
Anthony OroStanford University | SU · Department of Dermatology
Anthony Oro
MD/PhD
About
185
Publications
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Introduction
Additional affiliations
January 1995 - December 1998
June 1985 - May 1993
Salk Institute / Howard Hughes Medical Institute
Position
- Graduate Student MD/PhD
January 1999 - present
Publications
Publications (185)
While cell fate determination and maintenance are important in establishing and preserving tissue identity and function during development, aberrant cell fate transition leads to cancer cell heterogeneity and resistance to treatment. Here, we report an unexpected role for the transcription factor p63 (Trp63/TP63) in the fate choice of the squamous...
Cancer-associated inflammation is a double-edged sword possessing both pro- and anti-tumor properties through ill-defined tumor-immune dynamics. While we previously identified a carcinoma tumor-intrinsic resistance pathway, basal-to-squamous cell carcinoma transition, here, employing a multipronged single-cell and spatial-omics approach, we identif...
We present Dystrophic Epidermolysis Bullosa Cell Therapy (DEBCT), a scalable platform producing autologous organotypic iPS cell-derived induced skin composite (iSC) grafts for definitive treatment. Clinical-grade manufacturing integrates CRISPR-mediated genetic correction with reprogramming into one step, accelerating derivation of COL7A1-edited iP...
We present the Manatee variational autoencoder model to predict transcription factor (TF) perturbation-induced transcriptomes. We demonstrate that the Manatee in silico perturbation analysis recapitulates target transcriptomic phenotypes in diverse cellular lineage transitions. We further propose the Manatee in silico screening analysis for priorit...
Human pluripotent stem cell-derived tissue engineering offers great promise in designer cell-based personalized therapeutics. To harness such potential, a broader approach requires a deeper understanding of tissue-level interactions. We previously developed a manufacturing system for the ectoderm-derived skin epithelium for cell replacement therapy...
While cell fate determination and maintenance are important in establishing and preserving tissue identity and function during development, aberrant cell fate transition leads to cancer cell heterogeneity and resistance to treatment. Here, we report an unexpected role for the transcription factor p63 (Trp63/TP63) in the fate choice of squamous vers...
Genome-wide association studies have identified many loci associated with hair and skin disease, but identification of causal variants requires deciphering of gene-regulatory networks in relevant cell types. We generated matched single-cell chromatin profiles and transcriptomes from scalp tissue from healthy controls and patients with alopecia area...
While basal cell carcinomas (BCCs) arise from ectopic hedgehog pathway activation and can be treated with pathway inhibitors, sporadic BCCs display high resistance rates while tumors arising in Gorlin syndrome patients with germline Patched (PTCH1) mutations are uniformly suppressed by inhibitor therapy. In rare cases, Gorlin syndrome patients on l...
Cancer immunotherapies have revolutionized treatment but have shown limited success as single-agent therapies highlighting the need to understand the origin, assembly, and dynamics of heterogeneous tumor immune niches. Here, we use single-cell and imaging-based spatial analysis to elucidate three microenvironmental neighborhoods surrounding the het...
Background
Gene editing in induced pluripotent stem (iPS) cells has been hailed to enable new cell therapies for various monogenetic diseases including dystrophic epidermolysis bullosa (DEB). However, manufacturing, efficacy and safety roadblocks have limited the development of genetically corrected, autologous iPS cell-based therapies.
Methods
We...
Ectodermal dysplasias including skin abnormalities and cleft lip/palate result from improper surface ectoderm (SE) patterning. However, the connection between SE gene regulatory networks and disease remains poorly understood. Here, we dissect human SE differentiation with multiomics and establish GRHL2 as a key mediator of early SE commitment, whic...
Improved response to canonical therapies requires a mechanistic understanding of dynamic tumor heterogeneity by identifying discrete cellular populations with enhanced cellular plasticity. We have previously demonstrated distinct resistance mechanisms in skin basal cell carcinomas, but a comprehensive understanding of the cellular states and marker...
