# It Is Time to Consider the Lost Battle of Microdamaged Piezo2 in the Context of E. coli and Early-Onset Colorectal Cancer

## TL;DR

This paper explores how a malfunction in the Piezo2 protein might contribute to early-onset colorectal cancer by altering proton regulation and interacting with E. coli's colibactin.

## Contribution

The paper proposes a novel oscillatory signaling mechanism involving Piezo2 and proton tunneling in colorectal cancer pathogenesis.

## Key findings

- Piezo2 channelopathy disrupts proton regulation, favoring E. coli in the gut microbiota.
- Colibactin from E. coli interacts with Piezo2 dysfunction to cause DNA damage and Wnt signaling disruption.
- Piezo2 malfunction may drive cancer initiation, proliferation, and metastasis via altered mechanotransduction.

## Abstract

The recent identification of early-onset mutational signatures with geographic variations by Diaz-Gay et al. is a significant finding, since early-onset colorectal cancer has emerged as an alarming public health challenge in the past two decades, and the pathomechanism remains unclear. Environmental risk factors, including lifestyle and diet, are highly suspected. The identification of colibactin from Escherichia coli as a potential pathogenic source is a major step forward in addressing this public health challenge. Therefore, the following opinion manuscript aims to outline the likely onset of the pathomechanism and the critical role of acquired Piezo2 channelopathy in early-onset colorectal cancer, which skews proton availability and proton motive force regulation toward E. coli within the microbiota–host symbiotic relationship. In addition, the colibactin produced by the pks island of E. coli induces host DNA damage, which likely interacts at the level of Wnt signaling with Piezo2 channelopathy-induced pathological remodeling. This transcriptional dysregulation eventually leads to tumorigenesis of colorectal cancer. Mechanotransduction converts external physical cues to inner chemical and biological ones. Correspondingly, the proposed quantum mechanical free-energy-stimulated ultrafast proton-coupled tunneling, initiated by Piezo2, seems to be the principal and essential underlying novel oscillatory signaling that could be lost in colorectal cancer onset. Hence, Piezo2 channelopathy not only contributes to cancer initiation and impaired circadian regulation, including the proposed hippocampal ultradian clock, but also to proliferation and metastasis.