Targeting the IGF-axis potentiates immunotherapy for pancreatic ductal adenocarcinoma liver metastases by altering the immunosuppressive microenvironment.

AbstractPancreatic Ductal Adenocarcinoma (PDAC) has a five-year survival under 10%. Treatment is compromised due to a fibrotic-like stromal remodeling process, known as desmoplasia, which limits therapeutic perfusion, supports tumor progression, and establishes an immunosuppressive microenvironment. These processes are driven by cancer-associated fibroblasts (CAFs), functionally activated through transforming growth factor beta1 (TGFβ1). CAFs produce a topographically aligned extracellular matrix (ECM) that correlates with reduced overall survival. Paradoxically, ablation of CAF populations results in a more aggressive disease, suggesting CAFs can also restrain PDAC progression. Thus, unraveling the mechanism(s) underlying CAF functions could lead to therapies that reinstate the tumor-suppressive features of the pancreatic stroma. CAF activation involves the f-actin organizing protein palladin. CAFs express two palladin isoforms (iso3 and iso4) which are up-regulated in response to TGFβ1. However, the roles of iso3 and iso4 in CAF functions remain elusive. Using a CAF-derived ECM model, we uncovered that iso3/iso4 are required to sustain TGFβ1-dependent CAF activation, secrete immunosuppressive cytokines, and produce a pro-tumoral ECM. Findings demonstrate a novel role for CAF palladin and suggest that iso3/iso4 regulate both redundant and specific tumor-supportive desmoplastic functions. This study highlights the therapeutic potential of targeting CAFs to restore fibroblastic anti-tumor activity in the pancreatic microenvironment.

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The Proteomic Landscape of Pancreatic Ductal Adenocarcinoma Liver Metastases Identifies Molecular Subtypes and Associations with Clinical Response—Response

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-21-1220 ◽

2021 ◽

Vol 27 (14) ◽

pp. 4127-4127

Author(s):

Henry C.-H. Law ◽

Emalie J. Clement ◽

Paul M. Grandgenett ◽

Michael A. Hollingsworth ◽

Nicholas T. Woods

Keyword(s):

Liver Metastases ◽

Pancreatic Ductal Adenocarcinoma ◽

Clinical Response ◽

Molecular Subtypes ◽

Ductal Adenocarcinoma

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The Crosstalk Between Malignant Cells and Tumor-Promoting Immune Cells Relevant to Immunotherapy in Pancreatic Ductal Adenocarcinoma

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.821232 ◽

2022 ◽

Vol 9 ◽

Author(s):

Xuefei Liu ◽

Ziwei Luo ◽

Xuechen Ren ◽

Zhihang Chen ◽

Xiaoqiong Bao ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Rna Sequencing ◽

Immune Cells ◽

Immune Checkpoint ◽

Immune Cell ◽

Immune Checkpoint Blockade ◽

Ductal Adenocarcinoma ◽

Malignant Cells ◽

Sequencing Data ◽

Immunosuppressive Microenvironment

Background: Pancreatic ductal adenocarcinoma (PDAC) is dominated by an immunosuppressive microenvironment, which makes immune checkpoint blockade (ICB) often non-responsive. Understanding the mechanisms by which PDAC forms an immunosuppressive microenvironment is important for the development of new effective immunotherapy strategies.Methods: This study comprehensively evaluated the cell-cell communications between malignant cells and immune cells by integrative analyses of single-cell RNA sequencing data and bulk RNA sequencing data of PDAC. A Malignant-Immune cell crosstalk (MIT) score was constructed to predict survival and therapy response in PDAC patients. Immunological characteristics, enriched pathways, and mutations were evaluated in high- and low MIT groups.Results: We found that PDAC had high level of immune cell infiltrations, mainly were tumor-promoting immune cells. Frequent communication between malignant cells and tumor-promoting immune cells were observed. 15 ligand-receptor pairs between malignant cells and tumor-promoting immune cells were identified. We selected genes highly expressed on malignant cells to construct a Malignant-Immune Crosstalk (MIT) score. MIT score was positively correlated with tumor-promoting immune infiltrations. PDAC patients with high MIT score usually had a worse response to immune checkpoint blockade (ICB) immunotherapy.Conclusion: The ligand-receptor pairs identified in this study may provide potential targets for the development of new immunotherapy strategy. MIT score was established to measure tumor-promoting immunocyte infiltration. It can serve as a prognostic indicator for long-term survival of PDAC, and a predictor to ICB immunotherapy response.

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Liver Metastases in Newly Diagnosed Pancreatic Ductal Adenocarcinoma: A Population Based Analysis

10.21203/rs.2.20788/v1 ◽

2020 ◽

Author(s):

Guoyi Wu ◽

Xiaoben Pan ◽

Baohua Wang ◽

Xiaolei Zhu ◽

Jing Wu ◽

...

