Heterogeneity and plasticity of cancer-associated fibroblasts in the pancreatic tumor microenvironment

Boyd, Lenka N.C.; Andini, Katarina D.; Peters, Godefridus J.; Kazemier, Geert; Giovannetti, Elisa

doi:10.1016/j.semcancer.2021.03.006

Cited by 57 publications

(36 citation statements)

References 103 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Fibroblast activation protein (FAP) found ~90% CAFs and higher levels of tumor expression are associated with poor clinical outcomes in PDAC. Despite preclinical models showing anti-tumor effects of FAP-targeting/ablative strategies [132][133][134], a FAP antagonist mAb (sibrotuzumab) and small molecule inhibitors (talabostat) have not been able to translate this meaningful benefit to the clinical trial setting [135,136]. Recently, there has been a growing appreciation for the heterogeneity and plasticity of CAFs and their associated proand anti-tumorigenic functioning [136].…”

Section: [Io Strategy] Eliminating Cancer-associated Fibroblastsmentioning

confidence: 99%

“…Despite preclinical models showing anti-tumor effects of FAP-targeting/ablative strategies [132][133][134], a FAP antagonist mAb (sibrotuzumab) and small molecule inhibitors (talabostat) have not been able to translate this meaningful benefit to the clinical trial setting [135,136]. Recently, there has been a growing appreciation for the heterogeneity and plasticity of CAFs and their associated proand anti-tumorigenic functioning [136]. This phenotypic complexity may underly the preclinical observations that show depletion of CAFs paradoxically accelerates tumor progression [137,138].…”

Section: [Io Strategy] Eliminating Cancer-associated Fibroblastsmentioning

confidence: 99%

See 1 more Smart Citation

Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance

Heumann

Azad

2021

Cancer Metastasis Rev

View full text Add to dashboard Cite

To date, the use of immune checkpoint inhibitors has proven largely ineffective in patients with advanced pancreatic ductal adenocarcinoma. A combination of low tumor antigenicity, deficits in immune activation along with an exclusive and suppressive tumor microenvironment result in resistance to host defensives. However, a deepening understanding of these immune escape and suppressive mechanisms has led to the discovery of novel molecular targets and treatment strategies that may hold the key to a long-awaited therapeutic breakthrough. In this review, we describe the tumor-intrinsic and microenvironmental barriers to modern immunotherapy, examine novel immune-based and targeted modalities, summarize relevant pre-clinical findings and human experience, and, finally, discuss novel synergistic approaches to overcome immune-resistance in pancreatic cancer. Beyond checkpoint inhibition, immune agonists and anti-tumor vaccines represent promising strategies to stimulate host response via activation and expansion of anti-tumor immune effectors. Off-the-shelf natural killer cell therapies may offer an effective method for bypassing downregulated tumor antigen presentation. In parallel with this, sophisticated targeting of crosstalk between tumor and tumor-associated immune cells may lead to enhanced immune infiltration and survival of antitumor lymphocytes. A future multimodal treatment strategy involving immune priming/activation, tumor microenvironment reprogramming, and immune checkpoint blockade may help transform pancreatic cancer into an immunogenic tumor.

show abstract

Section: [Io Strategy] Eliminating Cancer-associated Fibroblastsmentioning

confidence: 99%

Section: [Io Strategy] Eliminating Cancer-associated Fibroblastsmentioning

confidence: 99%

Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance

Heumann

Azad

2021

Cancer Metastasis Rev

View full text Add to dashboard Cite

show abstract

“…Recently, TGFβ has been demonstrated to regulate the pro-and anti-tumorigenic properties of CAFs through phenotypic change (Figure 2). CAFs are both plastic and heterogeneous [132], and can be sub-categorized into inflammatory CAFs (iCAFs) that enhance local inflammatory cues through the secretion of cytokines such as interleukin 6 (IL-6) and leukemia inhibitory factor (LIF), and myofibroblastic CAFs (myCAFs) that express α smooth muscle actin (αSMA) and contribute to ECM deposition [133][134][135]. The balance between iCAFs and myCAFs is determined by competition between TGFβ and JAK/STAT signaling pathways.…”

