Rose, B. | bioRxiv Science

bioRxiv2023

Faulty Metabolism: A Potential Instigator of an Aggressive Phenotype in Cdk5-dependent Medullary Thyroid Carcinoma

Mechanistic modeling of cancers such as Medullary Thyroid Carcinoma (MTC) to emulate patient-specific phenotypes is challenging. The discovery of potential diagnostic markers and druggable targets in MTC urgently requires clinically relevant animal models. Here we established orthotopic mouse models of MTC driven by aberrantly active Cdk5 using cell-specific promoters. Each of the two models elicits distinct growth differences that recapitulate the less or more aggressive forms of human tumors. The comparative mutational and transcriptomic landscape of tumors revealed significant alterations in mitotic cell cycle processes coupled with the slow-growing tumor phenotype. Conversely, perturbation in metabolic pathways emerged as critical for aggressive tumor growth. Moreover, an overlapping mutational profile was identified between mouse and human tumors. Gene prioritization revealed putative downstream effectors of Cdk5 which may contribute to the slow and aggressive growth in the mouse MTC models. In addition, Cdk5/p25 phosphorylation sites identified as biomarkers for Cdk5-driven neuroendocrine tumors (NETs) were detected in both slow and rapid onset models and were also histologically present in human MTC. Thus, this study directly relates mouse and human MTC models and uncovers vulnerable pathways potentially responsible for differential tumor growth rates. Functional validation of our findings may lead to better prediction of patient-specific personalized combinational therapies. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC="FIGDIR/small/544755v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@196ed2dorg.highwire.dtl.DTLVardef@1ad2d59org.highwire.dtl.DTLVardef@7c6e84org.highwire.dtl.DTLVardef@13bd7db_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LICGRP driven aberrant Cdk5 activation develops early onset aggressive MTC C_LIO_LIGenetic alterations in mouse and human tumors disrupt common pathways C_LIO_LIAggressive tumor model characterized by alterations in metabolic pathways C_LIO_LISlow growing tumor model elicits disruption of mitotic spindle assembly C_LI

cancer biology↗

bioRxiv2019

Stress-induced dendritic branching in C. elegans requires both common arborization effectors and stress-responsive molecular pathways.

Stress influences the shape of dendritic arbors in neurons. During the stress-induced dauer stage of Caenorhabditis elegans, the IL2 neurons arborize to cover the anterior body wall. In contrast, the FLP neurons arborize to cover the anterior body wall during non-dauer development. Previous work showed that the membrane-bound receptor DMA-1 regulates FLP branching as part of a larger protein complex. Using forward genetics, we show that the IL2 neurons also use the DMA-1 complex to regulate branching. To understand the coordination of the IL2s and FLPs we conducted a time-course examination of FLPs and found previously undescribed branching patterns indicating a neighborhood effect wherein the FLPs and IL2s in the anterior have differential branching compared to the more posteriorly located PVD arborizing neurons. To determine how the IL2s and FLPs differentially regulate branching, we examined several regulators of DMA-1 localization. We show that the unfolded protein response sensor IRE-1, required for FLP branching, is only required for dauer-specific branching at elevated temperatures. Interestingly, we found that ire-1 mutants have broad, organism-wide temperature-dependent effects on dauer remodeling, suggesting a previously undescribed role for IRE-1 in phenotypic plasticity. We also found that defects in other regulators of dauer remodeling including DAF-16/FOXO, DAF-9/Cytochrome P450, and DAF-18/PTEN are required for proper IL2 arborization, but dispensable for FLP branching. Interestingly, we find that TOR adaptor protein DAF-15/RAPTOR is both required for promoting IL2 branching and inhibiting precocious development of the FLPs. Our results demonstrate specific genotypic by environmental interactions regulating dendrite arborization.\n\nSIGNIFICANCE STATEMENTNeurons have extensions called dendrites that receive information. Dendrites are often elaborately shaped with many branches. Adverse stress can reduce branching in some neurons, while increasing it in others. How stress can cause some neurons to change shape is unclear. We previously found a set of neurons in the head of the well-studied roundworm C. elegans that undergo reversible branching following exposure to specific adverse environmental conditions. Using various genetic tools, we find that branching in these neurons is controlled by a combination of branching genes common to many neuron types and others that only regulate branching in stress-responsive neurons. Our data demonstrate how experiencing stress acts through genetics pathways to cause changes to specific neurons.

neuroscience↗