New research from Memorial Sloan Kettering Cancer Center (MSK) provides insights into how BRCA2 promotes genomic integrity; illuminates how embryonic cells can develop without key amino acids; explores how the microbiome bounces back after antibiotic treatment; and investigates acquired resistance to immunotherapy in non-small cell lung cancer.
New insights about how BRCA2 promotes genomic integrity
When cells are unable to repair damage to their DNA, it can lead to mutations and the development of cancer. The protein BRCA2 plays an important role in helping cells maintain the integrity of their genomes. This helps explain why people who carry mutations in the BRCA2 gene have an increased likelihood of developing certain cancers, especially breast and ovarian cancers, but also cancers of the prostate and pancreas.
More than 20 years ago, the lab of Maria Jasin, PhD, in the Developmental Biology Program at MSK’s Sloan Kettering Institute demonstrated that BRCA2 repairs damage to DNA using a process called homologous recombination, in which the damaged DNA is repaired faithfully by copying from an unrepaired DNA. But since then, the story has become more complicated, as BRCA2 has been shown to participate in two other genome maintenance processes.
A recent study led by Pei Xin Lim, PhD, a senior research scientist in the Jasin lab, used cell lines and mouse models that express a variant of BRCA2 to interrogate the relative importance of the three processes. For this work, he focused on the C-terminal end of BRCA2, which interacts with another protein called RAD51 that forms filaments on DNA. This interaction results in highly stable RAD51 filaments, which is important in protecting replication forks and also suppressing the formation of replication gaps. Dr. Lim found that defective homologous recombination, but not defects in these latter two functions of BRCA2, accelerate tumor formation in mice and increase the sensitivity of cells to a number of drugs, including a class of drugs called PARP inhibitors used in cancer treatment. However, BRCA2 function in the suppression of gaps is important for protecting cells from a potentially new class of drugs resulting in the incorporation of aberrant nucleotides in DNA.
These findings underscore how mechanistic understanding of a tumor suppressor informs therapies that target specific molecular defects. Read more in Molecular Cell. The journal also published a Preview associated with the paper.
Illuminating how embryonic cells can develop without key amino acids
Despite the importance of the earliest cell divisions for development, little is known about the metabolic networks that define and enable these early embryonic states. New research from the lab of the Lydia Finley, PhD, in MSK’s Sloan Kettering Institute, used embryonic stem cells (ESCs) from mice to study the metabolic states that define early embryonic cell states, and found that naïve ESCs mimicking pre-implantation-like states can proliferate in the absence of several essential amino acids.
The study, led by postdoctoral fellow Pavlina Todorova, PhD, further demonstrated that naïve ESCs can proliferate without these amino acids by continuously absorbing external proteins through a process called micropinocytosis, and then digesting proteins through robust lysosomal digestion. As the ESCs transition to more committed, post-implantation-like states, however, the cells become dependent upon uptake of soluble amino acids. The team’s results provide an explanation for the long-standing observation that mammalian embryos can develop in the absence of soluble amino acids. They also underscore the diversity of metabolic strategies that can support rapid cell division in various contexts of health and disease. Read more in Nature Metabolism, including a related research briefing.
How Does the Microbiome Bounce Back After Antibiotic Treatment?
Investigators have long known that antibiotics can harm the microbiome — the community of microorganisms that live on and in the body. Now a study that focused on patients receiving long-term antibiotic treatment for Mycobacterium tuberculosis (TB) infection has shown for the first time how commensal bacteria living in the gut are able to recover from the potentially damaging effects of antibiotic treatment. The researchers found that commensal bacteria, often referred to as “friendly” strains, appear to bounce back by developing resistance to antibiotic drugs. Additionally, the researchers found that when the microbiome recovers more quickly, it may help to boost the natural immune response to the infection and thereby allow the infection to resolve more quickly.
This research was co-led by physician-scientist Michael Glickman, MD, of MSK’s Sloan Kettering Institute and microbiologist Vanni Bucci, PhD, of the University of Massachusetts Chan Medical School. Although it focused on TB, it has implications for the treatment of cancer patients as well. That’s because like people with TB, those undergoing cancer treatment also frequently need to take antibiotics for an extended period of time. In addition, antibiotic-induced changes in the gut microbiome have been associated with worse outcomes for some cancer treatments. These findings demonstrate the importance of conducting fundamental research on the microbiome, the immune system, and antibiotic resistance. Read more in Science Translational Medicine.
Investigating Acquired Resistance to Immunotherapy in Non-Small Cell Lung Cancer
Despite the success that immune checkpoint inhibitors have had for many patients with lung cancer, acquired resistance to treatment remains a challenge. A new study from thoracic oncologist Adam Schoenfeld, MD, and colleagues investigated the molecular features of primary and acquired resistance to PD-(L)1 blockade in 1,200 people with non-small cell lung cancer (NSCLC). While more than 230 of the patients with NSCLC achieved an initial response to treatment, within five years, 61% had developed acquired resistance.
Investigators discovered several differences between the primary and acquired resistance tumors. Instead of resistance being caused by “cold” tumors, characterized by low levels of immune activity, most tumors in the acquired resistance group exhibited increased inflammatory markers with significant upregulation of interferon-gamma, a protein that activates the anti-tumor immune response. This persistent inflammation may explain why some patients with acquired resistance can continue to survive for many years after treatment. Understanding these molecular and immunological alterations may guide the development of more effective therapeutic interventions for patients with acquired resistance to immune checkpoint inhibitors. Read more in Cancer Cell.