Outcomes In Pancreatic Ductal Adenocarcinoma Patients Research Articles

Nationwide trends over 10 years in epidemiology and management of pancreatic ductal adenocarcinoma: A real-world study from the French administrative database

Background & aimsSignificant progress has been made in the management of pancreatic ductal adenocarcinoma (PDAC) in recent years. In this population-based study, we aimed to compare incidence, therapeutic strategies, and survival outcomes of PDAC patients in France over a decade. MethodsThis study was performed using a nationwide French database. All patients receiving care for PDAC during years 2009, 2014 and 2018 were included. Treatment modalities and survival outcomes were analyzed. ResultsA total of 8143/8771/10494 patients were considered in 2009/2014/2018, respectively. Incidence increased mainly among patients aged >60 years. In localized PDAC, the proportion of patients receiving best supportive care (BSC) only decreased at 43.6/36.4/32.4 % and 27.8/29.1/34.3 % received chemo(radio)therapy alone. The rate of upfront surgery remained stable while 3/8/18 % of operated patients received neoadjuvant therapy. Median overall survival (OS) was 7.0/7.9/8.5 months in the overall population. Among treated patients, 1-year OS was 61.4/67.7/68.8 % and 30.3/36.3/38.8 % for localized and metastatic PDAC, respectively. ConclusionsThis study confirms the rising incidence of PDAC. Improved outcomes were seen in localized PDAC, with a wider use of chemotherapy and neoadjuvant strategies, and in treated metastatic patients. A modest survival gain was seen overall, hindered by the still high rate of patients receiving BSC only.

Cellular collusion: cracking the code of immunosuppression and chemo resistance in PDAC.

Despite the efforts, pancreatic ductal adenocarcinoma (PDAC) is still highly lethal. Therapeutic challenges reside in late diagnosis and establishment of peculiar tumor microenvironment (TME) supporting tumor outgrowth. This stromal landscape is highly heterogeneous between patients and even in the same patient. The organization of functional sub-TME with different cellular compositions provides evolutive advantages and sustains therapeutic resistance. Tumor progressively establishes a TME that can suit its own needs, including proliferation, stemness and invasion. Cancer-associated fibroblasts and immune cells, the main non-neoplastic cellular TME components, follow soluble factors-mediated neoplastic instructions and synergize to promote chemoresistance and immune surveillance destruction. Unveiling heterotypic stromal-neoplastic interactions is thus pivotal to breaking this synergism and promoting the reprogramming of the TME toward an anti-tumor milieu, improving thus the efficacy of conventional and immune-based therapies. We underscore recent advances in the characterization of immune and fibroblast stromal components supporting or dampening pancreatic cancer progression, as well as novel multi-omic technologies improving the current knowledge of PDAC biology. Finally, we put into context how the clinic will translate the acquired knowledge to design new-generation clinical trials with the final aim of improving the outcome of PDAC patients.

Deciphering the pancreatic cancer microbiome in Mainland China: Impact of Exiguobacterium/Bacillus ratio on tumor progression and prognostic significance

The existing body of research underscores the critical impact of intratumoral microbiomes on the progression of pancreatic ductal adenocarcinoma (PDAC), particularly in reshaping the tumor microenvironment and influencing gemcitabine resistance. However, peritumoral tissues’ microbiome, distinct from PDAC tumors, remain understudied, and Western-centric analyses overlooking potential variations in dietary-influenced microbiomes. Our study addresses this gap by 16 S rRNA sequencing of PDAC tumors and matched peritumoral tissues from Chinese Mainland patients. Our research has uncovered that the microbiome composition within tumors and paired peritumoral tissues exhibits a high degree of similarity, albeit with certain discrepancies. Notably, Exiguobacterium is found to be more abundant within the tumor tissues. Further investigations have revealed that a lower Exiguobacterium/Bacillus ratio in both the tumor and peritumoral tissues of PDAC patients is indicative of a more favorable prognosis. Further exploration utilizing an orthotopic tumor model demonstrates that the probiotic Bacillus Coagulans impedes PDAC progression, accompanied by an increased infiltration of inflammatory neutrophils in tumors. Additionally, in the subgroup with a low Exiguobacterium/Bacillus ratio, whole-exome sequencing reveals elevated missense mutations in ABL2 and MSH2. The elevated expression of ABL2 and MSH2 has been correlated with poorer prognostic outcomes in PDAC patients. Together, these insights shed light on risk factors influencing PDAC progression and unveil potential therapeutic targets, alongside probiotic intervention strategies.

