Like living species, cancer cell populations undergo evolution. They accumulate mutations and become heterogeneous, and the mutations that increase chances of survival become more common. In this way, a single genetic alteration can evolve into a tumor and eventually spread throughout the body. Understanding the evolutionary path that tumors follow, from a single-cell mutation to metastatic cancer, is essential for designing effective clinical interventions. However, environmental factors and other variables can confound efforts to trace a cancer’s development from beginning to end.

Cancer treatment decision-making depends on an accurate understanding of a patient’s prognosis. Mistaking a cancer’s aggressiveness can lead to either under- or overtreatment, both of which carry increased risk of fatality. Current methods of prognostication, which usually rely on examining cancerous tissue via X-ray or microscope, involve subjective judgments and sometimes fail to predict disease course. With the rise of DNA sequencing technologies, clinicians are increasingly looking to patients’ genomes for clues about how their cancer will behave.

Last fall, we published the story of Damon Runyon Clinical Investigator Jennifer M. Kalish, MD, PhD, a pediatric geneticist at the Children’s Hospital of Philadelphia who has dedicated her career to the study of Beckwith-Wiedemann Syndrome (BWS), a rare genetic condition that causes overgrowth in certain parts of the body and predisposes children to cancers of the kidney and liver. As Founding Director of the hospital’s Beckwith-Wiedemann Syndrome Clinic, Dr. Kalish established the country’s first and only active BWS patient registry and biorepository storing blood and tissue samples necessary for research. In December 2020, her lab unveiled the first human cell-based model of the syndrome, developed using cells from patients in the registry.

Damon Runyon alumni Ash Alizadeh, MD, PhD, and David Kurtz, MD, PhD, and others have shown that cancer can be detected via blood sample by measuring circulating tumor DNA (ctDNA). This approach, however, requires high concentrations of tumor DNA in the bloodstream and provides low resolution—in other words, it can detect cancer but cannot identify a specific cancer subtype.

Cells absorb hormones, proteins, and other molecules from their environment through a process called endocytosis. In this process, the molecule being absorbed—the “cargo”—binds to a receptor on the surface of the cell membrane, recruiting a protein called clathrin to the inside of the cell membrane. The membrane then pinches inward to form a clathrin-coated vesicle with the cargo protected inside. Endocytosis is mediated by a protein complex called AP2, which links the cargo-bound receptors to the clathrin coat (see below). The functionality of AP2 depends on its shape. When “closed,” it can only bind to the cell membrane; when “open,” it can bind to cargo-bound receptors and clathrin proteins. But how exactly it makes this conformational change from “closed” to “open” has long been unclear. 

Founded in 1780, the American Academy of Arts and Sciences is both an honorary society that recognizes and celebrates the excellence of its members and an independent research center that convenes leaders from across disciplines to address significant challenges facing the world. This year, four Damon Runyon scientists were among the 261 exceptional individuals elected to the Academy.

Patients with ovarian cancer have a 92% five-year survival rate if they are diagnosed at stage I. But a lack of effective screening methods and absence of symptoms in its early stages makes ovarian cancer particularly difficult to catch before it spreads. Patients and clinicians need a kind of internal alarm system, a device that can detect and communicate the presence of cancer cells in the body before they have a chance to inflict damage.

Messenger RNA (mRNA) vaccines have been shown to elicit immunity against a number of infectious diseases—including, notably, COVID-19—as well as several types of cancer. Unlike traditional vaccines, which introduce a small amount of the pathogen into the body, mRNA vaccines provide the body with instructions for how to make a specific protein found on the surface of a virus or cancer cell. Once the vaccine is delivered, molecular machines called ribosomes bind to the mRNA, “read” its instructions, and build the protein. This, in turn, prompts the immune system to produce the corresponding antibodies, so that it is ready when it encounters the real virus or cancer cell. Importantly, the mRNA molecules that contain these protein-making instructions are broken down by the cell after they have delivered their “message.”

The rise of single-cell RNA sequencing in recent years has transformed the study of gene expression, providing researchers with a detailed picture of how and when genes get turned “on” and “off” in individual cells within a given tissue. Analyzing cells’ RNA sequences, or transcriptomes, can reveal cell-to-cell variability, or in the case of cancer, mutations carried by small populations of tumor cells. Current single-cell sequencing methods, however, fail to capture the location of the cell within the tissue. Spatial transcriptomics techniques, on the other hand, define the spatial distribution of RNA molecules within a tissue sample, but lack single-cell resolution. To put this on a human scale, consider the different information you get about a neighborhood from a phone book versus a satellite image.

For many patients with colon cancer, the advent of immune checkpoint inhibitors has substantially improved their treatment options. Immune checkpoint inhibitors (ICIs) work by removing the “brakes” from immune T cells, unleashing them on cancer cells. Unfortunately, however, ICIs do not work for everyone, and they can have life-threatening side effects for some patients. Given these factors, ICIs should only be used in patients who have the potential to benefit from them—the problem is, clinicians are often unable to predict who those patients will be.