Organoid-trasplant model systems to study in vivo the effects of obesity on the pancreatic carcinogenesis

Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related mortality among adults in developed countries. The discovery of the most common genetic alterations as well as the development of organoids models of pancreatic cancer have provided insight into the fundamental pathways driving the progression from normal cell, to non-invasive precursor lesion, to widely metastatic disease, offering new opportunities for the discovery of key activated pathways along cancer progression. Obesity is one of the most serious public health challenges of the 21st century. Several epidemiological studies have shown the positive association between obesity and cancer-related morbidity/mortality, as well as poor prognosis and poorer treatment outcome. Despite strong evidence indicates a link between obesity and cancer incidence, the molecular basis of the initiating events remains largely elusive. This is mainly due to the lack of an accurate and reliable model of pancreatic carcinogenesis that mimics human obesity-associated PDAC, making data interpretation difficult and often confusing. Here we propose, to our knowledge, the best suitable and manageable preclinical tool, based on next-generation cell culture models, to study the effects of obesity on pancreatic carcinogenesis. Therefore we tracked the effects of obesity on the natural evolution of PDAC in a genetically-defined transplantable model of syngeneic murine pancreatic preneoplastic lesion (mP) and tumor (mT) derived organoids that recapitulates the progression of human disease from early preinvasive lesions to metastatic disease. Our models indicated that both genetic- and diet-induced obesity promoted incidence engraftment rate and growth of both preneoplastic and neoplastic organoids, favoring pancreatic cancer progression and distant metastases dissemination. Our obesity models of carcinogenesis mimic the evolution of human pancreatic cancer pathology, promoting carcinogenesis and concomitant accumulation of a myeloid infiltrate. These changes in cancer immune infiltrate were also associated to a specific pattern of anti-inflammatory Th2 signature. Moreover, gene expression profile analysis revealed a change in gene expression programs that addresses cells to different pancreatic subtypes and stromal conditions. Our results suggest that organoid-derived transplants in obese mice represent a suitable system to study early step of carcinogenesis and support the hypothesis that inflammation induced by obesity stimulates tumor progression and metastatization during pancreatic carcinogenesis.

胰腺导管腺癌（Pancreatic ductal adenocarcinoma, PDAC）是发达国家成人癌症相关死亡的第三大诱因。常见遗传改变的发现，以及胰腺癌类器官模型的建立，为阐明正常细胞向非浸润性前驱病变、再进展为广泛转移性疾病的核心驱动通路提供了新视角，也为挖掘癌症进展过程中关键激活通路带来了全新机遇。

肥胖是21世纪最严峻的公共卫生挑战之一。多项流行病学研究证实，肥胖与癌症相关发病及死亡、不良预后及较差治疗结局呈正相关。尽管已有大量证据表明肥胖与癌症发生率存在关联，但癌变起始事件的分子基础仍在很大程度上不明晰。这主要是因为缺乏能够模拟人类肥胖相关胰腺导管腺癌的精准可靠胰腺癌变模型，导致相关数据解读困难且常存在歧义。

据我们所知，本研究提出了基于新一代细胞培养模型的、目前最为适配且易于操作的临床前工具，用于探究肥胖对胰腺癌变的影响。因此，我们通过遗传定义的可移植同基因小鼠胰腺癌前病变（mP）及肿瘤（mT）来源类器官体系，追踪了肥胖对胰腺导管腺癌自然演进过程的影响——该类器官体系可重现人类疾病从早期浸润前病变到转移性疾病的完整进展历程。

我们的模型证实，遗传因素及饮食诱导的肥胖均可提升癌前及肿瘤性类器官的植入发生率与生长速率，促进胰腺癌进展及远处转移播散。本研究构建的肥胖相关癌变模型可模拟人类胰腺癌病理演进过程，不仅可推动癌变进程，还可伴随髓系浸润的积累。这类癌症免疫浸润的变化同时与特异性抗炎Th2特征谱相关。此外，基因表达谱分析显示，基因表达程序发生改变，使细胞朝向不同的胰腺亚型及基质微环境状态分化。我们的研究结果表明，肥胖小鼠体内的类器官来源移植体是研究癌变早期进程的适配体系，同时支持“肥胖诱导的炎症可刺激胰腺癌变过程中的肿瘤进展与转移”这一假说。