The AURKA/TPX2 axis drives colon tumorigenesis cooperatively with MYC.

BACKGROUND: The MYC oncogene has long been established as a central driver in many types of human cancers including colorectal cancer. However, the realization of MYC-targeting therapies remains elusive; as a result, synthetic lethal therapeutic approaches are alternatively being explored. A synthetic lethal therapeutic approach aims to kill MYC-driven tumors by targeting a certain co-regulator on the MYC pathway. PATIENTS AND METHODS: We analyzed copy number and expression profiles from 130 colorectal cancer tumors together with publicly available datasets to identify co-regulators on the MYC pathway. Candidates were functionally tested by in vitro assays using colorectal cancer and normal fibroblast cell lines. Additionally, survival analyses were carried out on another 159 colorectal cancer patients and public datasets. RESULTS: Our in silico screening identified two MYC co-regulator candidates, AURKA and TPX2, which are interacting mitotic regulators located on chromosome 20q. We found the two candidates showed frequent co-amplification with the MYC locus while expression levels of MYC and the two genes were positively correlated with those of MYC downstream target genes across multiple cancer types. In vitro, the aberrant expression of MYC, AURKA and TPX2 resulted in more aggressive anchorage-independent growth in normal fibroblast cells. Furthermore, knockdown of AURKA or TPX2, or treatment with an AURKA-specific inhibitor effectively suppressed the proliferation of MYC-expressing colorectal cancer cells. Additionally, combined high expression of MYC, AURKA and TPX2 proved to be a poor prognostic indicator of colorectal cancer patient survival. CONCLUSIONS: Through bioinformatic analyses and experiments, we proposed TPX2 and AURKA as novel co-regulators on the MYC pathway. Inhibiting the AURKA/TPX2 axis would be a novel synthetic lethal therapeutic approach for MYC-driven cancers.

Addiction to the IGF2-ID1-IGF2 circuit for maintenance of the breast cancer stem-like cells.

The transcription factor nuclear factor-κB (NF-κB) has important roles for tumorigenesis, but how it regulates cancer stem cells (CSCs) remains largely unclear. We identified insulin-like growth factor 2 (IGF2) is a key target of NF-κB activated by HER2/HER3 signaling to form tumor spheres in breast cancer cells. The IGF2 receptor, IGF1 R, was expressed at high levels in CSC-enriched populations in primary breast cancer cells. Moreover, IGF2-PI3K (IGF2-phosphatidyl inositol 3 kinase) signaling induced expression of a stemness transcription factor, inhibitor of DNA-binding 1 (ID1), and IGF2 itself. ID1 knockdown greatly reduced IGF2 expression, and tumor sphere formation. Finally, treatment with anti-IGF1/2 antibodies blocked tumorigenesis derived from the IGF1Rhigh CSC-enriched population in a patient-derived xenograft model. Thus, NF-κB may trigger IGF2-ID1-IGF2-positive feedback circuits that allow cancer stem-like cells to appear. Then, they may become addicted to the circuits. As the circuits are the Achilles' heels of CSCs, it will be critical to break them for eradication of CSCs.

Visual responses of morphologically identified tectal neurons in the crucian carp.

Tectal neurons of the crucian carp were functionally and morphologically identified by recording their electrical activity and simultaneously injecting dye (Procion yellow). Among intrinsic tectal neurons, visual neurons successfully stained with dye were pyramidal, pyriform and uncategorized neurons. The stained intrinsic tectal neurons were classified into 4 types, according to their visual response properties, i.e. sustained, dimming, transient and other response types. In 23 stained neurons we studied, no correlation was established between response properties and morphology of tectal neurons. In stained pyramidal neurons, the following receptive field (RF) organization could be recognized: (1) on-center, off-surround; off-center, on-surround; both with a small RF; and (2) excitatory or inhibitory center only, with a large RF.

An extensive projection of fish dorsolateral tegmental cells to the optic tectum revealed by intra-axonal dye marking.

