Tag: Liang

Meenhard Herlyn, D.V.M., D.Sc., is known internationally as one of the fathers of melanoma research. As the founder of The Wistar Institute Melanoma Research Center, he has led the way with breakthrough discoveries about this mysterious and hard-to-treat cancer. A highlight of his work includes building Wistar’s collection of patient-derived xenografts — a groundbreaking tool that allows tumor cells to be implanted into models for melanoma research.

Now, a new generation of melanoma researchers are building on that foundation. This up-and coming-scientific force includes Chengyu Liang, M.D., Ph.D., a rising star in studying how UV exposure damages cells.

“Dr. Herlyn is a great mentor and a great scientist,” Liang said. “He established the platform, the foundation, that has been indispensable not only for Wistar melanoma research, but for the entire melanoma research field.”

BUILDING A BETTER MODEL

“One of the guiding forces in our research has been to mimic human disease, to figure out what makes cells become cancer, and to use this knowledge for new strategies to develop therapies,” Herlyn said.

One of these strategies involves the use of artificial skin. Lab-grown skin had previously been developed for wound healing. Using this existing technology, Herlyn pioneered its application to melanoma research. Herlyn’s team was the first to use artificial skin to grow and study melanocytes — normal pigment cells — which they have used to understand how cancer cells form and how to make treatment more effective.

“We wanted to really know what tumor cells do, and to understand that, we first need to know what normal cells do and where the tumor cells come from,” he explained.

Herlyn joined Wistar in 1976 and spent the early years of his career focused on developing monoclonal antibody treatments, a breakthrough drug that mimics or enhances the immune system’s natural disease fighting activity to attack cancer cells.

One of Herlyn’s frequent collaborators during this time was his wife, Wistar scientist Dr. Dorothee Herlyn, who is now retired. “She was the immunologist of the family,” he said. Together, they helped develop a number of monoclonal antibody molecules, some of which are still used in cancer therapies today.

Herlyn is also behind Wistar’s patient-derived xenograft program which supports a collection of patient cancer tissues. These samples can be implanted into genetically altered mice to more closely mimic conditions in the human body. It’s a powerful tool scientists can use to conduct cancer experiments and test new treatments under conditions that more closely mimic the disease in humans.

“We now have more than 500 tumors from patients,” Herlyn said. “These come directly from the patient and are implanted without ever being cultured, making them much more like real life tumors.”

THE “SUNSCREEN GENE” AND MELANOMA

Dr. Liang didn’t set out to study melanoma. Originally trained as a medical doctor, she became a research scientist with the mission of improving patient outcomes. Her drive to understand cancer and develop better treatments became more personal after her mother passed away following a two-year battle with cancer.

“When someone you love has cancer, you’re trying to find answers. Why did this person have cancer? Why is this treatment not helping?” she said. “Eventually, that drove me to get my Ph.D. in medical science. I wanted to know more.”

Liang initially focused her research on tumor virology, studying how viruses cause cancer. During her research, she encountered a gene called UVRAG that piqued her interest in melanoma.

Previous work had found that this gene seemed to be involved in protecting skin cells from UV radiation, but the mechanism behind it was unclear. Liang’s team showed how the gene repaired DNA damage from UV radiation, and that disrupting the gene could increase a person’s risk of melanoma and other skin cancers. They nicknamed UVRAG the “sunscreen gene.”

The finding sparked many questions about how UV radiation causes genetic mutations that lead to cancer. “The question we asked is, ‘What makes melanoma melanoma?’” she said.

One thing that sets melanoma apart is its extremely high rate of genetic mutations — much higher than other cancers. “It’s in the skin, which is where the body interconnects with the environment and UV radiation, so in a way, that’s not surprising,” she explained.

Liang’s recent research has focused on identifying signs of DNA-repair deficiency as an early sign of damage that can trigger melanoma-driving mutations. “If we can find genetic signs that can predict this process, we might be able to catch the disease much earlier,” she noted.

CULTURING COLLABORATION

Herlyn not only laid the groundwork for Liang and fellow cancer researchers. He also serves as a leader and mentor who is generous with his knowledge and support, Liang said. “He’s like a big dictionary of melanoma,” she described. “When you have a question, he can always share something instructive.”

This philosophy of collaboration, Herlyn shared, has been a driving force in his work. “One of the major strengths at Wistar has been our flexibility and our ability to look for collaborators,” he pointed out. “My approach has always been to look for the best people I could work with.”

This has included a longtime collaboration with oncologists, pathologists, and other clinical colleagues at the University of Pennsylvania as well as other institutions. “I’ve always believed strongly in a good connection between the laboratory and the clinician,” he said.

Herlyn also helped found the Society for Melanoma Research, the first ever medical conference dedicated to bringing together researchers, clinicians, and patients to share knowledge about melanoma. Liang emphasized that with such a complex and unique disease, it’s critical for scientists to work together to find new diagnostic tools and treatments.

“There’s still a lot of mystery,” she stated. “Despite all the tremendous progress we have made in the melanoma field, I think we are still at the tip of the iceberg.”

A Q&A with Drs. Chengyu Liang and Meenhard Herlyn on skin cancer research at The Wistar Institute, including a few questions from melanoma survivors.

Melanoma is the most aggressive form of skin cancer. Work at The Wistar Institute’s Melanoma Research Center aims to understand the biology behind the disease to help develop new therapies and improve existing treatments. In this Q&A, we spoke with Dr. Chengyu Liang, a professor in the Molecular & Cellular Oncogenesis Program at Wistar’s Ellen and Ronald Caplan Cancer Center who joined Wistar in 2020 and Dr. Meenhard Herlyn, director of The Wistar Institute Melanoma Research Center and Professor in the Molecular & Cellular Oncogenesis Program. The research they conduct aims to have impacts on melanoma patients and survivors. Thus, this National Melanoma and Skin Cancer Awareness Month, we included questions from melanoma survivors and staunch Wistar supporters Eleanor Armstrong and Pat Dean who organize an annual fundraiser walk for the Institute’s melanoma research program.