Section: Tgfβ In Fibrosis and Stromal Cell Biologymentioning

confidence: 99%

TGFβ Signaling in the Pancreatic Tumor Microenvironment

Principe

Timbers

Atia

et al. 2021

Cancers

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor clinical outcomes, largely attributed to incomplete responses to standard therapeutic approaches. Recently, selective inhibitors of the Transforming Growth Factor β (TGFβ) signaling pathway have shown early promise in the treatment of PDAC, particularly as a means of augmenting responses to chemo- and immunotherapies. However, TGFβ is a potent and pleiotropic cytokine with several seemingly paradoxical roles within the pancreatic tumor microenvironment (TME). Although TGFβ signaling can have potent tumor-suppressive effects in epithelial cells, TGFβ signaling also accelerates pancreatic tumorigenesis by enhancing epithelial-to-mesenchymal transition (EMT), fibrosis, and the evasion of the cytotoxic immune surveillance program. Here, we discuss the known roles of TGFβ signaling in pancreatic carcinogenesis, the biologic consequences of the genetic inactivation of select components of the TGFβ pathway, as well as past and present attempts to advance TGFβ inhibitors in the treatment of PDAC patients.

show abstract

“…Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy that originates in the pancreas with an aggressive character and a dismal 5-year survival rate of 10.8% [ 1 , 2 , 3 ]. Due to its lethality, PDAC is expected to become the third leading cause of cancer-related deaths in Europe in 2025 [ 1 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

The Diagnostic Value of the CA19-9 and Bilirubin Ratio in Patients with Pancreatic Cancer, Distal Bile Duct Cancer and Benign Periampullary Diseases, a Novel Approach

Boyd

Ali

Kam

et al. 2022

Cancers

Self Cite

View full text Add to dashboard Cite

Distinction of pancreatic ductal adenocarcinoma (PDAC) in the head of the pancreas, distal cholangiocarcinoma (dCCA), and benign periampullary conditions, is complex as they often share similar clinical symptoms. However, these diseases require specific management strategies, urging improvement of non-invasive tools for accurate diagnosis. Recent evidence has shown that the ratio between CA19-9 and bilirubin levels supports diagnostic distinction of benign or malignant hepatopancreaticobiliary diseases. Here, we investigate the diagnostic value of this ratio in PDAC, dCCA and benign diseases of the periampullary region in a novel fashion. To address this aim, we enrolled 265 patients with hepatopancreaticobiliary diseases and constructed four logistic regression models on a subset of patients (n = 232) based on CA19-9, bilirubin and the ratio of both values: CA19-9/(bilirubin−1). Non-linearity was investigated using restricted cubic splines and a final model, the ‘Model Ratio’, based on these three variables was fitted using multivariable fractional polynomials. The performance of this model was consistently superior in terms of discrimination and calibration compared to models based on CA19-9 combined with bilirubin and CA19-9 or bilirubin alone. The ‘Model Ratio’ accurately distinguished between malignant and benign disease (AUC [95% CI], 0.91 [0.86–0.95]), PDAC and benign disease (AUC 0.91 [0.87–0.96]) and PDAC and dCCA (AUC 0.83 [0.74–0.92]) which was confirmed by internal validation using 1000 bootstrap replicates. These findings provide a foundation to improve minimally-invasive diagnostic procedures, ultimately ameliorating effective therapy for PDAC and dCCA.

show abstract

Heterogeneity and plasticity of cancer-associated fibroblasts in the pancreatic tumor microenvironment

Cited by 57 publications

References 103 publications

Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance

Next-generation immunotherapy for pancreatic ductal adenocarcinoma: navigating pathways of immune resistance

TGFβ Signaling in the Pancreatic Tumor Microenvironment

The Diagnostic Value of the CA19-9 and Bilirubin Ratio in Patients with Pancreatic Cancer, Distal Bile Duct Cancer and Benign Periampullary Diseases, a Novel Approach

Contact Info

Product

Resources

About