Fibroblast Heterogeneity, Plasticity and Functions in Pancreatic Cancer

胰腺癌是高度致命的，只有十分之一的患者在确诊后能存活5年。耐药是胰腺癌致死性的主要原因之一，主要由非癌性成分引起，非癌性成分占整个肿瘤肿块的90%，并在很大程度上促进了疾病的进展。在这些成分中，成纤维细胞是最丰富的细胞群，并已被证明发挥多种作用，促进耐药性和肿瘤生长，但也可能抑制癌症进展。我们最近发现胰腺癌成纤维细胞由不同的群体组成，这可以解释它们的功能多样性，并强调了设计选择性治疗的必要性。为了确定新的靶向脆弱性，我们的目标是了解胰腺癌细胞和不同的成纤维细胞群体如何相互作用和相互影响。此外，由于成纤维细胞也在炎症中发挥关键作用，我们的目标是确定这些细胞在正常、炎症和恶性状态下的差异和相似之处。为了解决这些问题，我们将使用小鼠模型和成纤维细胞和胰腺癌细胞作为类器官生长的三维共培养。结合这些模型，我们将采用遗传和药理学方法来表征成纤维细胞在胰腺癌进展和胰腺炎中的作用、动态性质和异质性。胰腺炎是胰腺炎症的病理状态，也是胰腺癌的危险因素。特别是，我们将定义胰腺癌细胞的不同遗传谱影响周围成纤维细胞异质性的机制。我们也将解剖成纤维细胞在胰腺癌和胰腺炎中的功能。为此，我们将开发新的方法，在新的共培养物和小鼠模型中实现不同成纤维细胞群体的基因消融。最后，我们将确定不同成纤维细胞群的代谢特征是如何被调节和影响疾病进展的。我们的分析将确定成纤维细胞群体以何种方式影响胰腺癌进展和胰腺炎，并将揭示治疗干预的新脆弱性。胰腺癌成纤维细胞的一些表型和功能在不同的癌症类型和炎症条件下是共享的，这表明我们的发现可以应用于其他恶性肿瘤和疾病状态。

Pancreatic cancer is highly lethal, with only 1 in 10 patients surviving 5 years after diagnosis. Drug resistance is one of the main reasons of pancreatic cancer lethality and is largely caused by non-cancerous components that constitute up to 90% of the overall tumour mass and substantially contribute to the progression of the disease. Among these components, fibroblasts are the most abundant cell population and have been shown to play diverse roles, promoting drug resistance and tumour growth, but also potentially restraining cancer progression. We recently showed that pancreatic cancer fibroblasts are comprised of distinct populations, which could explain their functional diversity and emphasises the need to design selective therapies. To identify new targetable vulnerabilities, we aim to understand how pancreatic cancer cells and distinct fibroblast populations interact and affect each other. Additionally, as fibroblasts also play key roles in inflammation, we aim to determine differences and similarities of these cells across normal, inflammatory and malignant states. To address these questions, we will use mouse models and three-dimensional co-cultures of fibroblasts and pancreatic cancer cells grown as organoids. In combination with these models, we will employ genetic and pharmacologic approaches to characterise the roles, dynamic nature and heterogeneity of fibroblasts during pancreatic cancer progression and in pancreatitis, which is a pathological condition of inflammation of the pancreas and a risk factor of pancreatic cancer. In particular, we will define the mechanisms through which different genetic profiles of pancreatic cancer cells affect the heterogeneity of surrounding fibroblasts. We will also dissect fibroblast functions in both pancreatic cancer and pancreatitis. To do this, we will develop novel approaches that will enable the genetic ablation of distinct fibroblast populations in new co-cultures and mouse models. Finally, we will determine how metabolic signatures of distinct fibroblast populations are regulated and affect disease progression. Our analysis will identify in what ways fibroblast populations differentially impact pancreatic cancer progression and pancreatitis and will reveal new vulnerabilities for therapeutic intervention. The emerging understanding that some phenotypes and functions of pancreatic cancer fibroblasts are shared among different cancer types and inflammatory conditions indicates that our findings could be applied to other malignancies and diseased states.