The cells of the dorsolateral tegmental (DLT) nucleus in the crucian carp (Carassius carassius) were physiologically identified and marked with Lucifer dye. All the identified DLT cells receive both visual and rhombencephalic inputs. These cells project their axons into the contralateral tectum via the tectal commissure as well as into the ipsilateral tectum. The most striking characteristic of the DLT cells was the wide distribution of their axonal branching in the ipsilateral tectum.

Efferent tectal cells of crucian carp: physiology and morphology.

Tectal cells of the crucian carp (Carassius ararssius) showing antidromic responses evoked by rhombencephalic electrical stimulation were physiologically studied and subsequently stained with Lucifer Yellow CH. The stained efferent tectal cells were fusiform, horizontal, and multipolar. The main axon of these efferent tectal cells descended along the wall of the deep tegmentum and could be traced to the motor area below the cerebellum. The axons gave off their collaterals in several brain areas: 1) descending collaterals in the torus semicircularis, dorso-lateral tegmental area and mesencephalic reticular formation and 2) an ascending collateral in the area between the hypothalamus and tegmentum. Fifty percent of the efferent cells were unresponsive to visual stimuli, but some of these cells were activated by visual or tactile stimulation in conjunction with rhombencephalic electrical stimulation. On the other hand, most of the visually active cells were On-transient and movement sensitive with habituation and some were bimodal.

Morphology and Physiology of the Thoracic and Abdominal Stretch Receptors of the Isopod Crustacean Ligia exotica.

In the terrestrial isopod Ligia exotica, paired stretch receptors, each comprising a separate rapidly and slowly adapting receptor cell, were found in the third to eighth thoracic segments and first five abdominal segments. The dendritic endings of the two sensory cells in each receptor terminate on a common receptor muscle; the cross-striation of this fiber is homogeneous throughout the segments. But the dendritic endings of the receptor cells differ: the rapidly adapting cell has a club-shaped ending restricted to the middle of the receptor muscle, whereas the slowly adapting receptor cell has a bifurcating ending that extends along the entire length of the muscle. Stretch applied to the receptor muscle evokes characteristically different responses in the two sensory cells. The slowly adapting receptor cell has a lower firing threshold and fires continuously for the duration of the stretch, while the rapidly adapting receptor cell has a higher threshold and fires a brief burst at the beginning of the stimulus. However, application of an intense stimulus will evoke continuous firing of the rapidly adapting receptor, which then changes to intermittent bursts. The adaptive significance of such a response is not known, nor is it likely to occur in nature. However, this unusual response is intrinsic to the rapidly adapting cell, as it can be evoked by current injection. In the second thoracic segment, instead of rapidly and slowly adapting cells, we found a single slowly adapting cell with a long robust dendrite attached to the extensor muscle.

Functional organisation of anterior thoracic stretch receptors in the deep-sea isopod Bathynomus doederleini: behavioural, morphological and physiological studies.

The relationship between segmental mobility and the organisation of thoracic stretch receptors was examined in the deep-sea isopod Bathynomus doederleini, which shows a developed adaptive behaviour during digging. The movements of segments during digging were analysed from video recordings, which showed that a large excursion occurred in the anterior thoracic segments. Dye-fills of axons revealed four types of thoracic stretch receptor (TSR): an N-cell type (TSR-1), a differentiated N-cell type (TSR-2), a muscle receptor organ (MRO)-type with a long, single receptor muscle (TSR-3) and an MRO-type with a short, single receptor muscle (TSR-4 to TSR-7). Physiologically, TSR-1 and TSR-2 are tonic-type stretch receptors. TSR-3 to TSR-7 show two kinds of stretch-activated responses, a tonic response and a phasico-tonic response in which responses are maintained as long as the stretch stimulus is delivered. Both TSR-2, with a long muscle strand, and TSR-3, with a single, long receptor muscle, have a wide dynamic range in their stretch-activated response. In addition, TSR-2 is controlled by an intersegmental inhibitory reflex from TSR-3. These results suggest that, although TSR-1 has no receptor muscle and TSR-2 has a less-differentiated receptor-like muscle, they are fully functional position detectors of segmental movements, as are the MRO-type receptors TSR-3 to TSR-7.