Cancer research, along with new drugs and disease elimination, is one of the most cited examples of how society benefits from science. And although the focus has shifted over the past year towards preventing and treating COVID-19, cancer researchers continue to move forward with their research and make groundbreaking discoveries. the Pew-Stewart Fellowship Program for Cancer Research, now in its eighth year, has supported promising early-career scientists in their research into the causes of cancer, leading to new knowledge on how to diagnose and treat the disease. From discovering when cells know how to divide to new methods of treating lung cancer, three Pew-Stewart researchers have provided critical information that can help speed recovery.

Better protein quality control

Cells in the body depend on proteins built into the cell membrane to perform essential tasks that keep people healthy, including cell-to-cell communication and immune signal coordination. However, a defect or change in the formation of these membrane proteins can be a warning sign for a range of diseases, including cancer. To better understand how these proteins are made, Rebecca Voorhees, a 2018 Pew-Stewart Fellow, studies the endoplasmic reticulum (ER) membrane protein complex (MEC) for clues.

Scientists know that before new membrane proteins can become functional, they are transported to the emergency room in an unfolded state to be modified and inserted into the membrane by EMF. To uncover the molecular details of this process, Voorhees’ team pioneered a technique called single-particle cryoelectron microscopy to assess the structure of EMF. The teams results suggest that this complex, composed of nine subunits, first captures the protein and then inserts it into the lipid bilayer of the membrane. Additionally, the team found that EMC can perform additional “quality checks” to help membrane proteins fold and assemble. This knowledge helps researchers interpret how the body regulates protein production and may trigger the development of new therapies when the process goes awry in diseases such as cancer.

How cells know when to divide

Cell division is a highly orchestrated event and any disruption in this process can be a telltale sign of cancer. Previous research indicates that a cell decides to divide for a short time early in its life by capturing a particular amount of nutrients from its environment. however, Sabrina spencer, 2017 Pew-Stewart Fellow, directed new search This gives an overview of why this may not be the case. Using single cell tracking technology and accelerated microscopy, his group filmed the cells to determine how cell division is controlled. He found that beyond the early detection of mitogens – molecules that stimulate growth – cells constantly monitor their environment and use this information to decide whether they should divide. This decision is transmitted from the original cells to the newly divided cells, which, in turn, influences the likelihood of the new cells dividing as well. Spencer’s discovery expands current understanding of how cell division is controlled. This may have important implications for the timing and use of cancer therapies that target the process of cell division.

New methods to treat lung cancer

About 15-25% of patients with lung cancer carry a mutation in KRAS, a key protein that acts as a molecular switch that alternates between “on” and “off”. When the switch is activated, cells are prompted to grow, divide, or develop specialized functions. However, a specific mutation in KRAS can prolong the length of time the protein stays “on” and cause cells to multiply out of control, causing a tumor to form. Piro Lito, a 2019 Pew-Stewart Fellow, seeks to develop a drug capable of targeting these protein mutations and keeping KRAS trapped in its “off” state, thereby reducing the rate of cell reproduction. Until recently, the KRAS protein was considered incurable with drugs. However, a team of scientists, including Lito, identified a way to inhibit a particular form of the KRAS mutant with a medicine called sotorasib. In a first clinical trial of the drug, 52 of 59 participants with lung cancer saw their tumors shrink or stop growing.

however, another study from Lito’s group shows that cancer cells treated with KRAS inhibitors can develop an adaptive response and become unresponsive to therapy. Therefore, the search for an effective treatment for lung cancer continues and Lito plans to examine cell diversity within the tumor population to test possible combined treatment strategies against tumors with the KRAS mutation.

Kara Coleman heads the biomedical programs of The Pew Charitable Trusts, including Biomedical Researchers, Pew-Stewart Researchers for Cancer Research and Latin American Fellowship programs, and Jennifer Villa is a senior associate supporting the programs.