Co-conspirators in Melanoma

By Lee Anna Sherman

Americans spend billions to beautify their outermost organ — to make it softer and younger, to erase wrinkles, conceal freckles, fake a tan, flaunt a tattoo. In our obsession with skin’s cosmetic qualities, it’s easy to forget the role it plays as nature’s biohazard suit. It defends our bodies against a barrage of environmental and biological assaults, from solar ultra-violet (UV) radiation and industrial pollution to extreme heat and deadly pathogens.

Skin cells work together in a deadly dance that leads to melanoma, a cancer that took the lives of more than 70,000 Americans in 2010 (Photo: Karl Maasdam)
Skin cells work together in a deadly dance that leads to melanoma, a cancer that took the lives of more than 70,000 Americans in 2010 (Photo: Karl Maasdam)

Given this constant battering, there’s little wonder that skin ranks No. 1 on the American Cancer Society’s list of most common cancers. Many of the 1 million new cases diagnosed in 2010 were easily treated. But the most lethal form of skin cancer — melanoma — took the lives of 70,000 Americans. Unlike more benign forms of skin cancer, melanoma can metastasize aggressively, spreading into lymph nodes and other distant organs of the body if not caught and treated early.

For two researchers in the Oregon State University College of Pharmacy, the statistics are unacceptable. In a warren of labs tucked into the recesses of the college’s historic building, Arup and Gitali Indra are urgently seeking — and beginning to find — clues to predicting, preventing and stopping this hard-to-treat disease before it spreads.

“Malignant melanoma continues to evade modern curative efforts as a result of the complex and elusive nature of metastatic tumors,” the researchers write in the journal Pigment Cell & Melanoma Research. Their research, which explores the chemical and genetic mechanisms of melanoma progression “could hold therapeutic value when combating metastatic disease.”

Skin Deep

When people look at each other, they perceive skin as a smooth surface that ranges in tone from pale pink to deep brown, depending on ancestry. But beneath the pigmented surface is a complex layering of cell types, each with its own function. Graphic renderings of human skin, magnified and cut away, bear an uncanny resemblance to geologists’ drawings of rock strata. How skin, a complex multi-cellular organ, develops from a handful of stem cells, and how the various skin cell types interact and “talk” with one another with the aid of proteins that regulate gene expression, are the focus of the Indras’ research. They began collaborating in the 1990s at the Institute of Genetics, Molecular and Cellular Biology (IGBMC), one of the leading European centers of biomedical research in Strasbourg, France. Arup was a post-doctoral researcher, and Gitali was a Ph.D. candidate.

“I was totally into skin,” says Gitali, whose Ph.D. in molecular and cellular biology focused on head and neck cancers, which originate from epithelial cells — cells that form linings on many body surfaces, including the skin. Two years ago, the Indras, in collaboration with their colleagues in France and in the College of Pharmacy, announced a breakthrough in human head and neck cancers by showing that tumors in these areas contain a five-fold spike in CTIP2, a gene regulator thought to play a role in tumor growth. The Indras’ findings, published in the journal PloS One, could lead to the development of a promising new prognostic kit for fast, sensitive and accurate detection of head and neck cancer and some other epithelial cancers.

Melanoma is the Indras’ nemesis. But in order to tackle that baneful foe, the researchers (who are partners in marriage as well as in science) investigate the full spectrum of mammalian skin, from the fetal to the fatal — from embryonic stem cells to metastatic cancer cells, from normal function to inflammatory disease and life-threatening cancers. Wound healing is yet another window into the mysteries of melanoma and the mechanisms that drive it.

Among skin researchers, there’s a common saying: Cancer is a wound that never heals. “The processes of wound healing and cancer progression have similar pathways,” explains Arup, whose mentor in France was renowned scientist Pierre Chambon, whom he calls a “guru” in the field of gene regulation. “They overlap.”

Scientists long have known that melanoma takes hold in the body’s pigment-producing cells, which are called melanocytes (that is, producers of melanin, which gives skin its color and protects it against the sun’s ultra-violet rays). But that’s only part of the story, as the Indras have discovered. In the “microenvironment,” or the local neighborhood, of the cancer site, the researchers have recently identified other skin cells that play a key role. Called keratinocytes (producers of keratin, a protein found in hair and nails as well as skin), these “co-conspirators” are not just bit players in the genesis of melanoma. They’re lead actors.

How Tumors Begin

How Tumors Begin

Skin cells conspire to set melanoma in motion.
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“These adjacent cells are actually the driver for the changes and malignant transformation in the pigment-producing cells,” Arup says. “So there are two avenues — the pigment-producing cells where the cancer develops, and the adjacent skin cells which ‘talk to’ the pigment-producing cells in the form of signals. They work in coordination. They are partners in crime.”

To study melanoma cells in isolation from their surrounding biochemical and molecular environment, therefore, is to miss the intricate series of related interactions that give rise to the disease, he stresses.

East to West

The daughter of a mining engineer in southern India, Gitali was a gifted athlete, winning glory in badminton and table tennis. Arup, the son of a marine engineer based in Kolkata (then Calcutta), was a talented young musician, studying sitar with Sangeetacharya Gokul Nag, a pre-eminent sitarist of the Vishnupur Gharana of Bengal (a traditional form of Indian music), and with a nephew of the legendary Ravi Shankar. But when it came time to choose careers, the couple report, both fathers steered their offspring firmly toward the sciences.

As his post-doc in France was winding down, Arup was invited to interview at OSU. Leafy Corvallis was an easy choice for the couple. The rimming mountains reminded them of Strasbourg’s picturesque Vosges range. The shadowed woods echoed the Black Forest. And the nearby ocean recalled India’s turquoise coastline. But it wasn’t just the natural beauty of the place that tugged at them.

“There’s so much collegiality here,” Gitali says. “It’s such a caring and loving community.”

When the lights burn late in the Pharmacy Building on the east edge of campus, chances are they’re illuminating the labs of Gitali and Arup (who is a self-confessed “workaholic”) as they follow the threads of the day’s investigations. For their recent “co-conspirator” research, they used cell cultures from both human samples as well as animal models that carry a mutation in a gene called Cdk4, an inherited predisposition to melanoma that has turned up in families in Norway, France, Australia and England.

Their studies, funded by the National Institutes of Health, have found that a protein called RXR-alpha in skin keratinocytes appears to protect pigment cells from damage and to prevent them from progressing to invasive melanoma. This protein co-operates with Cdk4 and suppresses the release of chemical signals to adjacent pigment cells. These signals can, in effect, promote and augment the abnormal proliferation of pigment-producing cells in laboratory mice. Not surprisingly, when the protein is removed or repressed, melanoma cells become aggressive and invade the animals’ lymph nodes.

However, the Indras caution, both the protective protein and pigment cells can suffer damage from chemical toxins or ultraviolet sunlight exposure in the skin cells, creating a “double-edged sword” in melanoma’s complex etiology.

The Indras’ findings could lead to promising new prevention tools down the road. The scientists plan to use their unique animal models to screen for novel natural compounds with anti-proliferative activity on cancer cells in collaboration with other medicinal chemists in the college.

“Better understanding this process will help us design new and novel strategies for prevention and, possibly, a cure,” Arup says. “This could be a predictive prognostic tool for discovering melanoma predisposition in humans. And that could lead to better and earlier diagnostics.”