2. Academic Validation
  3. Peptostreptococcus stomatis promotes colonic tumorigenesis and receptor tyrosine kinase inhibitor resistance by activating ERBB2-MAPK

Peptostreptococcus stomatis promotes colonic tumorigenesis and receptor tyrosine kinase inhibitor resistance by activating ERBB2-MAPK

  • Cell Host Microbe. 2024 Aug 14;32(8):1365-1379.e10. doi: 10.1016/j.chom.2024.07.001.
Pingmei Huang 1,  Fenfen Ji 1,  Alvin Ho-Kwan Cheung 2,  Kaili Fu 1,  Qiming Zhou 1,  Xiao Ding 1,  Danyu Chen 1,  Yufeng Lin 1,  Luyao Wang 1,  Ying Jiao 1,  Eagle S H Chu 1,  Wei Kang 2,  Ka Fai To 2,  Jun Yu 3,  Chi Chun Wong 4
Affiliations

Affiliations

  • 1 Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 2 Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 3 Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: junyu@cuhk.edu.hk.
  • 4 Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: chichun.wong@cuhk.edu.hk.
PMID: 39059397 DOI: 10.1016/j.chom.2024.07.001
Abstract

Peptostreptococcus stomatis (P. stomatis) is enriched in colorectal Cancer (CRC), but its causality and translational implications in CRC are unknown. Here, we show that P. stomatis accelerates colonic tumorigenesis in APCMin/+ and azoxymethane/dextran sodium sulfate (AOM-DSS) models by inducing cell proliferation, suppressing Apoptosis, and impairing gut barrier function. P. stomatis adheres to CRC cells through its surface protein fructose-1,6-bisphosphate aldolase (FBA) that binds to the Integrin α6/β4 receptor on CRC cells, leading to the activation of ERBB2 and the downstream MEK-ERK-p90 cascade. Blockade of the FBA-integrin α6/β4 abolishes ERBB2-mitogen-activated protein kinase (MAPK) activation and the protumorigenic effect of P. stomatis. P. stomatis-driven ERBB2 activation bypasses receptor tyrosine kinase (RTK) blockade by EGFR inhibitors (cetuximab, erlotinib), leading to drug resistance in xenograft and spontaneous CRC models of KRAS-wild-type CRC. P. stomatis also abrogates BRaf Inhibitor (vemurafenib) efficacy in BRafV600E-mutant CRC xenografts. Thus, we identify P. stomatis as an oncogenic bacterium and a contributory factor for non-responsiveness to RTK inhibitors in CRC.

Keywords

Peptostreptococcus Stomatis; colorectal cancer; drug resistance; host-microbe interaction; receptor tyrosine kinase inhibitor.

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