News
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12 2015
Journal of Investigative Dermatology published our collaborative work on Kinastrin mutations in basal cell carcinoma spearheaded by the Sarin labScott Atwood
KNSTRN encodes a kinetochore-associated protein that is an essential
component of the mitotic spindle and is required for faithful chromosomal segregation during mitosis. It is expressed in a broad range of tissues, including skin, and its mutations have been detected in both squamous cell
carcinoma (SCC) and melanoma, leading to its recent classification as an oncogene. Alongside recent data offering a role for KNSTRN in SCC and melanoma, our work supports the classification of KNSTRN as an oncogene and
an important contributor to the pathogenesis of malignancies related to UV-exposure. In both SCC and BCC, mutant KNSTRN disrupts sister chromatid cohesion and promotes genomic instability in functional assays. However,
unlike in SCC, KNSTRN mutations in BCC appear to occur late in disease progression and are preferentially found in advanced tumors.
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10 2015
Tuyen Nguyen has been awarded the GAANN fellowship! Congratulations! Scott Atwood
Tuyen Nguyen was awarded the Graduate Assistance in Areas of National Need (GAANN) fellowship at UC Irvine. This prestigious award is part of an exciting new educational initiative that provides enhanced training in research and teaching for doctoral students. The primary objectives of the GAANN Program in the Biological Sciences are to recruit and retain talented graduate students, provide a graduate education and apprenticeship model that allows for rigorous and integrated research and teaching experiences, and prepare students to assume post-graduate leadership roles in biological research and education – a designated area of national need.
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9 2015
Cancer Research published our collaborative work on RAS-MAPK-driven drug resistance in HH-dependent cancers spearheaded by the Segal labScott Atwood
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 mechanisms of resistance remain
poorly understood. Using new medulloblastoma models, we identify two distinct paradigms of resistance to Smo inhibition. Sufu mutations lead to maintenance of the Shh pathway in the presence of Smo inhibitors. Alternatively,
activation of the RAS/MAPK pathway circumvents Shh pathway-dependency, drives tumor growth and enhances metastatic behavior. Strikingly, in BCC patients treated with Smo inhibitor, squamous cell cancers with RAS/MAPK activation
emerged from the antecedent BCC tumors. Together these findings reveal a critical role of RAS/MAPK pathway in drug resistance and tumor evolution of Shh pathway-dependent tumors.
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8 2015
Michael Drummond has joined the lab! Scott Atwood
Michael Drummond has joined the lab as a postdoctoral research fellow. Mike performed his graduate work in the lab of Ken Prehoda at the University of Oregon. His thesis work was on aPKC regulation in Drosophila neuroblasts where he identified the lipid contributions to aPKC localization and activity. He plans to continue working on aPKC regulation in mouse skin and basal cell carcinoma. Welcome to the lab!
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8 2015
Journal of Investigative Dermatology published our paper on genetic diversity in basal cell carcinoma Scott Atwood
Genomic analysis by our group and others have revealed that basal cell carcinomas (BCCs) carry a high frequency of non-silent mutations, yet how these mutations
confer selective tumor growth without deleterious effects remains poorly understood. Here, we find that Smoothened (SMO) mutations are frequently found across many cancers with drug-resistant BCCs bearing the highest rate of recurrent
mutations at 66%. We identify 28 mutations in SMO that were either recurrent, overlap with the COSMIC database, or were region-specific and interrogated their ability to promote HH signaling. We find that each mutation exerts either neutral
or negative effects on HH signaling with a subset of mutations abolishing SMO function. This was surprising as nearly half of the residues lie in the pivot regions or the ligand binding pocket of SMO, which control protein activity and
binding of SMO inhibitors, respectively. Our data supports a model where tumors are permissive to genetic mutations, generating many genetically diverse clones that compete as a way to grow. As we expand our use of high-throughput sequencing
of tumors for personalized medicine, our results present a cautionary tale to functionally validate any mutation before concluding their ability to exert oncogenic effects.
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7 2015
Kerrigan Blake, Rachel Chow, and Tuyen Nguyen have joined the lab! Scott Atwood
Three excellent graduate students have decided to pursue their thesis work in the lab. Kerrigan Blake came from the
MCSB Program to work on zinc finger transcription factor regulation. Rachel Chow and Tuyen Nguyen came from the
CMB Program and are working on how basal cell carcinomas develop drug resistance to standard therapies. Welcome to the lab!
