Peptostreptococcus stomatis promotes colonic tumorigenesis and receptor tyrosine kinase inhibitor resistance by activating ERBB2-MAPK.
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.
Pubmed ID: 39059397 RIS Download
Research resources used in this publication
- LoVo (RRID:CVCL_0399) (cell line)
- DLD-1 (RRID:CVCL_0248) (cell line)
- HCT 116 (RRID:CVCL_0291) (cell line)
- Caco-2 (RRID:CVCL_0025) (cell line)
- HT-29 (RRID:CVCL_0320) (cell line)
- NCM460D (RRID:CVCL_IS47) (cell line)
- NU/J (RRID:IMSR_JAX:002019) (organism)
- C57BL/6J (RRID:IMSR_JAX:000664) (organism)
- C57BL/6J-ApcMin/J (RRID:IMSR_JAX:002020) (organism)
- cm[1] (RRID:BDSC_21) (organism)
Additional research tools detected in this publication
None foundAntibodies used in this publication
- Goat anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 488 (RRID:AB_2576217)
- Fibronectin antibody (RRID:AB_2105691)
- Recombinant Anti-ERK1 + ERK2 antibody [EPR17526] (RRID:AB_2802136)
- Recombinant Anti-MEK1 + MEK2 antibody [EPR16667] (RRID:AB_2891005)
- His-Tag (D3I1O) XP® (RRID:AB_2744546)
- Rabbit Anti-p90RSK, phospho (Ser380) Monoclonal Antibody, Unconjugated, Clone 9D9 (RRID:AB_561151)
- p44/42 MAPK (Erk1/2) (137F5) Rabbit mAb (RRID:AB_390779)
- Phospho-MEK1/2 (Ser217/221) (41G9) Rabbit mAb (RRID:AB_2138017)
- Phospho-c-Raf (Ser338) (56A6) Rabbit mAb (RRID:AB_2067317)
- Phospho-HER4/ErbB4 (Tyr1284) (21A9) Rabbit mAb (RRID:AB_2099987)
- Phospho-HER3/ErbB3 (Tyr1289) (D1B5) Rabbit mAb (RRID:AB_11178795)
- Phospho-HER2/ErbB2 (Tyr1221/1222) (6B12) Rabbit mAb (RRID:AB_490899)
- Rat Anti-Integrin alpha 6 / CD49f Monoclonal antibody, Unconjugated, Clone goh3 (RRID:AB_2128311)
- HER2/ErbB2 (D8F12) XP Rabbit mAb (RRID:AB_10557104)
- Phospho-EGF Receptor (Tyr1068) (D7A5) XP Rabbit mAb (RRID:AB_2096270)
- GST-Tag (26H1) Mouse mAb (RRID:AB_2189875)
- Integrin Beta 4 antibody (RRID:AB_10733888)
- E-Cadherin (4A2) (RRID:AB_2728770)
- Integrin alpha 6 Antibody (RRID:AB_11039415)
- Ki-67 (D3B5) Rabbit mAb (Mouse Preferred; IHC Formulated) (RRID:AB_2620142)
- β-Actin (13E5) Rabbit mAb (RRID:AB_2223172)
- CDK6 (D4S8S) Rabbit mAb (RRID:AB_2721897)
- cyclin D1 (H-295) (RRID:AB_2070433)
- Cleaved Caspase-9 (Asp315) Antibody (Human Specific) (RRID:AB_2290727)
- Caspase-9 (C9) Mouse mAb (RRID:AB_2068620)
- Cleaved PARP (Asp214) (D64E10) XP Rabbit mAb (RRID:AB_10699459)
- PARP (46D11) Rabbit mAb (RRID:AB_659884)
- Cleaved Caspase-7 (Asp198) Antibody (RRID:AB_2068144)
- Caspase-7 Antibody (RRID:AB_2228313)
- Mouse Anti-Occludin Monoclonal Antibody, Unconjugated, Clone E-5 (RRID:AB_2156317)
- Anti-Integrin B4 Antibody, clone ASC-8, Azide & Ascites Free (RRID:AB_3107035)
Associated grants
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This is a list of tools and resources that we have found mentioned in this publication.
Goat anti-Rabbit IgG (H+L) Highly Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 488 (antibody)
RRID:AB_2576217
This polyclonal secondary targets IgG (H+L)
View all literature mentionsFibronectin antibody (antibody)
RRID:AB_2105691
This polyclonal targets Fibronectin
View all literature mentionsRecombinant Anti-ERK1 + ERK2 antibody [EPR17526] (antibody)
RRID:AB_2802136
This recombinant targets ERK1 + ERK2
View all literature mentionsRecombinant Anti-MEK1 + MEK2 antibody [EPR16667] (antibody)
RRID:AB_2891005
This recombinant monoclonal targets MEK1 + MEK2
View all literature mentionsHis-Tag (D3I1O) XP® (antibody)
RRID:AB_2744546
This monoclonal targets His-Tag
View all literature mentionsRabbit Anti-p90RSK, phospho (Ser380) Monoclonal Antibody, Unconjugated, Clone 9D9 (antibody)
RRID:AB_561151
This monoclonal targets p90RSK, phospho (Ser380)
View all literature mentionsp44/42 MAPK (Erk1/2) (137F5) Rabbit mAb (antibody)
RRID:AB_390779
This monoclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsPhospho-MEK1/2 (Ser217/221) (41G9) Rabbit mAb (antibody)
RRID:AB_2138017
This monoclonal targets Phospho-MEK1/2 (Ser217/221)
View all literature mentionsPhospho-c-Raf (Ser338) (56A6) Rabbit mAb (antibody)
RRID:AB_2067317
This monoclonal targets c-Raf, phospho (Ser338)
View all literature mentionsPhospho-HER4/ErbB4 (Tyr1284) (21A9) Rabbit mAb (antibody)
RRID:AB_2099987
This monoclonal targets Erbb4
View all literature mentionsPhospho-HER3/ErbB3 (Tyr1289) (D1B5) Rabbit mAb (antibody)
RRID:AB_11178795
This monoclonal targets Phospho-HER3/ErbB3 (Tyr1289) (D1B5) Rabbit mAb
View all literature mentionsPhospho-HER2/ErbB2 (Tyr1221/1222) (6B12) Rabbit mAb (antibody)
RRID:AB_490899
This monoclonal targets Monoclonal antibodies are produced by immunizing rabbits with a synthetic phosphopeptide (KLH-coupled) corresponding to residues surrounding tyrosines 1221/1222 of human ErbB2 protein.
