A hearty congratulations to the following members who have received SU2C, MRA team science, and MRA young investigator awards.
SU2C Philip A. Sharp Award
Congratulations to Drs. Antoni Ribas and Muhammed Murtaza for winning the Stand Up to Cancer Philip A. Sharp Award for their project entitled “Fingerprinting the systemic microbiome in plasma to predict immunotherapy outcomes in melanoma”
2016 MRA Team Science Awards
Congratulations to Drs. Boris Bastian (University of California, San Francisco), Iwei Yeh (University of California, San Francisco), and Reinhard Dummer (University of Zurich) for winning the Melanoma Research Alliance Team Science Award in Acral Melanoma for their project entitled “Developing rational therapeutic approaches for acral melanoma”.
Congratulations to Drs. Marcus Bosenberg (Yale University), Susan Kaech (Yale University), Richard Kibbey (Yale University), and Sidi Chen (Yale University) for winning the Sokoloff Family-Melanoma Research Alliance Team Science Award for their project entitled “Metabolic regulation of the tumor immune response by the microenvironment”.
Congratulations to Drs. David E. Fisher (Massachusetts General Hospital, Dana-Farber Cancer Institute) and Frank Schoenen (University of Kansas) for winning the Melanoma Research Alliance Team Science Award for their project entitled “Small-molecule targeting of the lineage-specific melanoma oncogene MITF”.
Congratulations to Drs. Roger Lo (University of California, Los Angeles), Jeffrey Alan Sosman (Northwestern University, and Douglas Johnson (Vanderbilt University Medical Center) for winning the Leveraged Finance Fights Melanoma-MRA Team Science Award for their project entitled “ Determinants of response or resistance to PD-1/PD-L1 targeted therapy.
Congratulations to Drs. Yardena Samuels (Weizmann Institute of Science), Jennifer Wargo (University of Texas M.D. Anderson Cancer Center), Arie Admon (Technion Israel Institute of Technology), and Ravid Straussman (Weizmann Institute of Science) for winning the Saban Family Foundation MRA Team Science Award for their project entitled “Identifying somatic and microbial neo-antigens associated with melanoma responses”.
Congratulations to Drs. Gary Schwartz (Columbia University Medical Center), Andrew Aplin (Thomas Jefferson University), Anna Catherine Pavlick (New York University School of Medicine), Hanyin Cheng (Thomas Jefferson University), and Melissa Wilson (New York University School of Medicine) for winning the MRA Team Science Award in Uveal Melanoma in Honor of Judy Black for their project entitled “Inhibition of BET bromodomain proteins in uveal melanoma”.
Congratulations to Drs. Maria Soengas (Spanish National Cancer Research Centre), Ashani Weeraratna (The Wistar Institute), Elizabeth Patton (University of Edinburgh), Lynn Schuchter (University of Pennsylvania Health System), and Maria Soledad Sosa, (Icahn School of Medicine at Mount Sinai) for winning the L’Oreal Paris MRA Team Science Award for Women in Scientific Research for their project entitled “Imaging and targeting dormant and pro-metastatic melanoma lesions in vivo”.
2016 MRA Young Investigator Award
Congratulation to Dr. Ian Watson (McGill University) and his mentor Dr. Alan Spatz (Jewish General Hospital/Lady Davis Institute for Medical Research) for winning the MRA Young Investigator Award for his project entitled “Identification of therapeutic strategies to target NF1 mutant melanomas”.
Women in Melanoma Research
By Marie Webster
L’Oreal has been committed to supporting women in science in the U.S. for twenty years through the L’Oreal USA For Women in Science program, which awards five postdoctoral scientists annually with grants of $60,000 each for their contributions to the STEM fields. This program was founded on the belief that “the world needs science, and science needs women”. At a time when only 24% of the STEM workforce is made up of women, this is true now more than ever. Toward this goal of increasing the number of Women in STEM, L’Oreal has teamed up with Melanoma Research Alliance to fund top female scientists in the melanoma research field by creating the L’Oreal Paris Melanoma Research Alliance Team Science Award. The Melanoma Research Alliance is the largest private funder of melanoma research and the first melanoma research foundation to specifically fund a women in science award. Since its founding in 2007, the MRA has committed more that $79 million in funding to prevention, diagnosis, and development of new treatments for melanoma.
