A molecular subtype of colorectal cancers initiates independently of epidermal growth factor receptor and has an accelerated growth rate mediated by IL10-dependent anergy

Rojas, Carolina Mantilla; Yu, Ming; Rinella, Erica S.; Lynch, Rachel; Perry, Amie; Jaimes-Alvarado, Jorge; Anderson, Kathryn R; Barba, Estefania; Bourgeois, Evann J; Konganti, Kranti; Threadgill, David W.

doi:10.1038/s41388-021-01752-2

Cited by 3 publications

(8 citation statements)

References 52 publications

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“…However, recent gene expression profiling shows that these two models are highly similar [45], suggesting that the difference in the route of tumor initiation in the Apc Min/+ and AOM models likely does not contribute to molecular differences resulting in ERBB3 sensitivity. An alternative possibility is that a subset of intestinal polyps can grow independently of ERBB3, similar to previous results observed for EGFR [40,46] In this study, we observed a profound genetic background-dependent effect on tumorigenesis in the absence of ERBB3. The effect on tumorigenesis of removing ERBB3 may result from its unique link to PI3K/AKT and its downstream effector MAPK.…”

Section: Plos Geneticssupporting

confidence: 90%

Section: Discussionsupporting

confidence: 79%

“…The effect of reduced in polyp size with ERBB3 loss is opposite to the effect previously reported for loss of EGFR. Previously, Roberts et al, demonstrated that reduced EGFR activity promoted the development of larger intestinal tumors [40], and using the same conditional knockout allele of EGFR used here, we also confirmed that the EGFR-independent intestinal and colonic tumors are larger [41], highlighting the unique role of ERBB3-dependent signaling in regulating tumor growth.…”

Section: Plos Geneticssupporting

confidence: 86%

“…Mice were obtained from The Jackson Laboratory (C57BL/6J (B6)- Apc Min/+ ) and NCI-Frederick (B6;D2-Tg(Vil-Cre)20Syr) and maintained hemizygous on the C57BL/6J background. Tg(Vil1-Cre) was selected since it results in extensive target gene deletion throughout the intestinal and colonic epithelia with little expression elsewhere and was used in previous studies with EGFR and ERBB3 [ 23 , 41 ]. Erbb3 tm1 .…”

Section: Methodsmentioning

confidence: 99%

“…extensive target gene deletion throughout the intestinal and colonic epithelia with little expression elsewhere and was used in previous studies with EGFR and ERBB3 [23,41]. Erbb3 tm1.1Dwt (Erbb3 f ) and Egfr tm1Dmt (Egfr f ) mice were maintained on the C57BL/6J background.…”

Section: Plos Geneticsmentioning

confidence: 99%

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Epithelial-specific ERBB3 deletion results in a genetic background-dependent increase in intestinal and colon polyps that is mediated by EGFR

et al. 2021

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ERBB3 has gained attention as a potential therapeutic target to treat colorectal and other types of cancers. To confirm a previous study showing intestinal polyps are dependent upon ERBB3, we generated an intestinal epithelia-specific ERBB3 deletion in C57BL/6-ApcMin/+ mice. Contrary to the previous report showing a significant reduction in intestinal polyps with ablation of ERBB3 on a B6;129 mixed genetic background, we observed a significant increase in polyp number with ablation of ERBB3 on C57BL/6J compared to control littermates. We confirmed the genetic background dependency of ERBB3 by also analyzing polyp development on B6129 hybrid and B6;129 advanced intercross mixed genetic backgrounds, which showed that ERBB3 deficiency only reduced polyp number on the mixed background as previously reported. Increased polyp number with ablation of ERBB3 was also observed in C57BL/6J mice treated with azoxymethane showing the effect is model independent. Polyps forming in absence of ERBB3 were generally smaller than those forming in control mice, albeit the effect was greatest in genetic backgrounds with reduced polyp numbers. The mechanism for differential polyp number in the absence of ERBB3 was through altered proliferation. Backgrounds with increased polyp number with loss of ERBB3 showed an increase in cell proliferation even in non-tumor epithelia, while backgrounds showing reduced polyp number with loss of ERBB3 showed reduced cellular proliferation. Increase polyp number caused by loss of ERBB3 was mediated by increased epidermal growth factor receptor (EGFR) expression, which was confirmed by deletion of Egfr. Taken together, this study raises substantial implications on the use of ERBB3 inhibitors against colorectal cancer. The prediction is that some patients may have increased progression with ERBB3 inhibitor therapy, which is consistent with observations reported for ERBB3 inhibitor clinical trials.

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Section: Plos Geneticssupporting

confidence: 90%

Section: Discussionsupporting

confidence: 79%

Section: Plos Geneticssupporting

confidence: 86%

Section: Methodsmentioning

confidence: 99%

Section: Plos Geneticsmentioning

confidence: 99%

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Epithelial-specific ERBB3 deletion results in a genetic background-dependent increase in intestinal and colon polyps that is mediated by EGFR

et al. 2021

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Adding robustness to rigor and reproducibility for the three Rs of improving translational medical research

McGill,

Threadgill

2023

Journal of Clinical Investigation

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Mechanism and strategies of immunotherapy resistance in colorectal cancer

et al. 2022

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Colorectal cancer (CRC) is the third most common cancer in the world. Although there are standard treatment options for CRC, most patients respond poorly to these treatments. Immunotherapies have gradually emerged due to the increasing awareness and understanding of tumor immunity, exhibiting good therapeutic efficacy in various cancers. Immunotherapies include cytokines, immune checkpoint inhibitors (ICIs), and adoptive cell therapies. In particular, ICIs, which are antibodies against cytotoxic T lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1), or its ligand PD-L1, have been successfully applied clinically for solid tumors, relieving the inhibitory effect of the tumor microenvironment on T cells. However, only a minority of patients with cancer achieve a durable clinical response during immunotherapy. Several factors restrict the efficacy of immunotherapy, leading to the development of drug resistance. In this review, we aimed to discuss the current status of immunotherapy for CRC and elaborate on the mechanisms that mediate resistance to immunotherapy and other potential therapeutic strategies.

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A molecular subtype of colorectal cancers initiates independently of epidermal growth factor receptor and has an accelerated growth rate mediated by IL10-dependent anergy

Cited by 3 publications

References 52 publications

Epithelial-specific ERBB3 deletion results in a genetic background-dependent increase in intestinal and colon polyps that is mediated by EGFR

Epithelial-specific ERBB3 deletion results in a genetic background-dependent increase in intestinal and colon polyps that is mediated by EGFR

Adding robustness to rigor and reproducibility for the three Rs of improving translational medical research

Mechanism and strategies of immunotherapy resistance in colorectal cancer

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