No abstract

Cancer metastasis, i.e., the spreading of tumor cells from the primary tumor to distant organs, is responsible for the vast majority of cancer deaths. In the process, cancer cells migrate through narrow interstitial spaces substantially smaller in cross-section than the cell. During such confined migration, cancer cells experience extensive nuclear deformation, nuclear envelope rupture, and DNA damage. The molecular mechanisms responsible for the confined migrationinduced DNA damage remain incompletely understood. While in some cell lines, DNA damage is closely associated with nuclear envelope rupture, we show that in others, mechanical deformation of the nucleus is sufficient to cause DNA damage, even in the absence of nuclear envelope rupture. This deformation-induced DNA damage, unlike nuclear envelope ruptureinduced DNA damage, occurs primarily in S/G2 phase of the cell cycle and is associated with stalled replication forks. Nuclear deformation, resulting from either confined migration or external cell compression, increases replication fork stalling and replication stress, providing a molecular mechanism for the deformation-induced DNA damage. Thus, we have uncovered a new mechanism for mechanically induced DNA damage, linking mechanical deformation of the nucleus to DNA replication stress. This mechanically induced DNA damage could not only increase genomic instability in metastasizing cancer cells, but could also cause DNA damage in nonmigrating cells and tissues that experience mechanical compression during development, thereby contributing to tumorigenesis and DNA damage response activation.

Ataxia-telangiectasia mutated (ATM) is one of the three main apical kinases at the crux of DNA damage response and repair in mammalian cells. ATM activates a cascade of downstream effector proteins to regulate DNA repair and cell cycle checkpoints in response to DNA double-strand breaks. While ATM is predominantly known for its role in DNA damage response and repair, new roles of ATM have recently begun to emerge, such as in regulating oxidative stress or metabolic pathways. Here, we report the surprising discovery that ATM inhibition and deletion lead to reduced expression of the nuclear envelope protein lamin A. Lamins are nuclear intermediate filaments that modulate nuclear shape, structure, and stiffness. Accordingly, inhibition or deletion of ATM resulted in increased nuclear deformability and enhanced cell migration through confined spaces, which requires substantial nuclear deformation. These findings point to a novel connection between ATM and lamin A and may have broad implications for cells with ATM mutations—as found in patients suffering from Ataxia Telangiectasia and many human cancers—which could lead to enhanced cell migration and increased metastatic potential.

A cellular proliferation to milk allergens has been found in the cord blood cells of neonates. While this reflects a sensitivity during the fetal life, its clinical significance and disease, particularly its unconventional presentations, have remained largely unrecognized by care providers. Here, we report three cases of infants whose mothers consumed dairy products during pregnancy, who developed a severely constipated pre- and postnatal bowel. The passage of meconium was significantly delayed with subsequent early-onset infant constipation that was intractable to conventional therapies but remitted when milk proteins were withheld, recurred when milk proteins were reintroduced, and resolved again when switched to an extensively hydrolyzed or amino acid-based infant formula. Based on this and other observations, it is believed that these infants must have initiated and/or developed cow's milk protein allergy prenatally during fetal life. We suggest that a 2-week trial of cow's milk protein avoidance be applied to these neonate infants with early-onset constipation before an unnecessary invasive work-up for Hirschsprung disease and others is initiated per the current guidelines.

Ataxia-telangiectasia mutated (ATM) is one of the three main apical kinases at the crux of DNA damage response and repair in mammalian cells. ATM activates a cascade of downstream effector proteins to regulate DNA repair and cell cycle checkpoints in response to DNA double-strand breaks. While ATM is predominantly known for its role in DNA damage response and repair, new roles of ATM have recently begun to emerge, such as in regulating oxidative stress or metabolic pathways. Here, we report the surprising discovery that ATM inhibition and deletion lead to reduced expression of the nuclear envelope protein lamin A. Lamins are nuclear intermediate filaments that modulate nuclear shape, structure, and stiffness. Accordingly, inhibition or deletion of ATM resulted in increased nuclear deformability and enhanced cell migration through confined spaces, which requires substantial nuclear deformation. These findings point to a novel connection between ATM and lamin A and may have broad implications for cells with ATM mutations—as found in patients suffering from Ataxia Telangiectasia and many human cancers—which could lead to enhanced cell migration and increased metastatic potential.