Dr. Liang, what attracted you to studying melanoma?

Dr. Chengyu Liang: My passion and curiosity! A few years ago, we identified a so-called “sunscreen” gene that helps cells to repair after they have been damaged by UV rays; and we know that UV-induced DNA damage is a major risk factor for melanoma – the most aggressive type of skin cancer. This inspired us to find out more about how this genetic sunscreen system plays in human beings and what it means to melanocytes (the origin of melanoma) and melanoma when the system is running out of order.

What are you working on now specifically regarding melanoma and what is this work’s potential impact on cancer treatments?

CL: The question that we are always intrigued by is: What makes melanoma melanoma? Compared to most other types of human cancers, one striking feature of melanoma is that its genome is flooded with mutations associated with UV-induced damage. Now, the burning questions are: What drives such genetic change? What are the molecular mechanisms underlying the UV-footprint in melanoma? Understanding these mechanisms not only enable early-risk prediction but also help oncologists and researchers to develop cancer treatments with responses that have long-term durability.

Second, melanoma originates from an easily spread and multipotent cell population, which can help explain the inborn aggressiveness and treatment resistance of the skin cancer. In addition to targeting specific pro-cancer mechanisms to kill cancer cells that are often, if not always, encountered by tumor resistance, is it possible to force cancer cells to resume the process of normal growth control or differentiation? To this end, we are trying to understand the molecular mechanisms that control melanoma differentiation. This work holds promise to identify new vulnerabilities in melanoma that can be targeted to revert the negative effects of mutations and strengthen anti-tumor immune responses to melanoma.

How important is a person’s immune system in preventing skin cancer and is there anything that can be done to strengthen a person’s immune system against melanoma?

CL: It can’t be more important! Our immune system is like the ‘shepherd’; its duty is to keep ‘sheep’ protected. Melanoma is like the ‘wolf’. A powered immune system is an experienced shepherd that could easily and quickly identify and target the wolf in the flock and clear it up. As a matter of fact, what immunotherapy does is release the built-in brake system of our immune system and revive and direct its killing energy to cancer cells.

The immune system is an ecosystem – a complex network of cells, tissues, and organs that orchestrate to maintain homeostasis to protect human bodies against internal and/or external assaults. If a well-balanced immune system is considered healthy to life, a well-balanced life would also be considered beneficial to the immune system. Many tips have been suggested such as healthy diet, exercise, mental and physical support, etc. Notably, fasting and calorie restriction (CR), have been shown experimentally and in clinical trials, to be able to slow and even stop the progression of cancer, kill cancer cells, boost the immune system, and significantly improve the effectiveness of chemotherapy and radiation therapy. With our growing understanding of this sophisticated system, we might be able to come up with more effective strategy to boost it or manipulate it to outsmart cancer.

You’ve previously done research on UV radiation causing mutations that contribute to melanoma. What are some daytime hours that have the highest risk of damaging UV radiation and sun exposure?

CL: This depends. The lighter the skin, the more sensitive to sunburn and/or skin damage by UV rays. Human skin pigmentation is an evolutionary adaptation to UV radiation. Fair skinned people may easily burn within 20 minutes of exposure to direct sunlight, thus wearing a broad-spectrum sunscreen is always encouraged. Certainly, you also want to have a strong genetic sunscreen system as noted before.

What future directions will you take your work?

CL: Our ultimate goal is to make melanoma a curable disease. The current challenge is that we still have more than 50% of melanoma patients who are not responsive to any treatment. We need to solve this puzzle. We also need to figure out what’s the right therapy to be used for the right patient at the right time. Why does therapy work in some patients, but not others? We believe that prevention is the most effective treatment of melanoma. Thus, identifying a new biomarker for early detection is equally important and urgent. All these challenges depend on a deeper understanding of the biology of melanoma as a cancer, and the biology of melanoma interaction with the human body as a system.

Dr. Herlyn, why is building the cancer research talent at Wistar important (eg. Dr. Chengyu Liang joining the Cancer Center)?

Dr. Meenhard Herlyn: Every research field needs a critical mass of researchers, both junior and senior. Any institution needs ‘new blood’, meaning investigators who may have experience, knowledge, and connections in the critical field. Dr. Liang brings important expertise not only to Wistar but the entire larger field here and beyond. Her work on DNA damage and repair fills an important gap for us.

What would you like to see for the future of melanoma research at Wistar?

MH: Melanoma has been a major focus for research at Wistar. We have developed a strong outreach program in which we collaborate not only with our colleagues at Penn but also with numerous national and international research laboratories. Melanoma research at Wistar should remain multi-disciplinary. Our strong biology is the foundation and platform for collaborations that ensure continuing progress. Melanoma investigators should incorporate cutting edge technologies and strategies. We have developed strong ties to our clinical colleagues, and we expect that in the future these ties will strengthen as our research more and more directly benefits patients. Thus, we not only translate research from bedside-to-bench but also from bench-to-bedside.

Why are supporters such as those fundraising and donating to the Institute important?

MH: There are many areas of research that are essential to run a successful program but that cannot be funded through National Institute of Health or industry grants. For example, there are meetings with other scientists to exchange ideas and develop new collaborative strategies, seed funding for new projects that are still in the exploratory phase, collaborations with clinicians for specimens and preparing reagents for diagnostic studies, developing high risk/high gain projects and ideas, and obtaining new research tools. Supporters like our donors and fundraisers are integral to our work at Wistar, without whom we could not have as great an impact as we do.