View all literature mentionsRat Anti-Integrin alpha 6 / CD49f Monoclonal antibody, Unconjugated, Clone goh3 (antibody)
RRID:AB_2128311
This monoclonal targets Integrin alpha 6 / CD49f
View all literature mentionsHER2/ErbB2 (D8F12) XP Rabbit mAb (antibody)
RRID:AB_10557104
This monoclonal targets HER2/ErbB2 (D8F12) XP Rabbit mAb
View all literature mentionsPhospho-EGF Receptor (Tyr1068) (D7A5) XP Rabbit mAb (antibody)
RRID:AB_2096270
This monoclonal targets Phospho-EGF Receptor (Tyr1068)
View all literature mentionsGST-Tag (26H1) Mouse mAb (antibody)
RRID:AB_2189875
This monoclonal targets GST
View all literature mentionsIntegrin Beta 4 antibody (antibody)
RRID:AB_10733888
This polyclonal targets Integrin Beta 4
View all literature mentionsE-Cadherin (4A2) (antibody)
RRID:AB_2728770
This monoclonal targets E-Cadherin
View all literature mentionsIntegrin alpha 6 Antibody (antibody)
RRID:AB_11039415
This unknown targets Integrin alpha 6
View all literature mentionsKi-67 (D3B5) Rabbit mAb (Mouse Preferred; IHC Formulated) (antibody)
RRID:AB_2620142
This monoclonal targets Ki-67
View all literature mentionsβ-Actin (13E5) Rabbit mAb (antibody)
RRID:AB_2223172
This monoclonal targets beta-Actin
View all literature mentionsCDK6 (D4S8S) Rabbit mAb (antibody)
RRID:AB_2721897
This monoclonal targets CDK6
View all literature mentionscyclin D1 (H-295) (antibody)
RRID:AB_2070433
This polyclonal targets CCND1
View all literature mentionsCleaved Caspase-9 (Asp315) Antibody (Human Specific) (antibody)
RRID:AB_2290727
This polyclonal targets Cleaved Caspase-9 (Asp315) (Human Specific)
View all literature mentionsCaspase-9 (C9) Mouse mAb (antibody)
RRID:AB_2068620
This monoclonal targets Caspase 9
View all literature mentionsCleaved PARP (Asp214) (D64E10) XP Rabbit mAb (antibody)
RRID:AB_10699459
This monoclonal targets Cleaved PARP (Asp214)
View all literature mentionsPARP (46D11) Rabbit mAb (antibody)
RRID:AB_659884
This monoclonal targets PARP
View all literature mentionsCleaved Caspase-7 (Asp198) Antibody (antibody)
RRID:AB_2068144
This polyclonal targets Cleaved Caspase-7 (Asp198)
View all literature mentionsCaspase-7 Antibody (antibody)
RRID:AB_2228313
This polyclonal targets Casp7
View all literature mentionsMouse Anti-Occludin Monoclonal Antibody, Unconjugated, Clone E-5 (antibody)
RRID:AB_2156317
This monoclonal targets Ocln
View all literature mentionsAnti-Integrin B4 Antibody, clone ASC-8, Azide & Ascites Free (antibody)
RRID:AB_3107035
This monoclonal targets Integrin B4
View all literature mentionsLoVo (cell line)
RRID:CVCL_0399
Cell line LoVo is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsDLD-1 (cell line)
RRID:CVCL_0248
Cell line DLD-1 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsHCT 116 (cell line)
RRID:CVCL_0291
Cell line HCT 116 is a Cancer cell line with a species of origin Homo sapiens (Human)
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RRID:CVCL_0025
Cell line Caco-2 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsHT-29 (cell line)
RRID:CVCL_0320
Cell line HT-29 is a Cancer cell line with a species of origin Homo sapiens (Human)
View all literature mentionsNCM460D (cell line)
RRID:CVCL_IS47
Cell line NCM460D is a Spontaneously immortalized cell line with a species of origin Homo sapiens (Human)
View all literature mentionsNU/J (organism)
RRID:IMSR_JAX:002019
Mus musculus with name NU/J from IMSR.
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RRID:IMSR_JAX:000664
Mus musculus with name C57BL/6J from IMSR.
View all literature mentionsC57BL/6J-ApcMin/J (organism)
RRID:IMSR_JAX:002020
Mus musculus with name C57BL/6J-ApcMin/J from IMSR.
View all literature mentionscm[1] (organism)
RRID:BDSC_21
Drosophila melanogaster with name cm[1] from BDSC.
View all literature mentions