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7 2015
Gordon Research Seminar and Conference on Epithelial Differentiation and KeratinizationScott Atwood
I'll be chairing the Gordon Research Seminar on Epithelial Differentiation and
Keratinization at the Sunday River Resort in Newry, Maine July 11-12. The GRS is a unique forum for graduate students, post-docs, and other scientists with comparable levels of experience and education to present and exchange
new data and cutting edge ideas. This meeting will survey emerging themes in epithelial signaling and include how signaling events lead to the development and evolution of skin and its niche, the genetic and epigenetic landscape
of skin development and homeostasis, how changes in signaling lead to skin dysfunction and the cutting-edge therapeutics to treat epithelial diseases. Dr. Dennis Roop will kick off the meeting describing stem cell therapies for
inherited skin diseases and Dr. Valentina Greco will conclude by offering insight into mentoring as a business model.
Please apply before April 11, 2015 to be considered for a talk at the meeting. I would also encourage you to apply to the Gordon Research Conference to be held July 12-17 right after the end of the GRS meeting. -
5 2015
Some comments about our SMO drug resistance story in Cancer Cell Scott Atwood
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5 2015
Society for Investigative Dermatology Annual Meeting Scott Atwood
I will be giving a talk on how genetic diversity in basal cell carcinoma can give rise to drug resistance at the 2015 Society for Investigative Dermatology
(SID) annual meeting in Atlanta, Georgia. The SID mission is to advance and promote the sciences relevant to skin health and disease through education, advocacy and scholarly exchange of scientific information. Working under this mission,
the SID is committed to fostering scientific careers for young researchers, increasing public and government awareness about the need to support skin research, working with industry in the development of new technologies and cooperative ventures,
and encouraging scientific collaborations among researchers worldwide.
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4 2015
My lab officially opens in the Developmental and Cell Biology department at UCI!Scott Atwood
The Atwood lab doors open April 1, 2015 in the Developmental and Cell Biology department.
We will continue to study how cells choose their fate during development and cancer. I'm now accepting applications from talented graduate students and postdocs to join my lab. Just send me an email. Go Anteaters!!!
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3 2015
SMO drug resistance in the news Scott Atwood
Among people with advanced basal cell carcinomas who see their skin cancers shrink or disappear in response to a common drug therapy, about 20 percent will
relapse within months as the cancer cells become resistant to the treatment. The situation is frustrating to both patients and their physicians. Now, researchers at the Stanford University School of Medicine have identified specific mutations
in the cancer cells that confer resistance to the drug, vismodegib, which is sold under the brand name Erivedge. They’ve also shown that another class of drug, called a Gli antagonist, may be able to successfully tackle even vismodegib-resistant
cancers. The finding could hasten the use of Gli antagonists in the clinic, they said.
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3 2015
Cancer Cell previews our drug resistance paper Scott Atwood
In this issue of Cancer Cell, two complementary papers by Atwood and colleagues and Sharpe and colleagues show that basal cell carcinomas resistant to the
Smoothened (SMO) inhibitor vismodegib frequently harbor SMO mutations that limit drug binding, with mutations at some sites also increasing basal SMO activity.
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3 2015
Cancer Cell published our paper describing how the majority of basal cell carcinomas aquire drug resistance Scott Atwood
Advanced basal cell carcinomas (BCCs) frequently acquire resistance to Smoothened (SMO) inhibitors through unknown mechanisms. Here, we identify
SMO mutations in 50% (22/44) of resistant BCCs and show that these mutations maintain Hedgehog signaling in the presence of SMO inhibitors. Alterations include four ligand binding pocket mutations defining sites of inhibitor binding and
four variants confering constitutive activity and inhibitor resistance, illuminating pivotal residues that ensure receptor autoinhibition. These genetic alterations suggest that SMO functions similarly to other class A GPCRs despite less
than 10% sequence identity. In the presence of a SMO inhibitor, tumor cells containing both classes of SMO mutants effectively compete against cells containing wild type SMO. Finally, we show that both classes of SMO variants respond to
aPKC-ι/λ or GLI2 inhibitors that operate downstream of SMO, setting the stage for the clinical use of GLI antagonists.
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