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

Bulle, Ashenafi Shiferaw; Lim, Kian Huat

doi:10.1038/s41392-020-00341-1

Cited by 122 publications

(136 citation statements)

References 181 publications

(209 reference statements)

Supporting

Mentioning

123

Contrasting

Order By: Relevance

“…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.…”

Section: Non-diabetic Diseases Of Pancreasmentioning

confidence: 99%

“…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 ).…”

Section: Non-diabetic Diseases Of Pancreasmentioning

confidence: 99%

See 1 more Smart Citation

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

Szlachcic

Ziojla

Kizewska

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

A chronic inability to maintain blood glucose homeostasis leads to diabetes, which can damage multiple organs. The pancreatic islets regulate blood glucose levels through the coordinated action of islet cell-secreted hormones, with the insulin released by β-cells playing a crucial role in this process. Diabetes is caused by insufficient insulin secretion due to β-cell loss, or a pancreatic dysfunction. The restoration of a functional β-cell mass might, therefore, offer a cure. To this end, major efforts are underway to generate human β-cells de novo, in vitro, or in vivo. The efficient generation of functional β-cells requires a comprehensive knowledge of pancreas development, including the mechanisms driving cell fate decisions or endocrine cell maturation. Rapid progress in single-cell RNA sequencing (scRNA-Seq) technologies has brought a new dimension to pancreas development research. These methods can capture the transcriptomes of thousands of individual cells, including rare cell types, subtypes, and transient states. With such massive datasets, it is possible to infer the developmental trajectories of cell transitions and gene regulatory pathways. Here, we summarize recent advances in our understanding of endocrine pancreas development and function from scRNA-Seq studies on developing and adult pancreas and human endocrine differentiation models. We also discuss recent scRNA-Seq findings for the pathological pancreas in diabetes, and their implications for better treatment.

show abstract

Section: Non-diabetic Diseases Of Pancreasmentioning

confidence: 99%

Section: Non-diabetic Diseases Of Pancreasmentioning

confidence: 99%

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

Szlachcic

Ziojla

Kizewska

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…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 ].…”

Section: Introductionmentioning

confidence: 99%

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

Polani¹,

Grierson²,

Lim³

2021

WJG

Self Cite

View full text Add to dashboard Cite

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 shorter-lived. Aside from typically harboring genetic alterations that to date remain un-druggable 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 stroma-targeting strategies, new challenges revealed from recent preclinical and clinical studies, as well as new prospects in the treatment of PDAC.

show abstract

“…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.…”

Section: Clinical Characteristics Of the Patientsmentioning

confidence: 99%

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

Liu¹,

Shi²,

Xu³

et al. 2021

Preprint

View full text Add to dashboard Cite

Purpose Pancreatic tumors are characterized by abundant desmoplasia including cancer-associated fibroblasts (CAFs) that express fibroblast activation protein (FAP). Gallium-68-labeled fibroblast-activating protein inhibitor (FAPI) is promising probe for positron emission tomography/computed tomography (PET/CT) imaging of various types of cancers. This work aims to compare the diagnostic performances of [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT in detecting primary pancreatic tumors and metastasis prospectively.Methods We collected patients with pancreatic tumors during May 1 to August 1, 2020. All the patients underwent [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT within 5 days at diagnosis, recurrence detection or therapeutic evaluation. The clinical information, PET/CT image characteristics, maximum standardized uptake (SUVmax) value of pancreatic tumors and metastases, target-to-background ratio (TBR) of the liver metastases were collected for analysis. The pathological results or follow-up clinical diagnostic results were obtained. Results A total of 45 patients (18 females and 27 males; median age of 62.4 years; range: 42 - 84 years) were enrolled for analysis, including 37 patients with pancreatic cancers and 8 patients with other types of pancreatic tumors. [68Ga]Ga-DOTA-FAPI-04 PET/CT detected abnormal pancreatic uptake in 36 patients (97.30%) with a SUVmax of 14.0 ± 5.4 (range 5.4 to 25.1), while 34 patients (91.89%) with abnormal pancreatic uptake with a SUVmax of 7.6 ± 3.9 (2.9 to 20.4) were detected by [18F]FDG PET/CT. Moreover, [68Ga]Ga-DOTA-FAPI-04 detected more lymph nodes (LNs) and metastases than [18F]FDG. The SUVmax of [68Ga]Ga-DOTA-FAPI-04 in LNs and TBR of liver metastases was higher than that of [18F]FDG (LNs: 6.1 ± 2.7 vs. 4.4 ± 1.6, TBR: 5.0 ± 3.1 vs. 2.9 ± 1.4 p < 0.0001), respectively. [68Ga]Ga-DOTA-FAPI-04 PET/CT successfully unregulated the clinical stage in 2 patients, visualized recurrence in 1 patient, and detected residual active tumor tissues in 2 patients with discordant imaging results (FAPI+/FDG-). In addition, there was nearly no [68Ga]Ga-DOTA-FAPI-04 or [18F]FDG uptake in pancreatic cystic neoplasms. Most of neuroendocrine neoplasms showed negligible [68Ga]Ga-DOTA-FAPI-04 uptake. Conclusion Compared with [18F]FDG PET/CT, [68Ga]Ga-DOTA-FAPI-04 PET/CT detected pancreatic tumors and associated metastases with a higher sensitivity and SUVmax value. However, false-positive uptake of [68Ga]Ga-DOTA-FAPI-04 in pancreatitis, cholangitis, some benign liver disease, and inflammatory LNs was also prominent.

show abstract

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

Cited by 122 publications

References 181 publications

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

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

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

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

Contact Info

Product

Resources

About