Tissue scale agent-based simulation of premalignant progressions in Barrett’s esophagus

Barrett’s esophagus (BE) is a benign condition of the distal esophagus that initiates a multistage pathway to esophageal adenocarcinoma (EAC). Short of frequent intrusive (and costly) surveillance, effective screening for neoplasia in BE populations is yet to be established since progressors are rare and virtually undetectable without routine biopsies, which often sample only a small portion of the BE tissue. As a result, reliable estimation of the true prevalence of dysplasia in a BE population and evidence-based optimization of screening for at-risk individuals is challenging. Data-driven microsimulations, i.e., model-generated instances of disease history in a predefined virtual population, have found utility in the EAC screening literature as low-overhead alternatives to real-world hypothesis testing of optimal interventions for dysplasia. Despite the successes, computational limitations, paucity of knowledge and data on Barrett’s dysplasia, and the complexities of disease progression as a multiscale multiphysics process have hindered the treatment of disease progression in BE as a spatial process. Agent-based modeling of nucleation and proliferation processes in dysplasia warrants exploration in this context as an approximation that operates at a trade-off between computational tractability and precise representation of the composition and physics of the substrate (tissue). In this study, we describe spatially resolved simulations of premalignant progression toward EAC in a coarse-grained model of Barrett’s tissue that resolves the metaplastic tissue at a length scale of 0.42 mm (~3300 crypts/mm2). The model is calibrated to reproduce historical high-grade dysplasia prevalence when model-generated patients are screened using the Seattle protocol.

Successful Treatment of Actinic Keratosis with Kanuka Honey

Actinic keratoses form as rough, scaly plaques on sun-exposed areas; they can be an important step in premalignant progression to squamous cell cancer of the skin. Currently, pharmacological treatments consist of topical immunomodulatory agents with poor side effect profiles. Use of honey has been common in both ancient and modern medicine, where it is now a key therapy in the management of wound healing. In vitro studies show the New Zealand native Kanuka honey to have immunomodulatory and antimitotic effects, with recent evidence suggesting efficacy of topical application in a variety of dermatological contexts, including rosacea and psoriasis. Here, we present a case report of a 66-year-old gentleman with an actinic keratosis on his hand, which had been present for years. Regular application of Kanuka honey over three months resulted in remission immediately following the treatment period with no signs of recurrence at nine months.

A new paradigm for personalized cancer screening

A series of distinct histologic lesions precedes the onset of malignancy in many common cancers, yet early detection remains a major challenge. Many patients still experience late (stage IV) diagnoses and thus poor prognosis and limited options for therapeutic intervention. For cancers with known biomarkers of premalignant progression, optimized patient-specific screening protocols would minimize the risk of undetected progression to advanced stage disease. Here, we propose simple, cost-effective mathematical and statistical approaches to forecasting disease progression that could guide the personalization of optimal screening times for high-risk patients.

Leveraging premalignant biology for immune-based cancer prevention

Prevention is an essential component of cancer eradication. Next-generation sequencing of cancer genomes and epigenomes has defined large numbers of driver mutations and molecular subgroups, leading to therapeutic advances. By comparison, there is a relative paucity of such knowledge in premalignant neoplasia, which inherently limits the potential to develop precision prevention strategies. Studies on the interplay between germ-line and somatic events have elucidated genetic processes underlying premalignant progression and preventive targets. Emerging data hint at the immune system’s ability to intercept premalignancy and prevent cancer. Genetically engineered mouse models have identified mechanisms by which genetic drivers and other somatic alterations recruit inflammatory cells and induce changes in normal cells to create and interact with the premalignant tumor microenvironment to promote oncogenesis and immune evasion. These studies are currently limited to only a few lesion types and patients. In this Perspective, we advocate a large-scale collaborative effort to systematically map the biology of premalignancy and the surrounding cellular response. By bringing together scientists from diverse disciplines (e.g., biochemistry, omics, and computational biology; microbiology, immunology, and medical genetics; engineering, imaging, and synthetic chemistry; and implementation science), we can drive a concerted effort focused on cancer vaccines to reprogram the immune response to prevent, detect, and reject premalignancy. Lynch syndrome, clonal hematopoiesis, and cervical intraepithelial neoplasia which also serve as models for inherited syndromes, blood, and viral premalignancies, are ideal scenarios in which to launch this initiative.

Three-dimensional cultures modeling premalignant progression of human breast epithelial cells: role of cysteine cathepsins

The expression of the cysteine protease cathepsin B is increased in early stages of human breast cancer. To assess the potential role of cathepsin B in premalignant progression of breast epithelial cells, we employed a 3D reconstituted basement membrane overlay culture model of MCF10A human breast epithelial cells and isogenic variants that replicate the in vivo phenotypes of hyperplasia (MCF10AneoT) and atypical hyperplasia (MCF10AT1). MCF10A cells developed into polarized acinar structures with central lumens. In contrast, MCF10AneoT and MCF10AT1 cells form larger structures in which the lumens are filled with cells. CA074Me, a cell-permeable inhibitor selective for the cysteine cathepsins B and L, reduced proliferation and increased apoptosis of MCF10A, MCF10AneoT and MCF10AT1 cells in 3D culture. We detected active cysteine cathepsins in the isogenic MCF10 variants in 3D culture with GB111, a cell-permeable activity-based probe, and established differential inhibition of cathepsin B in our 3D cultures. We conclude that cathepsin B promotes proliferation and premalignant progression of breast epithelial cells. These findings are consistent with studies by others showing that deletion of cathepsin B in the transgenic MMTV-PyMT mice, a murine model that is predisposed to development of mammary cancer, reduces malignant progression.