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Nature Communications Apr 2024Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease for which better therapies are urgently needed. Fibroblasts and macrophages are heterogeneous cell...
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease for which better therapies are urgently needed. Fibroblasts and macrophages are heterogeneous cell populations able to enhance metastasis, but the role of a macrophage-fibroblast crosstalk in regulating their pro-metastatic functions remains poorly understood. Here we deconvolve how macrophages regulate metastasis-associated fibroblast (MAF) heterogeneity in the liver. We identify three functionally distinct MAF populations, among which the generation of pro-metastatic and immunoregulatory myofibroblastic-MAFs (myMAFs) critically depends on macrophages. Mechanistically, myMAFs are induced through a STAT3-dependent mechanism driven by macrophage-derived progranulin and cancer cell-secreted leukaemia inhibitory factor (LIF). In a reciprocal manner, myMAF secreted osteopontin promotes an immunosuppressive macrophage phenotype resulting in the inhibition of cytotoxic T cell functions. Pharmacological blockade of STAT3 or myMAF-specific genetic depletion of STAT3 restores an anti-tumour immune response and reduces metastases. Our findings provide molecular insights into the complex macrophage-fibroblast interactions in tumours and reveal potential targets to inhibit PDAC liver metastasis.
Topics: Pancreatic Neoplasms; Animals; Liver Neoplasms; STAT3 Transcription Factor; Macrophages; Carcinoma, Pancreatic Ductal; Humans; Mice; Cell Line, Tumor; Signal Transduction; Janus Kinases; Mice, Inbred C57BL; Fibroblasts; Male; Cancer-Associated Fibroblasts; Female
PubMed: 38678021
DOI: 10.1038/s41467-024-47949-3 -
Endocrine Pathology Jun 2024In the last two decades, the increasing availability of technologies for molecular analyses has allowed an insight in the genomic alterations of neuroendocrine neoplasms... (Review)
Review
In the last two decades, the increasing availability of technologies for molecular analyses has allowed an insight in the genomic alterations of neuroendocrine neoplasms (NEN) of the gastrointestinal tract and pancreas. This knowledge has confirmed, supported, and informed the pathological classification of NEN, clarifying the differences between neuroendocrine carcinomas (NEC) and neuroendocrine tumors (NET) and helping to define the G3 NET category. At the same time, the identification genomic alterations, in terms of gene mutation, structural abnormalities, and epigenetic changes differentially involved in the pathogenesis of NEC and NET has identified potential molecular targets for precision therapy. This review critically recapitulates the available molecular features of digestive NEC and NET, highlighting their correlates with pathological aspects and clinical characteristics of these neoplasms and revising their role as predictive biomarkers for targeted therapy. In this context, the feasibility and applicability of a molecular classification of gastrointestinal and pancreatic NEN will be explored.
Topics: Humans; Pancreatic Neoplasms; Neuroendocrine Tumors; Gastrointestinal Neoplasms; Biomarkers, Tumor
PubMed: 38470548
DOI: 10.1007/s12022-024-09807-2 -
Theranostics 2023Targeting emerging T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT)/CD155 axis shows promise for restoring anti-tumor immunity, but its immune...
Targeting emerging T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT)/CD155 axis shows promise for restoring anti-tumor immunity, but its immune phenotypes and prognostic significance in a large cohort of pancreatic ductal adenocarcinoma (PDAC) are limited. Three seven-color multispectral panels were rationally designed to investigate the protein expression, immune-microenvironmental feature, prognostic value, and the response to adjuvant chemotherapy of TIGIT/CD155 in 272 PDAC specimens using multiplex immunohistochemistry. We revealed low immunogenicity and high heterogeneity of the PDAC immune microenvironment featured by abundant CD3 T cells and CD68 macrophages and low infiltration of activated cytotoxic T lymphocytes. TIGIT and CD155 were highly expressed in PDAC tissues compared to paracancerous tissues. Tumor-infiltrating lymphocytes expressing TIGIT were correlated with high densities of CD45RO T cells; TIGTICD8 T cells were associated with high infiltration of CD3CD45ROFOXP3. CD155CK were significantly related to high densities of CD3 and CD3CD8CD45RO T cells. High positive rates for TIGIT in TCs, CD8 T cells, and CD155 in macrophages were correlated with poor progression-free and disease-specific survival, respectively, and their clinical significance was correlated with PD-L1 status. Notably, spatial co-existence of TIGITCK or TIGITCD8 and CD155CD68 indicated poor survival and resistance to adjuvant chemotherapy response in patients with PDAC. Our findings suggest that targeting TIGIT/CD155 immunosuppressive axis may guide patient stratification and improve the clinical outcome of PDAC.