Genome-wide association studies (GWAS) of hair and skin disease have identified many genetic variants associated with disease phenotypes, but identifying causal variants and interpreting their function requires deciphering gene-regulatory networks in disease-relevant cell types. To this end, we generated matched scRNA- and scATAC-seq profiles of hu...
The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Usi...
While squamous transdifferentiation within subpopulations of adenocarcinomas represents an important drug resistance problem, its underlying mechanism remains poorly understood. Here, using surface markers of resistant basal cell carcinomas (BCCs) and patient single-cell and bulk transcriptomic data, we uncover the dynamic roadmap of basal to squam...
The repurposing of biomedical data is inhibited by its fragmented and multi-formatted nature that requires redundant investment of time and resources by data scientists. This is particularly true for Type 1 Diabetes (T1D), one of the most intensely studied common childhood diseases. Intense investigation of the contribution of pancreatic β-islet an...
Purpose:
The mainstay of treatment for basal cell carcinoma (BCC) is surgical excision, which can result in significant associated morbidity, particularly for patients with recurrent tumors. We previously conducted a drug repositioning screen using molecular data from human BCCs and identified histone deacetylase (HDAC) inhibitors as a potential t...
The nucleoskeleton has been associated with partitioning the genome into active and inactive compartments that dictate local transcription factor (TF) activity. However, recent data indicate that the nucleoskeleton and TFs reciprocally influence each other in dynamic TF trafficking pathways through the functions of LEM proteins. While the conserved...
The perivascular microenvironment helps maintain stem cells in many tissues. We sought to determine if there is a perivascular niche for hair follicle stem cells. The association of vessels and follicle progenitor cells began by embryonic day 14.5 (E14.5), when nascent hair placodes had blood vessels approaching them. By birth, a vascular annulus s...
Spinocerebellar ataxias (SCA) are a genetically heterogeneous family of cerebellar neurodegenerative diseases characterized by abnormal firing of Purkinje neurons and degeneration. We recently demonstrated the slowed firing rates seen in several SCAs share a common etiology of hyper-activation of the Src family of non-receptor tyrosine kinases (SFK...
Nonsurgical therapies are needed for patients with multiple basal cell carcinomas (BCCs). Vismodegib reduces BCCs but causes severe adverse effects and cannot be formulated as a topical treatment.¹,2 Oral itraconazole is a weaker hedgehog (HH) pathway inhibitor and has shown evidence of reduced BCCs in Ptch1+/− mice and in 1 phase 2 trial.³⁻⁵ Howev...
Basal cell carcinomas (BCCs) rely on Hedgehog (HH) pathway growth signal amplification by the microtubule-based organelle, the primary cilium. Despite naive tumor responsiveness to Smoothened inhibitors (Smo ⁱ ), resistance in advanced tumors remains common. Although the resistant BCCs usually maintain HH pathway activation, squamous cell carcinoma...
Basosquamous carcinoma (BSC) is an aggressive skin neoplasm with the features of both basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). While genetic drivers of BCC and SCC development have been extensively characterized, BSC has not been well studied, and it remains unclear whether these tumors originally derive from BCC or SCC. In add...
Significance
The Src family of nonreceptor tyrosine kinases (SFK) is essential for nervous system function and may contribute to neurodegeneration. Spinocerebellar ataxias (SCAs) are neurodegenerative diseases in which Purkinje neurons fire irregularly and degenerate leading to motor problems. We show that the SFK suppressor Missing-in-metastasis (...
Human embryonic stem cell (hESC) differentiation promises advances in regenerative medicine1–3, yet conversion of hESCs into transplantable cells or tissues remains poorly understood. Using our keratinocyte differentiation system, we employ a multi-dimensional genomics approach to interrogate the contributions of inductive morphogens retinoic acid...
