Scott Atwood, PhD

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). In this issue, Kang et al. 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. Read more.

 

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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. Read more.

 

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. Read more.

 

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! Read more.

 

I will be giving a plenary talk and presenting a poster 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. Read more.