Biology subjects

Mimori, K.

Publications and source records attributed to Mimori, K..

4 recordsLinked to original sources

bioRxiv2025

Aberrant Hippo-YAP/TEAD signaling drives malignant transcriptional reprogramming in external auditory canal squamous cell carcinoma

PurposeExternal auditory canal squamous cell carcinoma (EACSCC) is an extremely rare malignancy. The molecular characteristics and evidence-based therapeutic strategies of EACSCC still remain to be elucidated. Experimental DesignComprehensive analyses of RNA sequencing (RNA-seq) and ChIP sequencing (ChIP-seq) utilizing YAP and H3K27Ac antibodies were performed in primary EACSCC and noncancerous ear skin samples. Functional experiments were performed in EACSCC-derived cells and Head and Neck Squamous Cell Carcinoma (HNSCC) cells in vitro and in vivo. Immunohistochemical staining of primary EACSCC tissues as well as survival analysis were conducted. ResultsRNA-seq indicated hyperactivation of YAP/TEAD-mediated transcriptional programs in EACSCC. H3K27Ac ChIP-seq suggested gained accessibility for transcription factor (TF) binding sites for TEAD, AP-1 and PITX TFs in EACSCC, and presence of EACSCC-specific super enhancers (SEs). YAP-bound SEs were involved in oncogenic transcription, including EGFR signaling. Small molecule TEAD inhibitor (smTEADi) VT104 showed significant suppression of proliferation and clonogenicity in EACSCC cells. Importantly, smTEADi not only inhibited YAP-TEAD interaction but also induced YAP-PITX2 binding, suggesting that PITX2 could represent an alternative partner TF of YAP under TEAD-inhibited conditions. Knockdown of PITX2 inhibited cell growth and migration of EACSCC and HNSCC cells, whereas overexpression of PITX2 induced expression of cell cycle, stemness, and EMT genes, as well as YAP/TAZ-TEAD target genes, and promoted tumor growth in vivo. Nuclear YAP and PITX2 expression were significantly correlated with poor prognosis of EACSCC patients. ConclusionsThis study highlighted the hyperactivation of the YAP-TEAD/PITX2 transcriptional program and its potential as a therapeutic target in EACSCC. Translational RelevanceExternal auditory canal squamous cell carcinoma (EACSCC) is an extremely rare malignancy related to chronic tissue damage and inflammation. Due to its rarity, the molecular characteristics of EACSCC are poorly understood, and evidence-based therapeutic strategies are not fully developed. Here, we provide evidence of hyperactivation of YAP/TEAD-driven transcriptional programs in EACSCC, utilizing comprehensive analyses of RNA-seq and YAP/H3K27Ac ChIP-seq in clinical tissue samples, as well as in vitro and in vivo experiments. In addition, our data suggest that the PITX2 transcription factor (TF) could represent an alternative partner TF of YAP under TEAD-inhibited conditions, which may rescue oncogenic transcription of TEAD. Importantly, YAP and PITX2 are co-expressed in EACSCC and predict poor prognosis of EACSCC patients. Our results provide a rationale for YAP-hyperactivation in EACSCC and contribute to a better understanding of this malignancy and the development of new therapeutic strategies.

cancer biology↗

bioRxiv2020

APC mutant cells exploit compensatory chromosome alterations to restore tumour cell fitness

Cancer cells tolerate copy number alterations (CNAs) of genomic regions that are lethal to non-cancer cells. Certain CNAs are preferentially associated with specific cancer types and lineages, but the mechanisms underlying the emergence and selection of specific CNAs remain unclear. Adenomatous polyposis coli (APC) mutations induce mitotic errors, but their impact on tumor evolution remains elusive. We investigated APC function in cultured cells and tumors and found that its loss led to {beta}-catenin accumulation at centrosomes, suppressing its maturation through inhibition of key centrosome regulators, including Aurora kinase A (AURKA) that promotes tumor growth. These defects collectively reduced cellular fitness, leading to impaired mitotic fidelity and delayed cell cycle progression. However, in APC-mutant tumors, AURKA activity was maintained, at least in part, through the amplification of chromosomes harboring AURKA and its activator genes, yet this alone was insufficient to fully restore proliferation: aberrant chromosomal reorganization also emerged and contributed to the adaptive fitness of APC-mutant cells. Such a process of adaptive CNA selection provides a framework for understanding how specific CNAs are selected to counteract disadvantages imposed by genetic alterations during tumor progression, providing one key insight into how specific CNAs are selected in this context.

cell biology↗

bioRxiv2019

A unified simulation model for understanding the diversity of cancer evolution

Because cancer evolution underlies the therapeutic difficulties of cancer, it is clinically important to understand the evolutionary dynamics of cancer. Thus far, a number of evolutionary processes have been proposed to be working in cancer evolution. However, there exists no simulation model that can describe the different evolutionary processes in a unified manner. In this study, we constructed a unified simulation model for describing the different evolutionary processes and performed sensitivity analysis on the model to determine the conditions in which cancer growth is driven by each of the different evolutionary processes. Our sensitivity analysis has successfully provided a series of novel insights into the evolutionary dynamics of cancer. For example, we found that, while a high neutral mutation rate shapes neutral intratumor heterogeneity (ITH) characterized by a fractal-like pattern, a stem cell hierarchy can also contribute to shaping neutral ITH by apparently increasing the mutation rate. Although It has been reported that the evolutionary principle shaping ITH shifts from selection to accumulation of neutral mutations during colorectal tumorigenesis, our simulation revealed the possibility that this evolutionary shift is triggered by drastic evolutionary events that occur in a a short time and confer a marked fitness increase on one or a few cells. This result helps us understand that each process works not separately but simultaneously and continuously as a series of phases of cancer evolution. Collectively, this study serves as a basis to understand in greater depth the diversity of cancer evolution.

cancer biology↗

bioRxiv2019

Single-cell DNA and RNA sequencing reveals the dynamics of intra-tumor heterogeneity in a colorectal cancer model

Intra-tumor heterogeneity (ITH) encompasses cellular differences in tumors and is related to clinical outcomes, such as drug resistance. However, little is known about the dynamics of ITH, owing to the lack of time-series analysis at the single-cell level. We performed single-cell exome and transcriptome sequencing of 200 cells and investigated how ITH is generated from one single cell in a mouse colorectal cancer model. The ITH of the transcriptome increased after transplantation from cultured organoids, while that of the exome decreased. Mutations generated in the culture did not greatly change at the transplantation at the bulk-cell level. The RNA ITH increase was due to the emergence of new transcriptional subpopulations. In contrast to the initial cells expressing mesenchymal-marker genes, new subpopulations repressed these genes at transplantation. Analyses of colorectal cancer data from The Cancer Genome Atlas revealed a high proportion of metastatic cases in human subjects with expression patterns similar to the new cell subpopulations in mouse. These results suggest that the birth of transcriptional subpopulations may be a key for adaptation to drastic micro-environmental changes when cancer cells have sufficient genetic alterations at later tumor stages. This study revealed an evolutionary dynamics of single-cell RNA and DNA changes in tumor progression, giving insights into the mesenchymal-epithelial transformation of tumor cells at metastasis in colorectal cancer.

genomics↗