Functional Characterisation of the ATOH1 Molecular Subtype Indicates a Pro-Metastatic Role in Small Cell Lung Cancer

Overview

Journal bioRxiv

Date 2024 Feb 26

PMID 38405859

Authors

Alessia Catozzi

Maria Peiris-Pages

Sam Humphrey

Mitchell Revill

Derrick Morgan

Jordan Roebuck

Yitao Chen

Bethan Davies-Williams

Alice Lallo

Melanie Galvin

Simon P Pearce

Alastair Kerr

Lynsey Priest

Victoria Foy

Mathew Carter

Rebecca Caeser

Joseph Chan

Charles M Rudin

Fiona Blackhall

Kristopher K Frese

Caroline Dive

Kathryn L Simpson

Affiliations

Soon will be listed here.

Abstract

Molecular subtypes of Small Cell Lung Cancer (SCLC) have been described based on differential expression of transcription factors (TFs) , and immune-related genes. We previously reported an additional subtype based on expression of the neurogenic TF within our SCLC Circulating tumour cell-Derived eXplant (CDX) model biobank. Here we show that ATOH1 protein was detected in 7/81 preclinical models and 16/102 clinical samples of SCLC. In CDX models, ATOH1 directly regulated neurogenesis and differentiation programs consistent with roles in normal tissues. In cultures of ATOH1-positive CDX, ATOH1 was required for cell survival. , ATOH1 depletion slowed tumour growth and suppressed liver metastasis. Our data validate ATOH1 as a oncogenic driver of SCLC with tumour cell survival and pro-metastatic functions. Further investigation to explore ATOH1 driven vulnerabilities for targeted treatment with predictive biomarkers is warranted.

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