Keyword(s):

Risk Factors ◽

Liver Metastases ◽

Pancreatic Ductal Adenocarcinoma ◽

Tumor Size ◽

Cox Regression ◽

Population Based ◽

The Body ◽

Ductal Adenocarcinoma ◽

Rank Test ◽

Factors Associated

Abstract Background Estimates of the incidence and prognosis of developing liver metastases at the pancreatic ductal adenocarcinoma (PDAC) diagnosis are lacking.Methods In this study, we analyzed the association of liver metastases and the PDAC patients outcome. The risk factors associated with liver metastases in PDAC patients were analyzed using multivariable logistic regression analysis. The overall survival (OS) was estimated using Kaplan-Meier curves and log-rank test. Cox regression was performed to identify factors associated with OS.Results Patients with primary PDAC in the tail of the pancreas had a higher incidence of liver metastases (62.2%) than those with PDAC in the head (28.6%). Female gender, younger age, primary PDAC in the body or tail of the pancreas, and larger primary PDAC tumor size were positively associated with the occurrence of liver metastases. The median survival of patients with liver metastases was significantly shorter than that of patients without liver metastases. Older age, unmarried status, primary PDAC in the tail of the pancreas, and tumor size ≥4 cm were risk factors for OS in the liver metastases cohort.Conclusions Population-based estimates of the incidence and prognosis of PDAC with liver metastases may help decide whether diffusion-weighted magnetic resonance imaging should be performed in patients with primary PDAC in the tail or body of the pancreas. The location of primary PDAC should be considered during the diagnosis and treatment of primary PDAC.

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Complete Response of Synchronous Liver Metastasis in a Pancreatic Ductal Adenocarcinoma, When Surgery Could Represent a Therapeutic Option

Canadian Journal of Gastroenterology and Hepatology ◽

10.1155/2020/8679751 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7 ◽

Cited By ~ 1

Author(s):

Antonella Argentiero ◽

Angela Calabrese ◽

Angela Monica Sciacovelli ◽

Sabina Delcuratolo ◽

Antonio Giovanni Solimando ◽

...

Keyword(s):

Liver Metastases ◽

Pancreatic Ductal Adenocarcinoma ◽

Lung Metastases ◽

Therapeutic Option ◽

Disease Free Survival ◽

Complete Response ◽

Ductal Adenocarcinoma ◽

Pancreatic Lesion ◽

Link Type ◽

Multiple Liver Metastases

Metastatic pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and short survival. Today, the use of new polytherapeutic regimens increases clinical outcome of these patients opening new clinical scenario. A crucial issue related to the actual improvement achieved with these new regimens is represented by the occasional possibility to observe a radiological complete response of metastatic lesions in patients with synchronous primary tumor. What could be the best therapeutic management of these patients? Could surgery represent an indication? Herein, we reported a case of a patient with PDAC of the head with multiple liver metastases, who underwent first-line chemotherapy with mFOLFIRINOX. After 10 cycles, he achieved a complete radiological response of liver metastases and a partial response of pancreatic lesion. A duodenocephalopancreasectomy was performed. Due to liver a lung metastases after 8 months from surgery, a second-line therapy was started with a disease-free survival and overall survival of 8 months and 45 months, respectively. Improvement in the molecular characterization of PDAC could help in the selection of patients suitable for multimodal treatments. This trial is registered with NCT02892305 and NCT00855634.

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Microfluidic Platforms for High-Throughput Pancreatic Ductal Adenocarcinoma Organoid Culture and Drug Screening

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.761807 ◽

2021 ◽

Vol 9 ◽

Author(s):

Marlene Geyer ◽

Karla Queiroz

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

High Throughput ◽

Ductal Adenocarcinoma ◽

Surgical Removal ◽

Cancer Type ◽

Tumor Type ◽

Hypoxic Conditions ◽

Physicochemical Features ◽

Immunosuppressive Microenvironment

Pancreatic Ductal Adenocarcinoma (PDAC), the most common pancreatic cancer type, is believed to become the second leading cause of cancer-related deaths by 2030 with mortality rates of up to 93%. It is often detected at a late stage due to lacking symptoms, and therefore surgical removal of the tumor is the only treatment option for patients. Only 20% of the tumors are resectable, mainly due to early metastasis. Therefore, for 80% of cases chemotherapeutic treatment is the leading therapy for patients. PDAC is characterized by high-density stroma which induces hypoxic conditions and high interstitial pressure. These factors impact carcinogenesis and progression of PDAC and support the formation of an immunosuppressive microenvironment that renders this tumor type refractory to immunotherapies. Most in vitro PDAC models have limited translational relevance, as these fail to recapitulate relevant aspects of PDAC complexity. Altogether, there is an urgent need for novel and innovative PDAC modeling platforms. Here, we discuss the relevance of microfluidic and organoid technologies as platforms for modeling bio- and physicochemical features of PDAC and as translational models that enable high-throughput phenotypic drug screenings, while also allowing for the development of novel personalized models used to identify treatment responsive patient subsets.

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