In its inaugural year, the L’Oreal Paris MRA Team Award was awarded to an international team of women from Spain, Scotland, and the United States. Drs. Maria Soengas, Ashani Weeraratna, Lynn Schuchter, Elizabeth Patton, and Maria Soledad Sosa, will work together to address metastasis and tumor dormancy in patients following surgical excision of the primary tumor by identifying and targeting signaling cascades responsible for cell fate and age-associated changes in the melanoma secretome. In addition to pursuing their scientific endeavors, the team will also work together to advance career development for women in science in order to empower female investigators and promote gender balance in science.
The Scientific Method
Seeking Singularity: Exploring the Multicellular Ecosystem of Metastatic Melanoma with Single-Cell RNA Sequencing
By Ken Dutton-Regester
The Scientific Method is a new section of the SMR newsletter highlighting novel technology, methods and resources of broad interest to the melanoma community. In this issue, we caught up with Benjamin Izar, MD, PhD from the Garraway Laboratory about his experiences using single-cell RNA-Sequencing to explore milieu of metastatic melanoma.
Benjamin Izar, MD, PHD from Garraway Laboratory
Tell us a little bit about yourself?
I completed my MD/PhD at the University of Giessen in Germany, followed by an Internal Medicine Residency at the Massachusetts General Hospital in Boston, Massachusetts. In 2014, I joined the lab of Levi Garraway at the Dana-Farber Cancer Institute and Broad Institute of Harvard MIT before starting my clinical fellowship. One of my main interests is bringing together cutting-edge technologies to the most relevant tissue models - patient samples.
You recently published a paper in Science (1) using single-cell RNA-seq to characterize the ecosystem of melanoma. What were the main findings?
This was a large collaborative team effort that involved sequencing of ~4600 single-cell transcriptomes of malignant and non-malignant cells from 19 patients; needless to say we had a very rich dataset. Amongst many interesting analyses, I would highlight three main findings.
Firstly, we found that individual melanoma cells can express a signature that is related to treatment resistance; this is characterized by expression of AXL and related genes. In each of the patients we examined, we found that a variable number of cells expressed this resistance signature - even prior to the exposure to any drugs, such as RAF/MEK-inhibitors. This indicates that a dormant population exists and that these cells could ultimately grow out under the pressure of drug treatment and cause cancer progression.
Secondly, we were able to make observations about non-tumor cells within the microenvironment, such as the effects of T cell exhaustion (or T cell dysfunction) in T cells. We found that cytotoxicity and exhaustion markers (such as PD-1, TIM-3, LAG-3 etc) were frequently co-expressed on the same T cell. By controlling for the cytotoxicity state of T cells, we were able to delineate a “pure” exhaustion signature, which may be more reflective of a salient T cell exhaustion program.
Finally, we applied the cell type specific signatures we developed from our single-cell analyses across the bulk-RNA profiles of TCGA samples to computationally deconvolve the different patterns of microenvironment in those tumors. Using this analysis as a back bone, we could infer cell-to-cell interactions, and found an interesting putative interaction between cancer-associated fibroblasts and T cells, which is mediated by complement factors.
About the single-cell RNA seq, it sounds like an interesting technology with a number of teams involved in generating the data. Can you give us a detailed run down of how you implemented the experimental pipeline at your institute?
This study was an amazing collaboration between the Aviv Regev (Broad Institute) and Alex Shalek laboratories (MIT), the Center for Cancer Precision Medicine at the Dana Farber Cancer Institute and Harvard Medical School. We were very fortunate to have a formidable team of oncologists, surgeons, interventional radiologists, and pathologists to help coordinate access to tissue. As one could appreciate, good communication and tissue handling is paramount to obtain high-quality single-cell data as any upstream delays can have significant effects on the results.
Once we obtain the fresh tissue, it gets rapidly disaggregated to generate a single-cell solution, and individual cells are then flow-sorted into 96-well plates prepared with a lysis buffer - one cell into each well - using either lineage or tumor specific markers (when available). From here, the plates can be stored or submitted for library preparation and subsequent sequencing.
How do you see single-cell RNA-seq being used in the future and what challenges do you foresee?
