A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren's disease.

Dupuytren's disease (DD) is a highly heritable fibrotic disorder of the hand with incompletely understood etiology. A number of genetic loci, including Wnt signaling members, have been previously identified. Our overall aim was to identify novel genetic loci, to prioritize genes within the loci for functional studies, and to assess genetic correlation with associated disorders. We performed a meta-analysis of six DD genome-wide association studies from three European countries and extensive bioinformatic follow-up analyses. Leveraging 11,320 cases and 47,023 controls, we identified 85 genome-wide significant single nucleotide polymorphisms in 56 loci, of which 11 were novel, explaining 13.3-38.1% of disease variance. Gene prioritization implicated the Hedgehog and Notch signaling pathways. We also identified a significant genetic correlation with frozen shoulder. The pathways identified highlight the potential for new therapeutic targets and provide a basis for additional mechanistic studies for a common disorder that can severely impact hand function.

Dupuytren's disease: a localised and accessible human fibrotic disorder.

We review the biology of Dupuytren's disease (DD), a common localised fibrotic disorder of the hand. The disease develops through a complex interplay of genetic and environmental factors, and epigenetic signalling. The early-stage disease nodules comprise a complex milieu of stromal and immune cells which interact to promote disease development. Recently, inhibition of tumour necrosis factor (TNF) locally resulted in softening and a decrease in nodule size, potentially controlling disease progression. Unlike fibrotic disorders of the visceral organs, the easy access to tissue in DD patients enables dissection of the cellular landscape and molecular signalling pathways. In addition, the study of DD may have wider benefits in enhancing our understanding of less-accessible fibrotic tissues.

A vasculature niche orchestrates stromal cell phenotype through PDGF signaling: Importance in human fibrotic disease.

SignificanceTissue fibrotic diseases, for example of the liver and lung, represent a huge unmet medical need. In this study, using single-cell RNA sequencing, cytometry by time of flight (CyTOF), tissue imaging, and functional assays, we identify a complex vascular niche in Dupuytren's disease (DD), a common localized fibrotic condition of the palm, where early-disease-stage tissue can be accessed readily. We uncover a population of myofibroblast precursors within the pericyte compartment and demonstrate that the endothelium instructs the differentiation of functionally distinct stromal cells, thereby orchestrating discrete microenvironments in the fibrotic milieu. Together, these findings provide a basis for the concept of targeting blood vessel signaling to control the progression of human fibrosis.

Cellular census of human fibrosis defines functionally distinct stromal cell types and states.

Fibrotic disorders are some of the most devastating and poorly treated conditions in developed nations, yet effective therapeutics are not identified for many of them. A major barrier for the identification of targets and successful clinical translation is a limited understanding of the human fibrotic microenvironment. Here, we construct a stromal cell atlas of human fibrosis at single cell resolution from patients with Dupuytren's disease, a localized fibrotic condition of the hand. A molecular taxonomy of the fibrotic milieu characterises functionally distinct stromal cell types and states, including a subset of immune regulatory ICAM1+ fibroblasts. In developing fibrosis, myofibroblasts exist along an activation continuum of phenotypically distinct populations. We also show that the tetraspanin CD82 regulates cell cycle progression and can be used as a cell surface marker of myofibroblasts. These findings have important implications for targeting core pathogenic drivers of human fibrosis.

Author Correction: Cellular census of human fibrosis defines functionally distinct stromal cell types and states.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Single cell force profiling of human myofibroblasts reveals a biophysical spectrum of cell states.

Mechanical force is a fundamental regulator of cell phenotype. Myofibroblasts are central mediators of fibrosis, a major unmet clinical need characterised by the deposition of excessive matrix proteins. Traction forces of myofibroblasts play a key role in remodelling the matrix and modulate the activities of embedded stromal cells. Here, we employ a combination of unsupervised computational analysis, cytoskeletal profiling and single cell traction force microscopy as a functional readout to uncover how the complex spatiotemporal dynamics and mechanics of living human myofibroblast shape sub-cellular profiling of traction forces in fibrosis. We resolve distinct biophysical communities of myofibroblasts, and our results provide a new paradigm for studying functional heterogeneity in human stromal cells.

Papillary breast cancer: A retrospective single-centre clinical study.

Papillary carcinoma (PC) of the breast is a rare malignancy that accounts for 0.5%-1% of breast cancers. PC remains an understudied cancer, and we still require further information on its behaviour, staging and management. In particular, a significant proportion of PC cases still undergo sentinel lymph node biopsy without clear empirical justification. In the present study, we provide a valuable cohort of 44 PC patients and examine the clinicopathological features and outcome of loco-regional staging. Our results provide important insights into the behaviour of PC and suggest SLNB may be spared in this condition. Crucially, we show only one histologically confirmed PC case had evidence of nodal metastasis. In addition, up to 5 years postsurgery, no patient in our cohort died from their cancer. Together, our results support further work in the utility of SLNB in PC and highlight the favourable prognosis of this tumour. We propose SLNB should not be routinely indicated for patients with PC treated with breast conservation, and future studies should aim to incorporate prospective data to help inform optimal management of PC.

Identification of TNFR2 and IL-33 as therapeutic targets in localized fibrosis.

Dissecting the molecular landscape of fibrotic disease, a major unmet need, will inform the development of novel treatment strategies to target disease progression and identify desperately needed therapeutic targets. Here, we provide a detailed single-cell analysis of the immune landscape in Dupuytren's disease, a localized fibrotic condition of the hand, and identify a pathogenic signaling circuit between stromal and immune cells. We demonstrate M2 macrophages and mast cells as key cellular sources of tumor necrosis factor (TNF) that promotes myofibroblast development. TNF acts via the inducible TNFR2 receptor and stimulates interleukin-33 (IL-33) secretion by myofibroblasts. In turn, stromal cell IL-33 acts as a potent stimulus for TNF production from immune cells. Targeting this reciprocal signaling pathway represents a novel therapeutic strategy to inhibit the low-grade inflammation in fibrosis and the mechanism that drives chronicity.

Osteoradionecrosis of the Temporal Bone Leading to Cerebellar Abscess.

Squamous cell carcinoma of the temporal bone is a rare and destructive malignancy and represents both diagnostic and therapeutic challenge. The complex regional anatomy of the temporal bone requires equally intricate surgical techniques to adequately resect the tumour mass during surgical excision. Adjuvant radiotherapy is offered to patients with advanced disease and has been showed to confer a survival benefit in carefully selected patients. One feared complication of radiotherapy is osteoradionecrosis and is a major obstacle faced in the treatment of head and neck cancers. The case presented here is a rare example of a patient who was successfully treated for SCC of the temporal with both surgical resection and adjuvant radiotherapy who subsequently developed two major complications: first, osteoradionecrosis of the temporal bone that leads to penetrating osteomyelitis; second, the formation of a large cerebellar abscess that required surgical drainage. This case is a rare example of the complications that are possible following radiotherapy to the head and the close follow-up that is required in patients.