Understanding how tissue stiffening affects cancer cell response to therapy

胰腺癌生存率低，迫切需要新的治疗方法。目前唯一可用的治疗方法是非特异性靶向DNA复制和细胞周期进展的化疗药物。然而，一类新的小分子抑制剂最近被开发出来，靶向KRAS，一种90%的胰腺癌中突变的致癌基因，这为靶向治疗提供了新的希望。胰腺癌如此难以治疗的原因之一是肿瘤被极其坚硬的纤维化细胞外基质（ECM）包围。这种改变的肿瘤微环境意味着肿瘤比健康组织要坚硬得多。组织硬化已被证明可以促进癌细胞的增殖、侵袭和转移，但也有助于对治疗的抵抗。这个为期4年的博士项目将研究细胞外环境的刚度如何影响胰腺癌细胞对治疗的反应，包括标准化疗药物和新的KRAS抑制剂。我们将使用各种细胞生物学技术，包括细胞培养，RNA测序和尖端显微镜来解开细胞对治疗反应的分子细节。为了了解组织硬化的影响，细胞将在微制造的腔室中生长，其中刚度和ECM成分可以改变，并且可以施加机械力（如压缩）。这是谢菲尔德大学海伦·马修斯（生物科学学院）和海伦·布莱恩特（肿瘤和代谢系）小组之间的合作项目。作为生物科学和肿瘤学部门的一部分，该项目将提供细胞和癌症生物学方面的广泛培训，并提供各种各样的发展机会，除了MRC DiMeN计划提供的机会之外。马修斯和布莱恩特的团队都在共享实验室，为我们的癌症研究人员提供友好、包容和支持的环境。

Pancreatic cancer has a low survival rate and new therapies are urgently needed. Currently the only treatments available are chemotherapy drugs that non-specifically target DNA replication and cell cycle progression. However, a new class of small molecule inhibitors have recently been developed targeting KRAS, an oncogene mutated in 90% of pancreatic cancers, which offer new promise for targeted therapy. One of the reasons that pancreatic cancer is so hard to treat is that tumours are surrounded by extremely rigid, fibrotic extra-cellular matrix (ECM). This altered tumour microenvironment means that tumours are far stiffer than healthy tissue. Tissue stiffening has been shown to promote cancer cell proliferation, invasion and metastasis but also contribute to resistance to therapy.This 4-year PhD project will investigate how the stiffness of the extracellular environment affects pancreatic cancer cell response to therapy, including standard chemotherapy drugs and new KRAS inhibitors. We will use a variety of cell biology techniques including cell culture, RNA sequencing and cutting-edge microscopy to unpick the molecular details of cells response to therapy. To understand the effects of tissue stiffening, cells will be grown in micro-fabricated chambers where the stiffness and ECM composition can be varied and mechanical forces (such as compression) can be applied.This is a collaborative project between the Helen Matthews' (School of Biosciences) and Helen Bryant's (Dept. of Oncology and Metabolism) groups at the University of Sheffield. Being embedded within both the Biosciences and Oncology departments, this project will provide a broad training in cell and cancer biology and give access to a wide variety of development opportunities, in addition to those provided by the MRC DiMeN scheme. Both the Matthews and Bryant groups are based in shared laboratories that provide friendly, inclusive and supportive environments for our cancer researchers.