I think the implementation of single-cell technologies into the care of patients could be a powerful addition to current profiling approaches. One major challenge towards this goal is sample preparation. At the moment, we work with fresh tissue, which means that we require staff to accept tissue at various times throughout the day (as they are being procured). To make implementation more feasible, it would be ideal if we had a method to store and ‘lock the transcriptomes’ of samples so that we could process them at convenient time points. Furthermore, streamlining the method to allow scale- sequencing of thousands of cells while standardizing the analytical tools required for data analysis are other opportunities for innovation.
Moving forward, we would like to implement single-cell RNA-seq into prospective clinical trials with well-defined patient populations and treatment, be it immune checkpoint inhibitors, targeted cancer therapies or others. Ideally, we would obtain pre-treatment, on-treatment and post-progression specimens to investigate changes in the tumor ecosystem, and how those changes relate to sensitivity and resistance to that particular treatment. If we can demonstrate feasibility of this approach, single-cell RNA-seq may serve as a versatile predictive and monitoring tool, while generating exciting data to better understand tumor biology.
What are your plans moving forward?
I’m excited to be completing my first year of clinical oncology training and will be heading back into the laboratory in July of this year. My goal is to develop our single-cell RNA-seq efforts in melanoma, and other tumors, and be part of the implementation of exciting new single-cell genomics tools in the Center for Cancer Precision Medicine. Having seen the remarkable success of immune checkpoint inhibitors in my own patients and their impact on the clinical oncology world, it comes as no surprise that this experience has significantly shaped my long-term research interests. My plan is to use high-throughput genomic and imaging methods to investigate the tumor-immune interface in patient-derived tumors. By applying these approaches to the most relevant “model” - i.e. patient tumors - I hope that we will better be able to understand what the underlying biology of responders vs non-responders are to different drug treatments. Working with tissue is challenging, but it provides the possibility to rapidly translate discoveries and targets to drug development and back to patients. Ultimately, I would like to focus on my research while still maintaining some level of patient care, the extent of which will certainly oscillate in the next few years.
1. Tirosh I, Izar B, et al. 2016. Science. Dissecting the Multicellular Ecosystem of Metastatic Melanoma by Single-Cell RNA-Seq. 352(6282):p189-196.
Tanning Bed Legislation in 2016
Are We Any Closer to Closing the Lid?
By Morganna Freemankeller
In the Surgeon General’s 2015 “Call to Action” on skin cancer, one of the identified goals was to reduce harms from indoor tanning, in particular melanoma, which remains the leading cause of cancer death in women aged 25-301. The most frequent indoor tanners in the United States are Caucasian females between the ages of 16 and 292, and while a clear association between tanning bed use and skin cancer has been well-established, education on these health risks has provided little impact on use. Despite the medical community’s understanding of melanoma as a potentially fatal, yet highly preventable, illness in young men and women, the incidence is rising,3 and the tanning bed industry remains financially robust, taking in approximately $3 billion annually4. A 2013 study from the National Health Interview Survey estimates that 7.8 million women and 1.9 million men in the United States tan indoors each year5; female high school students have the highest rates of use, and not surprisingly, skin cancer incidence rates are increasing in this demographic6.
By numbers, a 2014 meta-analysis estimated that more than 400,000 cases of skin cancer may be related to indoor tanning in the United States each year: 245,000 basal cell carcinomas, 168,000 squamous cell carcinomas, and 6,000 melanomas7. In the latter case, over the last 15 years there has been a significant increase in truncal melanomas in females, especially in geographic areas reporting a high prevalence of indoor tanning8, and in a 2014 National Cancer Institute study of melanoma patients, indoor tanning was four times as likely to be disease associated compared to sunburn (odds ratio, 3.87; P = 0.002)9. Couple this with the enormous rise in medical costs associated with treatment: the average annual expenditures increased from $3.6 billion (2002-2006) to $8.1 billion (2007-2011), an increase of 126% (compared to 25% in other cancers)10. This makes for a resounding argument, long made jointly by the scientific and policy communities, in opposition to indoor tanning. Why, then, have public health efforts appeared to flounder?
