News
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9 2013
Journal of Investigative Dermatology published our paper on genes associated with skin youthfullness Scott Atwood
To identify genes that promote facial skin youthfulness (SY), a genome-wide association study on an Ashkenazi-Jewish discovery group
(n=428) was performed. 6 SNPs were interrogated in a replication group (n=436) with confirmation of rs6975107, an intronic region of KCND2. A second replication group (n=371) confirmed rs318125, downstream of DIAPH2 and
rs7616661, downstream of EDEM1. DIAPH2 has been associated with premature ovarian insufficiency, an aging phenotype in humans. EDEM1 associates with lifespan in animal models, though not humans.
KCND2 is expressed in human skin, but has not been associated with aging. These genes represent new candidate genes to study the molecular basis of healthy skin aging.
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5 2013
JAMA Dermatology published our paper on neoadjuvant vismodegib therapy to treat BCC patients Scott Atwood
Vismodegib is useful to treat locally advanced or metastatic basal cell carcinomas (BCCs), but its use as a neoadjuvant to shrink BCCs before
surgery is unclear. This case illustrates the role of vismodegib as a neoadjuvant agent and highlights the fact that a patient with Gorlin syndrome can develop resistant BCCs while taking vismodegib.
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5 2013
International Investigative Dermatology Meeting Scott Atwood
I will be giving a plenary talk on aPKC function in drug-resistant basal cell carcinoma on May 10 at the International Investigative Dermatology (IID)
meeting in Edinburgh, Scotland. I have also been awarded the IID Trainee Retreat Travel Fellowship. The IID meeting brings together the ESDR, SID, and JSID every five years to showcase exciting science, collegiality, and social
interactions. Internationally renowned scientists will join the meeting and guarantee a stimulating exchange of the latest scientific information. Edinburgh was selected as the meeting venue for the IID meeting in 2013, because the
city is well-connected to international travel and offers a multitude of congress facilities, accomodation, as well as a stimulating atmosphere. Edinburgh itself is a beautiful ancient city that reflects a lot of Old Europe in a
charming way. Besides being a World Heritage City, Edinburgh also offers a special Scottish touch that is appreciated by many tourists every year and that makes the city one of the prime destinations for travellers in Britain.
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4 2013
Interesting role for Ptch1 in SCC development Scott Atwood
The tumor suppressor Patched1 (Ptch1) possesses well-described roles in regulating sonic hedgehog (SHH) signaling in the skin and preventing
the formation of basal cell carcinomas (BCCs). Kang and colleagues extend their previous work to show that a naturally occurring allele of Ptch1
found in FVB mice promotes early squamous cell carcinoma (SCC) growth without aberrant activation of the SHH pathway. The study reveals new roles for Ptch1 that lie at the nexus between BCC and SCC formation.
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3 2013
Some comments about our aPKC/Gli story in Nature Scott Atwood
Nature Reviews Cancer highlight: Read More
F1000 Prime Recommendation:
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2 2013
aPKC in the news Scott Atwood
The knock against the groundbreaking skin cancer drug Erivedge, which was developed by Curis Inc. (NASDAQ: CRIS) and South San Francisco-based Genentech Inc., is that the cancer can find a way around the targeted therapy. But in a paper Wednesday in the journal Nature, Stanford University researchers say they identified another way of blocking the so-called Hedgehog pathway. That could open the door to new treatments for basal cell carcinoma as well as aggressive tumors in pancreatic cancer, small cell lung cancer and colon cancer. Erivedge zeroes in on a protein dubbed Smoothened, which is a player near the beginning of the Hedgehog pathway. But Stanford dermatology professor Dr. Anthony Oro, postdoctoral scholar Scott Atwood and others believe that targeting another protein that they discovered, called aPKC, could block a positive feedback loop between aPKC and Gli, which is activated by Smoothened. Read More
Hailed as a major step forward in the effort to develop targeted cancer therapies, a recently approved drug for the most common type of skin cancer
has been a mixed blessing for patients. Although the initial response is
usually dramatic, the tumors often recur as the cancer becomes resistant to treatment. Now researchers at the Stanford University School of Medicine have identified a second way to block the activity of the signaling cascade,
called the Hedgehog pathway, that is abnormally active in these cancers. The researchers hope the new approach may not only one day help patients with tumors that have become resistant to the first drug, vismodegib
(marketed as Erivedge), but may also provide a novel combination therapy for newly diagnosed tumors that may be more effective than either treatment alone.
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2 2013
Nature published our paper on aPKC-dependent Gli activation in basal cell carcinomas Scott Atwood
Growth of basal cell carcinomas (BCCs) requires high levels of hedgehog (HH) signalling through the transcription factor GLI1. Although inhibitors
of membrane protein smoothened (SMO) effectively suppress
HH signalling, early tumour resistance illustrates the need for additional downstream targets for therapy. Here we identify atypical protein kinase C iota/lambda (aPKC) as a novel GLI regulator in mammals.
aPKC and its polarity signalling partners co-localize at the centrosome and form a complex with missing-in-metastasis (MIM), a scaffolding protein that potentiates HH signalling. Genetic or pharmacological loss of aPKC
function blocks HH signalling and proliferation of BCC cells. Prkci is a HH target gene that forms a positive feedback loop with GLI and exists at increased levels in BCCs. Genome-wide transcriptional profiling shows
that aPKC and SMO control the expression of similar genes in tumour cells. aPKC functions downstream of SMO to phosphorylate and activate GLI1, resulting in maximal DNA binding and transcriptional activation. Activated aPKC
is upregulated in SMO-inhibitor-resistant tumours and targeting aPKC suppresses signalling and growth of resistant BCC cell lines. These results demonstrate that aPKC is critical for HH-dependent processes and implicates aPKC
as a new, tumour-selective therapeutic target for the treatment of SMO-inhibitor-resistant cancers. Congratulations to all the authors on a job well done!
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2 2013
Journal of Visualized Experiments published our protocol on genetic manipulation of hair regeneration in mice Scott Atwood
Hair follicle morphogenesis, a complex process requiring interaction between epithelia-derived keratinocytes and the underlying mesenchyme,
is an attractive model system to study organ development and tissue-specific signaling. Although hair follicle development is genetically tractable, fast and reproducible analysis of factors essential for this process remains
a challenge. Here we describe a procedure to generate targeted overexpression or shRNA-mediated knockdown of factors using lentivirus in a tissue-specific manner. Using a modified version of a hair regeneration model, we can
achieve robust gain- or loss-of-function analysis in primary mouse keratinocytes or dermal cells to facilitate study of epithelial-mesenchymal signaling pathways that lead to hair follicle morphogenesis. We describe how to isolate
fresh primary mouse keratinocytes and dermal cells, which contain dermal papilla cells and their precursors, deliver lentivirus containing either shRNA or cDNA to one of the cell populations, and combine the cells
to generate fully formed hair follicles on the backs of nude mice. This approach allows analysis of tissue-specific factors required to generate hair follicles within three weeks and provides a fast and convenient
companion to existing genetic models. View video
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