Understanding transcription factor navigation through the nucleus remains critical for developing targeted therapeutics. The GLI1 transcription factor must maintain maximal Hedgehog pathway output in basal cell carcinomas (BCCs), and we have previously shown that resistant BCCs increase GLI1 deacetylation through atypical protein kinase Cι/λ (aPKC)...
Innate DNA repair mechanisms play a critical role in protecting skin keratinocytes from UV mutagenesis and skin cancer development. We hypothesized that individuals who develop frequent skin cancers may harbor germline defects in DNA repair genes and have increased predisposition to internal malignancies. We enrolled 61 patients with unusually freq...
Primary cilia are polarized organelles that allow detection of extracellular signals such as Hedgehog (Hh). How the cytoskeleton supporting the cilium generates and maintains a structure that finely tunes cellular response remains unclear. Here, we find that regulation of actin polymerization controls primary cilia and Hh signaling. Disrupting acti...
Tissue development results from lineage-specific transcription factors (TF) programming a dynamic chromatin landscape through progressive cell fate transitions. Here, we interrogate the epigenomic landscape during epidermal differentiation and create an inference network that ranks the coordinate effects of TF-accessible regulatory element-target g...
Human embryonic stem cell (hESC) differentiation promises advances in regenerative medicine(1-3), yet conversion of hESCs into tissues such as keratinocytes requires a better understanding of epigenetic interactions between the inductive morphogens retinoic acid (RA) and bone morphogenetic protein 4 (BMP), and the master regulator p63(4,5). Here we...
The genetically heterogeneous Spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of non-receptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reve...
Basal cell carcinoma (BCC) is the most frequent human cancer and is becoming an important health problem in an ageing population. Based on their clinical and histological characteristics, thick BCC are typically divided into low-risk nodular and high-risk infiltrative subtypes, although the underlying mechanisms are poorly understood. We have ident...
Hedgehog pathway–dependent cancers can escape Smoothened (SMO) inhibition through mutations in genes encoding canonical hedgehog pathway components; however, around 50% of drug-resistant basal cell carcinomas (BCCs) lack additional variants of these genes. Here we use multidimensional genomics analysis of human and mouse drug-resistant BCCs to iden...
We will describe for the first time the optimization and pharmacological characterisation of azaquinazoline based ATP-competitive inhibitors of the aPKC isoforms. The serine/threonine kinase protein kinase C iota (PKCι) and protein kinase C zeta (PKCζ) together define the atypical sub-class of the protein kinase C superfamily (aPKC). Both isoforms...
Advanced basal cell carcinomas (BCCs) circumvent Smoothened (SMO) inhibition by activating GLI transcription factors to sustain the high levels of Hedgehog (HH) signaling required for their survival. Unfortunately, there is a lack of efficacious therapies. We performed a gene expression-based drug repositioning screen in silico and identified the F...
Whether invasive tumor phenotypes like EMT arise from oncogenic drivers or from priming of the pre-tumor cell of origin remains unknown. In this issue of Cell Stem Cell, Latil et al. (2017) show that the pre-tumor niche establishes a chromatin state predisposing squamous cell carcinomas to undergo EMT and metastasis, suggesting that the pre-tumor e...
The Hedgehog pathway is a potent regulator of cellular growth and plays a central role in the development of many cancers including basal cell carcinoma (BCC). The majority of BCCs arise from mutations in the Patched receptor resulting in constitutive activation of the Hedgehog pathway. Secondary driver mutations promote BCC oncogenesis and occur f...
SUFU variants that do not increase GLI1 transcript levels have normal protein function.
HEK-293T cells were co-transfected with SUFU:TAP and GFP:GLI and co-immunoprecipitated to determine interaction between the two proteins. This figure depicts the results for the SUFU variants that showed no change in function at the mRNA level.
(EPS)
Nuclear/cytoplasmic fractionation assay confirms SUFU variants’ loss of function.
3T3 cells were transfected with peGFP-C1 SUFU constructs. The cells were fractionated and probed for SUFU, GLI1, and Lamin A + C, a nuclear loading control in order to assay for nuclear depletion of GLI1 in the presence of a functional SUFU. Asterisks indicate the cor...
