Pancreatic cancer is thought to arise from precursor lesions called pancreatic intraepithelial neoplasias (PanINs), which are challenging to study due to their small size and their inability to be detected using conventional imaging techniques. For these reasons, the prevalence of PanINs in the healthy pancreas, their clonal relationships, and the factors that determine progression to malignancy remain poorly characterized. To address these issues, Braxton et al. collected healthy pancreas samples from 38 individuals. Using a method called CODA, they generated 3D models from thousands of tissue slabs. This allowed them to identify and microdissect PanINs for DNA sequencing. Their results showed that PanINs are surprisingly pervasive — possibly hundreds in a single healthy pancreas, all characterized by oncogenic KRAS mutations. Most PanINs from an individual had independent origins, but a subset was polyclonal and harbored multiple different KRAS mutations, potentially the products of fusion events between different PanIN lesions. Marrying the multitude of PanINs with the relative rarity of pancreatic cancer suggests that the progression to malignancy is restrained in most cases, and identifying the mechanisms that underpin this might provide crucial insights for the prevention of pancreatic cancer. This work provides a much-needed glimpse into the genesis of this deadly disease and provides ample fodder for subsequent studies.

Original reference: Nature 629, 679–687 (2024)

胰腺癌被认为是由称为胰腺上皮内瘤变 (PanIN) 的前驱病变引起的，由于其体积小且无法使用传统成像技术检测到，因此研究具有挑战性。由于这些原因，健康胰腺中 PanIN 的患病率、它们的克隆关系以及决定恶性肿瘤进展的因素仍然知之甚少。为了解决这些问题，布拉克斯顿等人。从 38 个人身上收集了健康的胰腺样本。他们使用一种名为 CODA 的方法，从数千块组织板中生成了 3D 模型。这使他们能够识别和显微解剖 PanIN 以进行 DNA 测序。他们的结果表明，PanIN 出人意料地普遍存在——在一个健康的胰腺中可能有数百个，所有这些都以致癌KRAS突变为特征。来自个体的大多数 PanIN 都有独立的起源，但有一个子集是多克隆的，并含有多种不同的KRAS突变，可能是不同 PanIN 病变之间融合事件的产物。将大量的 PanIN 与胰腺癌的相对罕见性结合起来表明，在大多数情况下，恶性肿瘤的进展受到抑制，而确定其背后的机制可能为预防胰腺癌提供重要的见解。这项工作为了解这种致命疾病的起源提供了急需的一瞥，并为后续研究提供了充足的素材。

原始参考文献： Nature 629 , 679–687 (2024)