Indoor Tanners Are Not Risk Averse
In 2009, as a response to data highlighting the risks associated with indoor tanning, the World Health Organization International Agency for Research on Cancer (IARC) placed artificial sources of UV radiation alongside tobacco and asbestos in the highest category of carcinogen11. Arguably the dangers of UV radiation are not as immediately apparent as smoking, and a common misconception among indoor tanners is that artificial UVR produces a “safer” tan than outdoor sunlight12. Appearance concerns are among the most consistent motivators of indoor tanning13: a study of US adolescents reported it was “worth getting burnt to get a good tan” and that tanned skin was preferred over pale skin14. The concept of being addicted to high-risk behavior has been theorized as physiologic, and may explain why even patients diagnosed with melanoma may continue to tan indoors15. The antiquated association of a tanned complexion with good health contributes further to this problem16, and may be transferred generationally: increased indoor tanning among parents presents an increased risk of indoor tanning to their children17.
Ease of Access Promotes Use
Proximity to tanning salons is a major contributor to use: Mayer et al found that living within 2 miles of an indoor tanning facility was associated with a greater likelihood of indoor tanning among adolescents18, and there are approximately 18,000 to 19,000 indoor tanning salons and 15,000 to 20,000 other facilities, such as health clubs, spas, and other commercial establishments, that offer tanning services in the U.S4. The emergence of indoor tanning facilities on college campuses is even more problematic: a 2015 study of 125 US colleges and universities showed 48.0% had indoor tanning facilities either on campus or in off-campus housing, and 14.4% allowed campus cash cards to be used to pay for tanning19. Most alarming: although on-campus tanning facilities was more significantly associated with enrollment (p = .01), most off-campus housing facilities with indoor tanning (96%) provided it free to tenants. While the health and beauty industry have attempted to address the issue in popular articles in Cosmopolitan20 and Allure21, it seems little has impacted this dangerous behavior, given the widely accessible (and often free) service.
Policy Implementation: Still More to Do
The Society of Behavioral Medicine issued a position statement calling for a ban on indoor tanning in minors in 2014, and the American Academies of Dermatology and Pediatrics also support a total ban on indoor tanning in individuals under the age of 1822. As of 2015, more than 41 states (and the District of Columbia) have passed age-related bans on indoor tanning23, and in May 2014 the FDA issued a final order reclassifying indoor tanning devices as Class II medical devices, requiring mandatory warning displays24. Unfortunately studies have shown failure with this compliance, as salons continue to promote false safety benefits of indoor tanning and continue to provide services to underage tanners25. The 10% tax on indoor tanning imposed by the Affordable Care Act in 2010 has shown some potential: a 2012 study of tanning salons in Illinois reported 26% of salons had a drop in patronage after tax enforcement, although the authors noted that they were unable to completely distinguish the impact of the tax from the economic climate at the time of the study26.
New York state, which has long been a stalwart of public health issues, recently made a high-profile win against the tanning industry. In November 2015, the exercise giant Planet Fitness reached a settlement with state Attorney General Eric Schneiderman, after an April 2015 filing claimed the company violated state law by failing to provide required warnings to customers. Planet Fitness agreed not to offer “unlimited” indoor tanning sessions as part of its premium membership packages, agreed not to make claims about the potential health benefits of red lamp devices, and was fined $50,000 in fees and penalties27. Unfortunately, the tanning industry has found ways to fight back: In July 2015, Nebraska-based salon operators filed a lawsuit against the Nebraska Cancer Coalition, stating the group’s false and misleading anti-tanning campaign has harmed the plaintiffs’ reputations and livelihoods28.
Heeding the Call to Action
As a scientific community, it is doubtless that melanoma scientists and physicians have made a tremendous impact on the lives of our patients. However, our science is challenged multifold by outdated beauty concepts, ease of access, and poor understanding of the risks of indoor tanning. Ongoing grassroots efforts should continue to combat the ongoing prevalence of risky behavior in our youth and the policy challenges described above, and represent opportunities for us, and our Society, to engage patients, families, and policy stakeholders in closing this issue once and for all.
