As we age, our tissues are repeatedly challenged by mutational insult, yet cancer occurrence is a relatively rare event. Cells carrying cancer-causing genetic mutations compete with normal neighbours for space and survival in tissues. However, the mechanisms underlying mutant-normal competition in adult tissues and the relevance of this process to cancer remain incompletely understood. Here, we investigate how the adult pancreas maintains tissue health in vivo following sporadic expression of oncogenic Kras (KrasG12D), the key driver mutation in human pancreatic cancer. We find that when present in tissues in low numbers, KrasG12D mutant cells are outcompeted and cleared from exocrine and endocrine compartments in vivo. Using quantitative 3D tissue imaging, we show that prior to being cleared, KrasG12D cells lose cell volume, segregate from normal cells and decrease E-cadherin-based cell-cell adhesions with normal neighbours. We identify EphA2 receptor is an essential signal in the clearance of KrasG12D cells from exocrine and endocrine tissues in vivo. In the absence of functional EphA2, KrasG12D cells no longer segregate, E-cadherin-based cell-cell adhesions increase and KrasG12D cells are retained in tissues. Retention of KRasG12D cells leads to an increased burden of premalignant pancreatic intraepithelial neoplasia (PanINs) in tissues. Our data show that adult pancreas tissues remodel to clear KrasG12D cells and maintain tissue health. This study provides evidence to support a conserved functional role of EphA2 in Ras-driven cell competition in epithelial tissues and suggests that EphA2 is a novel tumour suppressor in pancreatic cancer.

中文翻译：

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KRASG12D突变细胞在成年胰腺中被EPHA2依赖性的野生型邻居竞争。

随着年龄的增长，我们的组织会反复受到突变侮辱的挑战，但是癌症的发生是相对罕见的事件。携带致癌基因突变的细胞与正常邻居竞争组织中的空间和生存。然而，在成人组织中突变体正常竞争的潜在机制以及该过程与癌症的相关性仍未完全了解。在这里，我们研究成年胰腺如何在致癌性Kras（KrasG12D）（人类胰腺癌的关键驱动基因突变）的偶发表达后在体内维持组织健康。我们发现，当在组织中以低数量存在时，KrasG12D突变细胞在体内被竞争并从外分泌和内分泌区室清除。使用定量3D组织成像，我们显示KrasG12D细胞在被清除之前会失去细胞体积，从正常细胞中分离出来，并减少基于E-钙粘蛋白的细胞与正常邻居的粘附。我们确定EphA2受体是从体内外分泌和内分泌组织清除KrasG12D细胞的重要信号。在缺少功能性EphA2的情况下，KrasG12D细胞不再分离，基于E-钙粘着蛋白的细胞间粘附增加，并且KrasG12D细胞保留在组织中。保留KRasG12D细胞会导致组织中癌前胰腺上皮内瘤变（PanINs）的负担增加。我们的数据表明，成年胰腺组织会重塑以清除KrasG12D细胞并维持组织健康。这项研究提供证据支持EphA2在上皮组织中Ras驱动的细胞竞争中的保守功能作用，并表明EphA2是胰腺癌中的新型肿瘤抑制因子。