Stroma-targeting strategies in pancreatic cancer:Past lessons,challenges and prospects

Pancreatic ductal adenocarcinoma(PDAC)is projected to emerge as the second leading cause of cancer-related death after 2030.Extreme treatment resistance is perhaps the most significant factor that underlies the poor prognosis of PDAC.To date,combination chemotherapy remains the mainstay of treatment for most PDAC patients.Compared to other cancer types,treatment response of PDAC tumors to similar chemotherapy regimens is clearly much lower and shorterlived.Aside from typically harboring genetic alterations that to date remain undruggable and are drivers of treatment resistance,PDAC tumors are uniquely characterized by a densely fibrotic stroma that has well-established roles in promoting cancer progression and treatment resistance.However,emerging evidence also suggests that indiscriminate targeting and near complete depletion of stroma may promote PDAC aggressiveness and lead to detrimental outcomes.These conflicting results undoubtedly warrant the need for a more in-depth understanding of the heterogeneity of tumor stroma in order to develop modulatory strategies in favor of tumor suppression.The advent of novel techniques including single cell RNA sequencing and multiplex immunohistochemistry have further illuminated the complex heterogeneity of tumor cells,stromal fibroblasts,and immune cells.This new knowledge is instrumental for development of more refined therapeutic strategies that can ultimately defeat this disease.Here,we provide a concise review on lessons learned from past stromatargeting strategies,new challenges revealed from recent preclinical and clinical studies,as well as new prospects in the treatment of PDAC.

Beyond just a tight fortress:contribution of stroma to epithelial-mesenchymal transition in pancreatic cancer

Novel effective treatment is direly needed for patients with pancreatic ductal adenocarcinoma(PDAC).Therapeutics that target the driver mutations,especially the KRAS oncoprotein and its effector cascades,have been ineffective.It is increasing clear that the extensive fibro-inflammatory stroma(or desmoplasia)of PDAC plays an active role in the progression and therapeutic resistance of PDAC.The desmoplastic stroma is composed of dense extracellular matrix(ECM)deposited mainly by the cancer-associatedfibroblasts(CAFs)and infiltrated with various types of immune cells.The dense ECM functions as a physical barrier that limits tumor vasculatures and distribution of therapeutics to PDAC cells.In addition,mounting evidence have demonstrated that both CAFs and ECM promote PDAC cells aggressiveness through multiple mechanisms,particularly engagement of the epithelial-mesenchymal transition(EMT)program.Acquisition of a mesenchymal-like phenotype renders PDAC cells more invasive and resistant to therapyinduced apoptosis.Here,we critically review seminal and recent articles on the signaling mechanisms by which each stromal element promotes EMT in PDAC.We discussed the experimental models that are currently employed and best suited to study EMT in PDAC,which are instrumental in increasing the chance of successful clinical translation.