- Chris J Marshall Award: Deadline is August 1, 2016
- SU2C Catalyst Research Grants: Merk-supported projects offering $1M-$3M over three years for projects involving pembrolizumab. The Application deadline is July 20, 2016
- NCI F32: August 8, 2016 and October 8, 2016
- NCI K99/R00: New application: June 12, 2016 and October 12, 2016 Resubmission: July 12, 2016 and November 12, 2016
- NCI K22 New application: June 12, 2016 and October 12, 2016 Re-submission: July 12, 2016 and November 12, 2016
- NCI RO1 New applications: June 5, 2016 and October 5, 2016 Renewal/Resubmission/Revision: July 5, 2016 and November 5, 2016
Melanoma Medical Oncology Fellowships at the Princess Margaret Cancer Centre
Located in downtown Toronto, PMCC is the largest cancer centre in Canada. The melanoma unit comprises a multidisciplinary team of medical oncologists, surgeons, radiation oncologists, and anatomic and molecular pathologists. The medical oncology site sees over 250 new consultations and 2000 follow-up visits per year, and has an active program of clinical trials in melanoma and other cutaneous malignancies. There is an active engagement in early phase clinical trials and at the forefront of immunotherapeutic treatment strategies.
We are taking applications for two-year fellowship positions for 2016, with an option of extension for an additional year of training. The fellows will manage patients with melanoma and other cutaneous malignancies; will participate and design clinical trials; and are expected to present and publish the results of her/his research at National/International meetings and in peer-reviewed journals. The goal of this program is to produce individuals who will be expert in the management of melanoma and other skin cancers, and who will be future leaders in cutaneous oncology.
Applicants need to have finished a general medical oncology fellowship; meet requirements for an educational license in Ontario; be fluent in spoken and written English; and be energetic and motivated.
The start date will be on or before July 1, 2016. Please send applications, including a letter of interest, CV, and a list of three references, to:
Post-doctoral position available in the laboratory of Dr. John D’Orazio in the NCI-designated Markey Cancer Center at the University of Kentucky. The laboratory is interested in molecular mechanisms that determine melanocyte susceptibility to malignancy with a long-term goal of developing rational melanoma-preventive agents. The current project will follow up on recent findings linking melanocortin 1 receptor (MC1R) signaling to DNA repair (Mol Cell. 2014 Jun 19;54(6):999-1011). Projects include mechanistic studies with clear translational scope. The ideal candidate will have expertise in cell culture, mouse work, protein and mRNA analysis as well as molecular techniques. Interested applicants should send their curriculum vitae and a short statement describing previous research experience, future goals and contact information of three referees to:
Postdoctoral Fellow Position
The White lab at Memorial Sloan Kettering Cancer Center (https://www.mskcc.org/research-areas/labs/richard-white) is seeking a postdoctoral fellow to study the tumor microenvironment. Our laboratory utilizes the zebrafish to study cancer metastasis, with a focus on a model of BRAF-driven melanoma. The zebrafish is an ideal system for this because of its strengths in high-resolution in vivo imaging combined with its capacity for unbiased genetic and small molecule screens. We wish to identify new mechanisms by which cancer cells successfully colonize secondary organs, and the current project focuses on understanding how heterogeneity within the cancer cell population (genetic, epigenetic, developmental) interfaces with the tumor microenvironment (TME). We use state of the art in vivo imaging, CRISPR screening and small molecules to interrogate this. The applicant should have a background in any related field, including cancer, developmental biology, cell biology, imaging or screens. Interested candidates should send a CV, a letter explaining their interest, and any relevant publications to firstname.lastname@example.org
Post-doctoral Fellow Position
The Haq Lab is looking for an enthusiastic post-doctoral fellow to work on projects studying resistance to melanoma therapies. We are located within the world-renowned Dana-Farber Cancer Institute, which offers a dynamic, multidisciplinary environment with close interaction with other basic and clinical scientists. This is an ideal opportunity for an highly motivated and committed biologist to make an important contribution to understanding melanoma biology.
- Global Summit on Melanoma and Carcinoma will be held in Brisbane, Australia during July 14-15, 2016
- 16th World Congress on Cancers of the Skin will be held in Vienna, Austria August 31-September 3, 2016.
- European Society for Pigment Cell Research will be held in Milano, Italy during September 12-15, 2016.
- PanAmerican Society for Pigment Cell Research will be held in Baltimore, Maryland October 5-8, 2016
- The Australasian Melanoma Conference will be held in Sydney, Australia during October 28-29th, 2016
- Society for Melanoma Research will be held in Boston, Massachusetts during November 6-9, 2016 *Abstract submission deadline is August 1, 2016 at 11:59 PM ET.
Reminder: The SMR Congress will be held on USA Election Tuesday. Please remember to get your absentee vote in!