Background:
Alopecia areata (AA) is an autoimmune disease characterized by hair loss mediated by CD8+T cells. There are no reliably effective therapies for AA. Based on recent developments in the understanding of the pathomechanism of AA, JAK inhibitors appear to be a therapeutic option; however, their efficacy for the treatment of AA has not been...
Cosmetic skin and hair care compositions for enhancing the growth and appearance of mammalian hair in an individual are provided, which compositions comprise a dose of an R-spondin agonist effective to promote anagen phase of the hair cycle.
Wnt signaling is required for development of the hair follicle, and for inciting the growth (anagen) phase of the hair cycle. Most strategies to enhance Wnt signaling for hair growth create a state of constitutive Wnt activation, which leads to neoplastic transformation of the epithelial hair matrix. Using Axin2(LacZ/+) and Axin2(Cre/+)R26R(mTmG/+)...
Importance
Tumor resistance is an emerging problem for Smoothened (SMO) inhibitor–treated metastatic basal cell carcinoma (BCC). Arsenic trioxide and itraconazole antagonize the hedgehog (HH) pathway at sites distinct from those treated by SMO inhibitors.Objective
To determine whether administration of intravenous arsenic trioxide and oral itraco...
Purpose: To assess the tumor response to the smoothened (SMO) inhibitor, sonidegib (LDE225), in patients with an advanced basal cell carcinoma (BCC) resistant to treatment with vismodegib (GDC0449).
Experimental Design: Nine patients with an advanced BCC that was previously resistant to treatment with vismodegib were given sonidegib in this invest...
Purpose: To assess the tumor response to the smoothened (SMO) inhibitor, sonidegib (LDE225), in patients with an advanced basal cell carcinoma (BCC) resistant to treatment with vismodegib (GDC0449).
Experimental Design: Nine patients with an advanced BCC that was previously resistant to treatment with vismodegib were given sonidegib in this invest...
Purpose:
To assess the tumor response to the smoothened (SMO) inhibitor, sonidegib (LDE225), in patients with an advanced basal cell carcinoma (BCC) resistant to treatment with vismodegib (GDC0449).
Experimental design:
Nine patients with an advanced BCC that was previously resistant to treatment with vismodegib were given sonidegib in this inve...
Abbreviations: BCC, basal cell carcinoma; CNV, copy-number variation; COSMIC, Catalogue of Somatic Mutations in Cancer; HH, sonic hedgehog pathway; KNSTRN, kinetochore-localized astrin/SPAG5 binding protein; PTCH1, patched 1; SCC, squamous-cell carcinoma; SMO, smoothened; TP53, tumor protein 53
Basal cell carcinomas (BCCs) are locally invasive epithelial tumors that are caused by activating mutations in the Hedgehog (HH) pathway, typically through the loss of the receptor Patched1 or by activating the G-protein-coupled receptor Smoothened (SMO). Genomic analysis by our group and others have revealed that BCCs are typically diploid and car...
Aberrant Shh signaling promotes tumor growth in diverse cancers. The importance of Shh signaling is particularly evident in medulloblastoma and basal cell carcinoma (BCC), where inhibitors targeting the Shh pathway component Smoothened (Smo) show great therapeutic promise. However, the emergence of drug resistance limits long-term efficacy and the...
Abbreviations: BCC, basal cell carcinoma; HH, Hedgehog; MEF, mouse embryonic fibroblast; SMO, Smoothened; SNV, single-nucleotide variant; WT, wild type
Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here we identify SMO mutations in 50% (22 of 44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defini...
Basal cell carcinomas (BCCs) are the most common cancers in the United States, with an annual national incidence of ~2 million (Lomas et al., 2012). Although the majority are localized to the skin and cured by surgery, in rare cases, they can progress to advanced and metastatic tumors that result in severe morbidity and death. BCCs are typically ca...