Targeting Tumor Plasticity: New Dermatology Faculty Stefan Schieke, MD, Searches for CTCL Cures

Text and Photo by Jonathan M. Bartnik

What causes relapses in Cutaneous T-cell Lymphoma (CTCL)? How can future drugs and therapies target the cancer’s strengths and turn them into weaknesses? New UW Dermatology Assistant Professor Stefan Schieke, MD, hopes his research will shed light on these questions and more.

Proliferative Plasticity

There are many potential causes of a relapse in CTCL, says Dr. Schieke, but one known factor is “proliferative plasticity” within the tumor’s cancerous cells.

Cancer cells from different patients and even from within a single tumor site in a patient can vary considerably. One variation can be the time it takes for a cell to divide: some cells will divide slowly and infrequently; some cells will divide quickly and at short, regular intervals. These cells may be genetically identical, but are differentiated by their proliferative state. And they periodically fluctuate between these two states in a continuous process known as proliferative plasticity.

Recent research by Schieke and others in the field focuses on the slow growing, slow-cycling proliferative state of cancer cells. “The slow-cycling cells seem to be more treatment-resistant and better able to form new—more and larger—tumors,” Schieke explains. “As long as we have a resistant subpopulation, we can’t cure the cancer. Not only are they resistant—they are most likely to be the source of a relapse.”

Dr. Schieke’s current research uses mouse models of CTCL to focus on the mechanisms of proliferative plasticity, and to study more closely the role of slow-cycling cells in the disease’s progression and treatment resistance. Eventually, Dr. Schieke hopes that his work will lead to a way to kill off an entire tumor and prevent relapse of the cancer.

Critical Vulnerabilities

Broadly speaking, cancer cells have a different metabolism from normal, non-cancerous cells. In part this is what defines them as cancerous, even though according to Dr. Schieke, the metabolic process in a cancer cell is still largely identical to that of a normal cell.

Still, by studying the metabolic exceptions in CTCL, Schieke is investigating a rather remarkable phenomenon. “When we stress the mitochondria of malignant T cells with certain drugs, they do something pretty smart. The cells are able to survive by activating a pathway that regulates lifespan.” Doing so slows down metabolism and allows the cells to survive metabolic or mitochondrial stress.

The most remarkable aspect of this recently discovered pathway is that it is unique not just among cancerous or skin or even human cells, but among all studied mammalian cells. The closest analogue resides in the microscopic worm C. elegans, “one of the most evolutionarily basic organisms used to study cell life and ageing,” according to Schieke. “The lymphoma cells seem to have ‘rediscovered’ this pathway that evolution has gotten rid of, and which has not been described in other cancer or normal cells.”

“This can be exploited beautifully for treatment,” says Schieke. “If we inhibit that pathway while subjecting the cells to stress, the cells die,” thus turning one of CTCL’s most unique resistances into a critical vulnerability to treatment.

Moving to the University of Wisconsin-Madison

Dr. Schieke joined the UW’s Dermatology faculty in March of this year and hopes to spend the next several years building up his laboratory and expanding his research program. Originally from Düsseldorf, Germany, where he completed medical school and residency at Heinrich-Heine University, Schieke relocated to the US in 2003 to do post-doctoral research at the NIH, then completed a second residency at Boston University before making his way to Wisconsin. A husband and a father of one son, he enjoys spending his free time with his family and either cooking or cycling.

He is very excited to join the Department of Dermatology at the UW. “It’s a very strong department, clinically and scientifically, embedded in an excellent research environment on the UW campus. There are countless opportunities for research collaborations with the department, the UW Carbone Cancer Center and beyond. Being a part of that is simply fantastic.”

Dr. Schieke has a dual appointment with the Department of Veterans’ Affairs, and in addition to teaching and conducting research, he sees patients with a focus on CTCL at the William S. Middleton Memorial VA Hospital and at UW Health’s West dermatology clinic.

For more information on Dr. Schieke’s research program, email him here.