Protein-truncating variants in the breast cancer susceptibility gene CHEK2 are associated with a moderately increased risk of breast cancer. By contrast, for missense variants of uncertain... Show moreProtein-truncating variants in the breast cancer susceptibility gene CHEK2 are associated with a moderately increased risk of breast cancer. By contrast, for missense variants of uncertain significance (VUS) in CHEK2 the associated breast cancer risk is often unclear. To facilitate their classification, functional assays that determine the impact of missense VUS on CHK2 protein function have been performed. Here we discuss these functional analyses that consistently reveal an association between impaired protein function and increased breast cancer risk. Overall, these findings suggest that damaging CHEK2 missense VUS are associated with a risk of breast cancer similar to that of protein-truncating variants. This indicates the urgency of expanding the functional characterization of CHEK2 missense VUS to further understand the associated cancer risk. Show less
Mehta, P.; Rahman, Z.; Dijke, P. ten; Boukany, P.E. 2022
An early step of metastasis requires a complex and coordinated migration of invasive tumor cells into the surrounding tumor microenvironment (TME), which contains extracellular matrix (ECM). It is... Show moreAn early step of metastasis requires a complex and coordinated migration of invasive tumor cells into the surrounding tumor microenvironment (TME), which contains extracellular matrix (ECM). It is being appreciated that 3D matrix -based microfluidic models have an advantage over conventional in vitro and animal models to study tumor progression events. Recent microfluidic models have enabled recapitulation of key mechanobiological features present within the TME to investigate collective cancer cell migration and invasion. Microfluidics also allows for functional interrogation and therapeutic manipulation of specific steps to study the dynamic aspects of tumor progression. In this review, we focus on recent developments in cancer cell migration and how microfluidic strategies have evolved to address the physiological complexities of the TME to visualize migration modes adapted by various tumor cells. Show less
The small ubiquitin-like modifier (SUMO) signaling cascade is critical for gene expression, genome integrity, and cell cycle progression. In this review, we discuss the important role SUMO may play... Show moreThe small ubiquitin-like modifier (SUMO) signaling cascade is critical for gene expression, genome integrity, and cell cycle progression. In this review, we discuss the important role SUMO may play in cancer and how to target SUMO signaling. Recently developed small molecule inhibitors enable therapeutic targeting of the SUMOylation pathway. Blocking SUMOylation not only leads to reduced cancer cell proliferation but also to an increased antitumor immune response by stimulating interferon (IFN) signaling, indicating that SUMOylation inhibitors have a dual mode of action that can be employed in the fight against cancer. The search for tumor types that can be treated with SUMOylation inhibitors is ongoing. Employing SUMO conjugation inhibitory drugs in the years to come has potential as a new therapeutic strategy. Show less
There is major interest in understanding the role of the tumor microenvironment in immune escape. In a recent report, Marijt et al. shed light on the signaling cascade that leads to decreased... Show moreThere is major interest in understanding the role of the tumor microenvironment in immune escape. In a recent report, Marijt et al. shed light on the signaling cascade that leads to decreased surface expression of MHC class I by tumor cells triggered by low oxygen and glucose availability, revealing new opportunities for therapeutic intervention. Show less
Glioblastoma cells release extracellular vesicles (EVs), sometimes referred to as microvesicles and exosomes, to transfer immune modulating molecules to immune cells, resulting in an immune... Show moreGlioblastoma cells release extracellular vesicles (EVs), sometimes referred to as microvesicles and exosomes, to transfer immune modulating molecules to immune cells, resulting in an immune privileged microenvironment. Here we discuss the potential EV-mediated mechanisms underlying glioma immune modulation, as well as the technical difficulties in studying these interactions. Show less
