, Shizuka; Nakamura, Yoshikuni; Azumi, Haruya; Shin-Gyou-Uchi, Ryutaro; Oki, Ken Taro; Morita, Yukiko; Sonoda, Koh Hei

doi:10.1167/iovs.15-18763

Cited by 4 publications

(4 citation statements)

References 43 publications

(48 reference statements)

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“…This study provides evidence to suggest that palladin isoforms play a role in known CAF functions like d-ECM production (able to support tumor growth), and secretion of immunosuppressive cytokines 6,13,26 . Our data suggest that palladin isoform specific roles may vary; especially with regards to TGFβ1-dependent fibroblastic activation 22,[36][37][38][39][40][41][42][43][44] . Experiments using palladin KD CAFs advocate in favor of a palladin isoform interdependency.…”

Section: Discussionmentioning

confidence: 87%

Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma

Alexander

Vendramini–Costa

Francescone

et al. 2021

Sci Rep

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Pancreatic Ductal Adenocarcinoma (PDAC) has a five-year survival under 10%. Treatment is compromised due to a fibrotic-like stromal remodeling process, known as desmoplasia, which limits therapeutic perfusion, supports tumor progression, and establishes an immunosuppressive microenvironment. These processes are driven by cancer-associated fibroblasts (CAFs), functionally activated through transforming growth factor beta1 (TGFβ1). CAFs produce a topographically aligned extracellular matrix (ECM) that correlates with reduced overall survival. Paradoxically, ablation of CAF populations results in a more aggressive disease, suggesting CAFs can also restrain PDAC progression. Thus, unraveling the mechanism(s) underlying CAF functions could lead to therapies that reinstate the tumor-suppressive features of the pancreatic stroma. CAF activation involves the f-actin organizing protein palladin. CAFs express two palladin isoforms (iso3 and iso4) which are up-regulated in response to TGFβ1. However, the roles of iso3 and iso4 in CAF functions remain elusive. Using a CAF-derived ECM model, we uncovered that iso3/iso4 are required to sustain TGFβ1-dependent CAF activation, secrete immunosuppressive cytokines, and produce a pro-tumoral ECM. Findings demonstrate a novel role for CAF palladin and suggest that iso3/iso4 regulate both redundant and specific tumor-supportive desmoplastic functions. This study highlights the therapeutic potential of targeting CAFs to restore fibroblastic anti-tumor activity in the pancreatic microenvironment.

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Section: Discussionmentioning

confidence: 87%

Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma

Alexander

Vendramini–Costa

Francescone

et al. 2021

Sci Rep

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“…We again found TEAD1 highly associated with ECM expression. A focused visualization of the TF activity score per fibroblast subtype, clearly indicated a higher predicted TEAD1 activity in ECM-Fib and two interesting genes involved in TEAD1 activity ( Mical2 45 , Palld 46 ), were found to be specifically expressed and upregulated in ECM-Fib (Fig. 4h and Supplementary Fig.…”

Section: Resultsmentioning

confidence: 97%

Mapping the cardiac vascular niche in heart failure

et al. 2022

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The cardiac vascular and perivascular niche are of major importance in homeostasis and during disease, but we lack a complete understanding of its cellular heterogeneity and alteration in response to injury as a major driver of heart failure. Using combined genetic fate tracing with confocal imaging and single-cell RNA sequencing of this niche in homeostasis and during heart failure, we unravel cell type specific transcriptomic changes in fibroblast, endothelial, pericyte and vascular smooth muscle cell subtypes. We characterize a specific fibroblast subpopulation that exists during homeostasis, acquires Thbs4 expression and expands after injury driving cardiac fibrosis, and identify the transcription factor TEAD1 as a regulator of fibroblast activation. Endothelial cells display a proliferative response after injury, which is not sustained in later remodeling, together with transcriptional changes related to hypoxia, angiogenesis, and migration. Collectively, our data provides an extensive resource of transcriptomic changes in the vascular niche in hypertrophic cardiac remodeling.

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“…TGF-β increased palladin expression in human corneal fibroblasts in a manner dependent on Smad and MAPK signaling. Moreover, palladin was required for the TGF-β-induced upregulation of α-SMA [43]. Palladin activates fibroblasts inducing them to become myofibroblasts.…”

Section: Discussionmentioning

confidence: 98%

Differential Quantitative Proteomics of Human Microvascular Endothelial Cells 1 by iTRAQ Reveals Palladin to be a New Biomarker During TGF-?1 Induced Endothelial Mesenchymal Transition

Stasiak¹,

Gawryś²,

Popielarski³

et al. 2017

J Proteomics Bioinform

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The study uses global quantitative proteomics to investigate the molecular mechanisms behind the induction of endothelial-mesenchymal transition (EndMT) by transforming growth factor-β (TGF-β). Orbitrap Velos mass spectrometers and iTRAQ -a labeling-based analysis were used to perform a global and quantitative comparison of two proteomes of Human Microvascular Endothelial Cells-1 (HMEC-1) treated or not treated by TGF-β1. iTRAQ analysis identified 43 differentially-expressed proteins in the early stages of EndMT induced by TGF-β1. From 5522 identified proteins, 26 were downregulated and 17 were upregulated, including proteins such as palladin, POTE I, torsin A and nucleoporin (NDC1). Further analysis of palladin revealed its increased mRNA and protein expression in response to TGF-β and Snail transcription factor. Our findings demonstrate that the newly-identified proteins may be involved in early stages of biological processes leading to EndMT.

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Coordinated Regulation of Palladin and α–Smooth Muscle Actin by Transforming Growth Factor–β in Human Corneal Fibroblasts

Cited by 4 publications

References 43 publications

Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma

Palladin isoforms 3 and 4 regulate cancer-associated fibroblast pro-tumor functions in pancreatic ductal adenocarcinoma

Mapping the cardiac vascular niche in heart failure

Differential Quantitative Proteomics of Human Microvascular Endothelial Cells 1 by iTRAQ Reveals Palladin to be a New Biomarker During TGF-?1 Induced Endothelial Mesenchymal Transition

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