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.
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DOI：
10.1371/journal.pgen.1009931
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发表时间：
2021-11
期刊：
影响因子：
4.5
通讯作者：
Threadgill DW
中科院分区：
文献类型：
--
作者：
Mantilla Rojas C;McGill MP;Salvador AC;Bautz D;Threadgill DW
ERBB 3作为治疗结直肠癌和其他类型癌症的潜在治疗靶点已引起关注。为了证实先前的研究显示肠息肉依赖于ERBB 3，我们在C57 BL/6-ApcMin/+小鼠中产生了肠上皮特异性ERBB 3缺失。与先前的报告显示在B6;129混合遗传背景下ERBB 3消融显著减少肠息肉相反，我们观察到与对照同窝仔相比，在C57 BL/6 J上ERBB 3消融的息肉数量显著增加。我们还通过分析B6129杂种和B6;129高级杂交混合遗传背景上的息肉发育证实了ERBB 3的遗传背景依赖性，这表明ERBB 3缺陷仅减少了混合背景上的息肉数量，如先前报道的。在用氧化偶氮甲烷处理的C57 BL/6 J小鼠中也观察到ERBB 3消融增加的息肉数量，表明该作用是模型无关的。在没有ERBB 3的情况下形成的息肉通常比对照小鼠中形成的息肉小，尽管在息肉数量减少的遗传背景中效果最大。在缺乏ERBB 3的情况下，息肉数量差异的机制是通过改变增殖。息肉数量增加伴ERBB 3缺失的背景显示即使在非肿瘤上皮细胞中细胞增殖也增加，而息肉数量减少伴ERBB 3缺失的背景显示细胞增殖减少。ERBB 3缺失引起的息肉数量增加是由表皮生长因子受体（EGFR）表达增加介导的，这一点通过Egfr缺失得到证实。总之，这项研究提出了使用ERBB 3抑制剂治疗结直肠癌的实质性意义。预测结果是，一些患者可能在ERBB 3抑制剂治疗后进展加快，这与ERBB 3抑制剂临床试验报告的观察结果一致。在临床前研究中有效的靶向癌症疗法并不总是转化为临床。这可能是由于同质临床前模型不代表异质患者人群。用于结直肠癌的ERBB 3的小分子抑制剂在临床前研究中有效地抑制了肿瘤发生，但在临床试验中未能显示出疗效，甚至倾向于促进癌症生长。使用两种具有不同遗传背景的小鼠结直肠癌模型，我们表明ERBB 3的上皮缺失可以导致从抑制到增强肿瘤生长的结果。分子分析表明EGFR可能是在缺乏ERBB 3的情况下增强肿瘤生长的介质。使用表皮缺失EGFR和ERBB 3的小鼠来显示ERBB 3的背景依赖性由EGFR介导。这些结果表明，癌症治疗的遗传背景对将临床前结果转化为临床具有深远的意义。
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. Targeted cancer therapeutics that are efficacious in pre-clinical studies do not always translate to the clinic. This can be due to the homogenous pre-clinical models not representing heterogeneous patient populations. Small molecular inhibitors to ERBB3 for colorectal cancer efficiently inhibited tumorigenesis in pre-clinical studies, but in clinical trials failed to show efficacy and even trended toward enhancing cancer growth. Using two mouse colorectal cancer models with variable the genetic backgrounds, we show that epithelial deletion of ERBB3 can result in outcomes ranging from inhibition to enhanced tumor growth. Molecular profiling implicated EGFR as a likely mediator of enhanced tumor growth in the absence of ERBB3. Mice with epithelial deletion of both EGFR and ERBB3 were used to show that the background dependency of ERBB3 is mediated by EGFR. These results show that genetic context of cancer therapeutics can have profound implications on translating pre-clinical results into the clinic.
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