Topics: Humans; CD8-Positive T-Lymphocytes; Carcinoma, Pancreatic Ductal; Pancreatic Neoplasms; Chemotherapy, Adjuvant; Tumor Microenvironment; Receptors, Immunologic
PubMed: 37649613
DOI: 10.7150/thno.86547 -
Cancer Discovery Aug 2023Germline BRCA-associated pancreatic ductal adenocarcinoma (glBRCA PDAC) tumors are susceptible to platinum and PARP inhibition. The clinical outcomes of 125 patients...
UNLABELLED
Germline BRCA-associated pancreatic ductal adenocarcinoma (glBRCA PDAC) tumors are susceptible to platinum and PARP inhibition. The clinical outcomes of 125 patients with glBRCA PDAC were stratified based on the spectrum of response to platinum/PARP inhibition: (i) refractory [overall survival (OS) <6 months], (ii) durable response followed by acquired resistance (OS <36 months), and (iii) long-term responders (OS >36 months). Patient-derived xenografts (PDX) were generated from 25 patients with glBRCA PDAC at different clinical time points. Response to platinum/PARP inhibition in vivo and ex vivo culture (EVOC) correlated with clinical response. We deciphered the mechanisms of resistance in glBRCA PDAC and identified homologous recombination (HR) proficiency and secondary mutations restoring partial functionality as the most dominant resistant mechanism. Yet, a subset of HR-deficient (HRD) patients demonstrated clinical resistance. Their tumors displayed basal-like molecular subtype and were more aneuploid. Tumor mutational burden was high in HRD PDAC and significantly higher in tumors with secondary mutations. Anti-PD-1 attenuated tumor growth in a novel humanized glBRCA PDAC PDX model. This work demonstrates the utility of preclinical models, including EVOC, to predict the response of glBRCA PDAC to treatment, which has the potential to inform time-sensitive medical decisions.
SIGNIFICANCE
glBRCA PDAC has a favorable response to platinum/PARP inhibition. However, most patients develop resistance. Additional treatment options for this unique subpopulation are needed. We generated model systems in PDXs and an ex vivo system (EVOC) that faithfully recapitulate these specific clinical scenarios as a platform to investigate the mechanisms of resistance for further drug development. This article is highlighted in the In This Issue feature, p. 1749.
Topics: Humans; Poly(ADP-ribose) Polymerase Inhibitors; Platinum; Pancreatic Neoplasms; Mutation; Carcinoma, Pancreatic Ductal
PubMed: 37449843
DOI: 10.1158/2159-8290.CD-22-0412 -
Cancer Metastasis Reviews Sep 2023Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with poor prognosis due to early metastasis, low diagnostic rates at early stages, and resistance... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with poor prognosis due to early metastasis, low diagnostic rates at early stages, and resistance to current therapeutic regimens. Despite numerous studies and clinical trials, the mortality rate for PDAC has shown limited improvement. Therefore, there is a pressing need to attain. a more comprehensive molecular characterization to identify biomarkers enabling early detection and evaluation of treatment response. MicroRNA (miRNAs) are critical regulators of gene expression on the post-transcriptional level, and seem particularly interesting as biomarkers due to their relative stability, and the ability to detect them in fixed tissue specimens and biofluids. Deregulation of miRNAs is common and affects several hallmarks of cancer and contribute to the oncogenesis and metastasis of PDAC. Unique combinations of upregulated oncogenic miRNAs (oncomiRs) and downregulated tumor suppressor miRNAs (TsmiRs), promote metastasis, characterize the tumor and interfere with chemosensitivity of PDAC cells. Here, we review several oncomiRs and TsmiRs involved in chemoresistance to gemcitabine and FOLFIRINOX in PDAC and highlighted successful/effective miRNA-based therapy approaches in vivo. Integrating miRNAs in PDAC treatment represents a promising therapeutic avenue that can be used as guidance for personalized medicine for PDAC patients.
