A Systems-Based Key Innovation-Driven Approach Infers Co-option of Jaw Developmental Programs During Cancer Progression

Cancer acquires metastatic potential and evolves via co-opting gene regulatory networks (GRN) of embryonic development and tissue homeostasis. Such GRNs are encoded in the genome and frequently conserved among species. Considering that all metazoa have evolved from a common ancestor via major macroevolutionary events which shaped those GRNs and increased morphogenetic complexity, we sought to examine whether there are any key innovations that may be consistently and deterministically linked with metastatic potential across the metazoa clades. To address tumor evolution relative to organismal evolution, we revisited and retrospectively juxtaposed seminal laboratory and field cancer studies across taxa that lie on the evolutionary lineage from cnidaria to humans. We subsequently applied bioinformatics to integrate species-specific cancer phenotypes, multiomics data from up to 42 human cancer types, developmental phenotypes of knockout mice, and molecular phylogenetics. We found that the phenotypic manifestations of metastasis appear to coincide with agnatha-to-gnathostome transition. Genes indispensable for jaw development, a key innovation of gnathostomes, undergo mutations or methylation alterations, are aberrantly transcribed during tumor progression and are causatively associated with invasion and metastasis. There is a preference for deregulation of gnathostome-specific versus pre-gnathostome genes occupying hubs of the jaw development network. According to these data, we propose our systems-based model as an in silico tool the prediction of likely tumor evolutionary trajectories and therapeutic targets for metastasis prevention, on the rationale that the same genes which are essential for key innovations that catalyzed vertebrate evolution, such as jaws, are also important for tumor evolution.

Species-specific sensitivity to TGFβ signaling and changes to the Mmp13 promoter underlie avian jaw development and evolution

Developmental control of jaw length is critical for survival. The jaw skeleton arises from neural crest mesenchyme and previously we demonstrated that these progenitors upregulate bone-resorbing enzymes including Matrix metalloproteinase 13 (Mmp13) when generating short quail beaks versus long duck bills. Inhibiting bone resorption or Mmp13 increases jaw length. Here, we uncover mechanisms establishing species-specific levels of Mmp13 and bone resorption. Quail show greater activation of, and sensitivity to Transforming Growth Factor-Beta (TGFβ) signaling than duck; where mediators like SMADs and targets like Runx2, which bind Mmp13, become elevated. Inhibiting TGFβ signaling decreases bone resorption. We discover a SMAD binding element in the quail Mmp13 promoter not found in duck and single nucleotide polymorphisms (SNPs) near a RUNX2 binding element that affect expression. Switching the SNPs and SMAD site abolishes TGFβ-sensitivity in the quail Mmp13 promoter but makes duck responsive. Thus, differential regulation of TGFβ signaling and Mmp13 promoter structure underlie avian jaw development and evolution.

An Unusual Tooth Shedding with Internal Resorption: A Case Report

Humans have two sets of teeth, deciduous teeth and permanent teeth. When primary teeth fall out, permanent teeth erupt to maintain the chewing function and jaw development. Shedding occurs with increasing level of mobility in primary teeth as a result of root resorption. This report describes an uncommon clinical case that occurred in primary molars with internal resorption and pinkish discoloration. Pink tooth is worrisome for children and parents. Children should have their teeth examined on a regular basis to detect any problems in the process of tooth shedding and eruption.