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

Abstract

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-associated-fibroblasts (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 therapy-induced 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.

Endocrine Pancreas Development and Dysfunction Through the Lens of Single-Cell RNA-Sequencing

“…Pancreatic ductal adenocarcinoma (PDAC) is one of the leading death-causing cancer types worldwide, yet early malignancy markers allowing detection and treatment at pre-metastatic stage and prior to drug resistance acquisition are missing ( Storz and Crawford, 2020 ). PDAC develops from benign lesions through a complex interplay between transformed exocrine cells and microenvironment, as it has been thoroughly reviewed elsewhere ( Bulle and Lim, 2020 ; Storz and Crawford, 2020 ). The two essential components for PDAC development are: (1) acquisition of an oncogenic mutation by acinar or ductal cells, with KRAS oncogene counting for 90% of cases; (2) inflammation within microenvironment which drives early lesion development.…”

“…Several recent scRNA-Seq studies focused on role of TME components, for example CAFs, in PDAC development. CAFs are actively involved in tumor growth, metastasis and drug resistance in various types of cancers ( Bulle and Lim, 2020 ; Hosein et al, 2020 ). Myofibroblastic myCAFs and inflammatory iCAFs were recently described as two subtypes present in PDAC and originating from activated pancreatic stellate cells ( Öhlund et al, 2017 ).…”

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

“…Major components of the TME include a dense fibrotic matrix deposited by cancer-associated fibroblasts (CAFs), and significant infiltration of various subsets of immunosuppressive myeloid cells, vascular cells, and nerve cells[ 13 - 15 ]. The dense stroma plays an important role in tumor growth, proliferation, epithelial-mesenchymal transition (EMT), immune evasion and resistance to various therapies[ 16 ]. The low vascularity combined with elevated interstitial pressure dramatically limits vascular delivery and diffusion of therapeutic agents to tumor cells[ 17 - 19 ].…”

[68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT in the Assessment of Pancreatic Tumors: A Comparison Study

“…It is worth noting that the whole pancreas showed diffuse signi cant uptake in some patients, which covered the tumors. As we all know, desmoplasia and in ammation are two major hallmarks of pancreatic cancer [24,25]. In this circumstance, the combination with other examinations or close follow-up is of great importance for the accurate diagnosis.…”