Topics: Humans; MicroRNAs; Pancreatic Neoplasms; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Biomarkers; Gene Expression Regulation, Neoplastic
PubMed: 37490255
DOI: 10.1007/s10555-023-10127-w -
International Journal of Molecular... Nov 2023Pancreatic ductal adenocarcinoma (PDAC), a highly malignant neoplasm, is classified as one of the most severe and devastating types of cancer. PDAC is a notable... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC), a highly malignant neoplasm, is classified as one of the most severe and devastating types of cancer. PDAC is a notable malignancy that exhibits a discouraging prognosis and a rising occurrence. The interplay between diabetes and pancreatic cancer exhibits a reciprocal causation. The identified metabolic disorder has been observed to possess noteworthy consequences on health outcomes, resulting in elevated rates of morbidity. The principal mechanisms involve the suppression of the immune system, the activation of pancreatic stellate cells (PSCs), and the onset of systemic metabolic disease caused by dysfunction of the islets. From this point forward, it is important to recognize that pancreatic-cancer-related diabetes (PCRD) has the ability to increase the likelihood of developing pancreatic cancer. This highlights the complex relationship that exists between these two physiological states. Therefore, we investigated into the complex domain of PSCs, elucidating their intricate signaling pathways and the profound influence of chemokines on their behavior and final outcome. In order to surmount the obstacle of drug resistance and eliminate PDAC, researchers have undertaken extensive efforts to explore and cultivate novel natural compounds of the next generation. Additional investigation is necessary in order to comprehensively comprehend the effect of PCRD-mediated apoptosis on the progression and onset of PDAC through the utilization of natural compounds. This study aims to examine the potential anticancer properties of natural compounds in individuals with diabetes who are undergoing chemotherapy, targeted therapy, or immunotherapy. It is anticipated that these compounds will exhibit increased potency and possess enhanced pharmacological benefits. According to our research findings, it is indicated that naturally derived chemical compounds hold potential in the development of PDAC therapies that are both safe and efficacious.
Topics: Humans; Diabetes Mellitus, Type 2; Biological Products; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Pancreatic Stellate Cells; Tumor Microenvironment
PubMed: 37958889
DOI: 10.3390/ijms242115906 -
Clinical and Translational Science Aug 2023Pancreatic adenocarcinoma remains a leading cause of cancer-related deaths. In order to develop appropriate therapeutic and prognostic tools, a comprehensive mapping of...
Pancreatic adenocarcinoma remains a leading cause of cancer-related deaths. In order to develop appropriate therapeutic and prognostic tools, a comprehensive mapping of the tumor's molecular abnormalities is essential. Here, our aim was to integrate available transcriptomic data to uncover genes whose elevated expression is simultaneously linked to cancer pathogenesis and inferior survival. A comprehensive search was performed in GEO to identify clinical studies with transcriptome-level gene expression data of pancreatic carcinoma with overall survival data and normal pancreatic tissues. After quantile normalization, the entire database was used to identify genes with altered expression. Cox proportional hazard regression was employed to uncover genes most strongly correlated with survival with a Bonferroni corrected p < 0.01. Perturbed biological processes and molecular pathways were identified to enable the understanding of underlying processes. A total of 16 available datasets were combined. The aggregated database comprised data of 1640 samples for 20,443 genes. When comparing with normal pancreatic tissues, a total of 2612 upregulated and 1977 downregulated genes were uncovered in pancreatic carcinoma. Among these, we found 24 genes with higher expression which significantly correlated with overall survival length also. The most significant genes were ANXA8, FAM83A, KRT6A, MET, MUC16, NT5E, and SLC2A1. These genes remained significant after a multivariate analysis also including grade and stage. Here, we assembled a large-scale database of pancreatic carcinoma samples and used this cohort to identify carcinoma-specific genes linked to altered survival outcomes. As our analysis focused on genes with higher expression, these could serve as future therapy targets.
Topics: Humans; Pancreatic Neoplasms; Transcriptome; Prognosis; Adenocarcinoma; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Neoplasm Proteins
PubMed: 37260110
DOI: 10.1111/cts.13563 -
Journal of Gastroenterology Oct 2023Trajectories of serological and morphological signatures have not been documented in pancreatic carcinogenesis related to intraductal papillary mucinous neoplasms...
Clinical trajectory of intraductal papillary mucinous neoplasms progressing to pancreatic carcinomas during long-term surveillance: a prospective series of 100 carcinoma cases.
BACKGROUND
Trajectories of serological and morphological signatures have not been documented in pancreatic carcinogenesis related to intraductal papillary mucinous neoplasms (IPMNs).
