Defining Genomic Programs of Dormancy and Reactivation in Melanoma 

Even after successfully removing a cutaneous melanoma (CM) primary tumor, the cancer can sometimes return years or decades later in other parts of the body; the main reason this cancer can be fatal. This recurrence happens because a few cancer cells escape the original tumor early on and travel elsewhere in the body, where they lie dormant, or “asleep,” for an extended period of time before suddenly “waking up” to form a new tumor. A critical mystery is what causes these cells to wake up when they do. Our research tackles this problem based on two key ideas. First, we believe only a subset of cells within the original tumor are primed to spread, lie dormant, and later wake up. Second, we can calculate how long these cells were dormant by reading the genetic changes accumulated in their DNA, like reading a molecular clock. In our preliminary work, we found that tumors with specific, recurring errors in genes that control cell growth were more likely to spread.

These errors, which make the cancer cells’ chromosomes unstable, seem to give them a special ability to travel and survive in the body. We have gathered a unique collection of tissue samples from 80 melanoma patients, each including their original tumor and the later metastasis. This direct comparison is essential to see what changed in the cells’ DNA during this dormant “asleep” period. Our first goal is to compare the primary and metastatic tumors to identify the exact “founder” cells that started the metastasis and understand what makes these founder cells different from the others. Our second goal is to use the DNA changes as a timer to calculate the dormancy period and pinpoint the specific genetic features that cause some cells to wake up quickly while others stay asleep for years. By understanding the mechanisms that keep these dangerous cells asleep and what triggers them to wake up, we hope to identify new treatment targets that can extend dormancy and prevent the cancer from returning.