New research from Memorial Sloan Kettering Cancer Center (MSK) and the Sloan Kettering Institute — a hub for basic science and translational research within MSK — discovered ferroptosis regulators that suggest therapeutic opportunities against hormone receptor-positive cancers; examined how tumor-associated macrophages might be turned against cancer; acquired new insights into joint inflammation in rheumatoid arthritis; developed a systems-level platform called epichaperomics to map changes in interactors among thousands of proteins involved in cancer-related processes; and investigated how artificial intelligence could help diagnose an invasive form of breast cancer.
Newly discovered ferroptosis regulators suggest therapeutic opportunity against hormone receptor-positive cancers
Ferroptosis is a form of cell death that occurs when a chemical reaction — known as phospholipid peroxidation — between iron and phospholipids in our cells goes awry. Phospholipids are a vital component of cell membranes, and this out-of-control reaction causes the cell membrane to lose its integrity and function, leading to the death of the cell. The body has natural surveillance mechanisms for keeping these reactions under control — which is important because every cell in our bodies contains iron and phospholipid, and phospholipid peroxidation is a natural outcome of cellular metabolism. Meanwhile, scientists like cell biologist Xuejun Jiang, PhD, of the Sloan Kettering Institute, have also been studying the potential beneficial role of ferroptosis as a tumor suppressive mechanism and as a novel way to treat cancers with certain genetic profiles (see previous findings from the Jiang Lab in Nature and PNAS).
Now, new research from Jiang Lab identified two phospholipid modifying enzymes — MBOAT1 and MBOAT2 — that protect cells from ferroptosis and function independently of the two previously known surveillance mechanisms. The team, led by first author Deguang Liang, PhD, a senior research scientist in the lab, found that these enzymes are regulated by estrogen and androgen receptors, respectively, and thus targeting the receptors in combination with inducing ferroptosis could be a promising approach to treating estrogen or androgen receptor-positive cancers, especially those that don’t respond to single-agent hormone therapies. In mouse models, drugs that block the estrogen receptor sensitized estrogen receptor-positive breast cancer to ferroptosis by downregulating MBOAT1, the scientists found. The same was true for androgen receptor antagonists in androgen-receptor positive prostate cancer via downregulation of MBOAT2. “Understanding ferroptosis is important for fundamental biology as well as disease,” Dr. Jiang says. “We wanted to determine whether there were unknown mechanisms cancer cells could exploit to evade ferroptosis, and conversely, whether it might be possible to target these mechanisms therapeutically.” Read more in Cell.
Turning Tumor-Associated Macrophages from Cancer Friend to Cancer Foe
The transcription factor MYC is involved in cell growth and proliferation. When MYC is expressed at high levels in a cell, it can activate genes that give the cell a competitive advantage over neighboring cells. The MYC allele is frequently amplified in cancer, suggesting the molecular machinery of cell competition promotes the survival of aggressive cancer cells — with cancer cells that lose this competition feeding the growth of “winner” cells. A research team led by immunologist Ming Li, PhD, of the Sloan Kettering Institute, showed that tumor-associated macrophages (TAMs) can be reprogrammed — either genetically or with dietary changes in mouse models — to outcompete cancer cells that overexpress MYC. In a mouse model of aggressive breast cancer, a low-protein diet activated mTORC1 in TAMs, resulting in inhibition of cancer cell mTORC1 signaling and tumor growth through cell competition; mTORC1 is an important metabolic regulator, sensing a variety of cell growth signals. This mTORC1-dependent reprogramming of the TAMs in mice prompted a shift in social cell behavior where they went from cooperating with the cancer cells to competing with them for resources through engulfment. The findings suggest that this pathway might be harnessed as a novel type of immunotherapy against aggressive cancers that are fueled by cancer cell competition. Read more in Nature.
Towards understanding joint inflammation in rheumatoid arthritis
Rheumatoid arthritis is a chronic inflammatory disorder in which the body’s immune system targets its own joints. In this disorder, different types of immune cells infiltrate the joint lining, also known as the synovium, resulting in the main symptoms of the disease: joint pain and swelling. While a lot of research has focused on the role of the immune cells in rheumatoid arthritis, it was less clear how these immune cells affect the resident cells of the synovium and if the resident cells might contribute to disease pathogenesis. In a collaboration with researchers from Hospital for Special Surgery, a team led by Sloan Kettering Institute researchers Alexander Rudensky, PhD, and Christina Leslie, PhD studied how pro-inflammatory cytokines, secreted molecules produced by invading immune cells, change the properties and behavior of the resident synovial cells. In the study, they focused on synovial fibroblasts, which make up the synovial structure and produce the synovial fluid that lubricates the joints. They found different types of immune responses in different “geographical” locations, or sub-regions, of the synovium and that the fibroblasts directly adjacent to the synovial fluid have a heightened inflammatory response. These findings help pave the road for the development of new types of fibroblast-directed treatments in rheumatoid arthritis. Read more in Nature Immunology.
Studying protein-protein interactions to better understand disease mechanisms
Biological molecules, including genes and gene products, operate within intricate networks called “interactomes,” shaping functions and outcomes in different cell types and states. This influences the phenotypic expressions of cells, tissues, and organisms. Mapping connections between cellular components, rather than merely inventorying them, is therefore necessary to grasp disease fully. However, this task of mapping thousands of molecular interactions and deciphering their disease implications is technically challenging at a systems level.
To tackle this challenge, the lab of Gabriela Chiosis, PhD, of the Sloan Kettering Institute developed a systems-level platform called epichaperomics. In a proof-of-principle study, they applied this method to cancer cells, mapping the changes in interactors among thousands of proteins involved in cancer-related processes. They discovered rewired mitotic regulator proteins that affect spindle formation and identified a context-specific mechanism that enhances the fitness of mitotic protein pathways in cancer. This research highlights the platform’s potential to identify and study dysfunctions in protein-protein interaction networks, offering mechanistically and therapeutically relevant insights that other “omics” approaches cannot provide. The implications of this work extend beyond cancer research to include Alzheimer’s and Parkinson’s diseases as well. Read more in Nature Communications.
AI shows promise for helping to diagnose invasive lobular carcinoma of the breast
In ultrasound images, artificial intelligence (AI) might help radiologists identify invasive lobular carcinoma of the breast, a cancer that can be hard to diagnose due to its variable appearance, MSK research found. In a retrospective study of 75 patients who were diagnosed by biopsy or surgery, the AI system’s results were compared to assessments done by radiologists. The AI correctly identified all 83 tumors with no false negatives — putting it on par with radiologists, who had initially recommended biopsies for 82 of the 83 tumors. The findings from the research, which was led by MSK radiologist Tali Amir, MD, suggested that the AI might be most helpful in analyzing lesions smaller than 1 centimeter with characteristics that were more difficult to discern on the ultrasound. “In our study, the AI decision support accurately characterized 100% of detected cancer lesions as suspicious or probably malignant,” Dr. Amir notes. “This definitely suggests AI may be helpful in increasing radiologist confidence when assessing these cancers on ultrasound.” Read more in Clinical Imaging.
Dr. Liang. is an inventor on a patent related to autophagy. Dr. Jiang is an inventor on patents related to autophagy and cell death and holds equity in and consults for Exarta Therapeutics and Lime Therapeutics.
MSK holds the intellectual property rights to the epichaperomics portfolio. Dr. Chiosis and two members of her lab are inventors on the intellectual property.