METHODS
Using a prospective cohort of 3437 IPMN patients, we identified 100 IPMN patients who developed pancreatic carcinomas during long-term surveillance. We examined serial changes of blood markers (carbohydrate antigen 19-9 [CA19-9], hemoglobin A1c [HbA1c], and pancreatic enzymes) and morphological features (worrisome features and high-risk stigmata) during the prediagnostic period of pancreatic carcinomas, overall and by carcinoma types (IPMN-derived vs. concomitant pancreatic carcinomas).
RESULTS
CA19-9 elevation was observed in 39 patients and was associated with a metastatic stage. Compared to IPMN-derived carcinomas, concomitant carcinomas were more likely to represent CA19-9 elevation (60% vs. 30%, respectively; P = 0.005). HbA1c levels elevated only in 3 patients. Pancreatic enzyme elevation was observed in 18 patients with no differences in frequencies between the carcinoma types. All patients with elevated levels of blood markers had positive findings on cross-sectional imaging. High-risk stigmata or worrisome features were observed in all patients but one with concomitant carcinoma. The most common types of worrisome features were the main pancreatic duct dilatation and CA19-9 elevation in IPMN-derived and concomitant carcinomas, respectively. Compared to IPMN-derived carcinomas, concomitant carcinomas were less likely to harbor high-risk stigmata (16% vs. 86%, respectively; P < 0.001).
CONCLUSIONS
The usefulness of currently available blood biomarkers was limited in early detection of pancreatic carcinomas related to IPMNs. Morphological alterations were well correlated with long-term risk of IPMN-derived carcinomas, but not with that of concomitant carcinomas.
Topics: Humans; Carcinoma, Pancreatic Ductal; Pancreatic Intraductal Neoplasms; CA-19-9 Antigen; Glycated Hemoglobin; Adenocarcinoma, Mucinous; Retrospective Studies; Pancreatic Neoplasms; Pancreatic Ducts
PubMed: 37507590
DOI: 10.1007/s00535-023-02028-0 -
Frontiers in Immunology 2023Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. It is characterized by a complex and immunosuppressive tumor microenvironment (TME), which... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies. It is characterized by a complex and immunosuppressive tumor microenvironment (TME), which is primarily composed of tumor cells, stromal cells, immune cells, and acellular components. The cross-interactions and -regulations among various cell types in the TME have been recognized to profoundly shape the immunosuppression features that meaningfully affect PDAC biology and treatment outcomes. In this review, we first summarize five cellular composition modules by integrating the cellular (sub)types, phenotypes, and functions in PDAC TME. Then we discuss an integrated overview of the cross-module regulations as a determinant of the immunosuppressive TME in PDAC. We also briefly highlight TME-targeted strategies that potentially improve PDAC therapy.
Topics: Humans; Tumor Microenvironment; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Immunosuppression Therapy
PubMed: 37771596
DOI: 10.3389/fimmu.2023.1258538 -
World Journal of Gastroenterology Sep 2023Pancreatic ductal adenocarcinoma (PDAC) remains a significant public health challenge and is currently the fourth leading cause of cancer-related mortality in developed... (Review)
Review
Pancreatic ductal adenocarcinoma (PDAC) remains a significant public health challenge and is currently the fourth leading cause of cancer-related mortality in developed countries. Despite advances in cancer treatment, the 5-year survival rate for patients with PDAC remains less than 5%. In recent years, neoadjuvant therapy (NAT) has emerged as a promising treatment option for many cancer types, including locally advanced PDAC, with the potential to improve patient outcomes. To analyze the role of NAT in the setting of locally advanced PDAC over the past decade, a systematic literature search was conducted using PubMed and Web of Science. The results suggest that NAT may reduce the local mass size, promote tumor downstaging, and increase the likelihood of resection. These findings are supported by the latest evidence-based medical literature and the clinical experience of our center. Despite the potential benefits of NAT, there are still challenges that need to be addressed. One such challenge is the lack of consensus on the optimal timing and duration of NAT. Improved criteria for patient selection are needed to further identify PDAC patients likely to respond to NAT. In conclusion, NAT has emerged as a promising treatment option for locally advanced PDAC. However, further research is needed to optimize its use and to better understand the role of NAT in the management of this challenging disease. With continued advances in cancer treatment, there is hope of improving the outcomes of patients with PDAC in the future.
Topics: Humans; Neoadjuvant Therapy; Pancreas; Pancreatic Neoplasms; Neoplasms, Second Primary; Carcinoma, Pancreatic Ductal
PubMed: 37744290
DOI: 10.3748/wjg.v29.i35.5094