Neoadjuvant chemotherapy is associated with suppression of the B cell-centered immune landscape in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at advanced stages and associated with early distant metastasis and poor survival. Besides clinical factors, the tumor microenvironment (TME) emerged as a crucial determinant of patient survival and therapy response in many tumors, including PDAC. Thus, the presence of tumor-infiltrating lymphocytes and the formation of tertiary lymphoid structures (TLS) is associated with longer survival in PDAC. Although neoadjuvant therapy (NeoTx) has improved the management of locally advanced tumors, detailed insight into its effect on various TME components is limited. While a remodeling towards a proinflammatory state was reported for PDAC-infiltrating T cells, the effect of NeoTx on B cell subsets, including plasma cells, and TLS formation is widely unclear. We thus investigated the frequency, composition, and spatial distribution of PDAC-infiltrating B cells in primary resected (PR) versus neoadjuvant-treated patients using a novel multiplex immunohistochemistry panel. The NeoTx group displayed significantly lower frequencies of pan B cells, GC B cells, plasmablasts, and plasma cells, accompanied by a reduced abundance of TLS. This finding was supported by bulk RNA-sequencing analysis of an independent fresh frozen tissue cohort, which revealed that major B cell pathways were downregulated in the NeoTx group. We further observed that plasma cells frequently formed aggregates that localized close to TLS and that TLS+ patients displayed significantly higher plasma cell frequencies compared to TLS- patients in the PR group. Additionally, high densities of CD20+ intratumoral B cells were significantly associated with longer overall survival in the PR group. While CD20+ B cells held no prognostic value for NeoTx patients, an increased frequency of proliferating CD20+Ki67+ B cells emerged as an independent prognostic factor for longer survival in the NeoTx group. These results indicate that NeoTx differentially affects PDAC-infiltrating immune cells and may have detrimental effects on the existing B cell landscape and the formation of TLS. Gaining further insight into the underlying molecular mechanisms is crucial to overcome the intrinsic immunotherapy resistance of PDAC and develop novel strategies to improve the long-term outcome of PDAC patients.

Impact of Neoadjuvant Therapy for Pancreatic Cancer: Transatlantic Trend and Postoperative Outcomes Analysis.

The introduction of modern chemotherapy a decade ago has led to increased use of neoadjuvant therapy (NAT) in patients with pancreatic ductal adenocarcinoma (PDAC). A recent North American study demonstrated increased use of NAT and improved operative outcomes in patients with PDAC. The aims of this study were to compare the use of NAT and short-term outcomes in patients with PDAC undergoing pancreatoduodenectomy (PD) among registries from the US and Canada, Germany, the Netherlands, and Sweden. Databases from 2 multicenter (voluntary) and 2 nationwide (mandatory) registries were queried from 2018 to 2020. Patients undergoing PD for PDAC were compared based on the use of upfront surgery vs NAT. Adoption of NAT was measured in each country over time. Thirty-day outcomes, including the composite measure (ideal outcomes), were compared by multivariable analyses. Sensitivity analyses of patients undergoing vascular resection were performed. Overall, 11,402 patients underwent PD for PDAC with 33.7% of patients receiving NAT. The use of NAT increased steadily from 28.3% in 2018 to 38.5% in 2020 (p < 0.0001). However, use of NAT varied widely by country: the US (46.8%), the Netherlands (44.9%), Sweden (11.0%), and Germany (7.8%). On multivariable analysis, NAT was significantly (p < 0.01) associated with reduced rates of serious morbidity, clinically relevant pancreatic fistulae, reoperations, and increased ideal outcomes. These associations remained on sensitivity analysis of patients undergoing vascular resection. NAT before PD for pancreatic cancer varied widely among 4 Western audits yet increased by 26% during 3 years. NAT was associated with improved short-term outcomes.

Cyclophosphamide maintenance to extend combination chemotherapy-free interval in metastatic pancreatic ductal adenocarcinoma.

Administering chemotherapy until progression to metastatic pancreatic ductal adenocarcinoma (PDAC) patients lacks of supporting evidence and causes cumulative toxicity. We explored the role of cyclophosphamide as maintenance therapy. PDAC germline BRCA1-2 wild-type patients who were progression-free after ≥6 months of any regimen and line of chemotherapy and received maintenance cyclophosphamide (mCTX) (50mg/day), were included in the analysis. 42 patients were included in the analysis. Thirty-nine patients had progression of disease. Median PFS was 3.5 (range 1.0-31+) months. PFS rates at 6 and 12 months were 26.2% and 11.9%. At a median follow-up of 20.0 months (range 12.1-31.0 months), 20 patients died and 22 are alive. Median OS was 20.0 months (range 2.2-31.0+). OS at 6 and 12 months was 97.6% (95%CI: 93.4-100), and 73.8% (95% CI: 61.1-86.5), respectively. Only 2 patients receiving mCTX had Grade 3 toxicity. mCTX therapy yielded promising PFS and OS outcome in PDAC patients who were progression-free after induction chemotherapy, with unremarkable toxicity. Accordingly, this approach warrants further investigation.

Abstract C113: The mitochondrial calcium uniporter supports epithelial to mesenchymal transition of pancreatic ductal adenocarcinoma

Abstract In spite of many new developments in cancer treatments and targeted therapies over the past few decades, outcomes for pancreatic ductal adenocarcinoma (PDAC) patients continue to be poor. Calcium signaling and mitochondrial function are known to contribute to cancer outcomes in many paradigms, yet much remains unknown in the context of PDAC. The mitochondrial Ca2+ uniporter, MCU, is the main route by which mitochondria can take up Ca2+ into the mitochondrial matrix, where it drives metabolic activity in the tricarboxylic acid cycle and promotes ATP synthesis by the electron transport chain. Our previous work suggests that Ca2+ flux from the endoplasmic reticulum (ER) into the mitochondria at mitochondria-associated membranes (MAMs) may be important to drive malignancy. Here, we show that MCU expression is associated with poor outcomes in PDAC patients and disease progression in murine organoid models of cancer development. Further, deletion of Mcu in murine KPC cells results in ablation of mitochondrial Ca2+ uptake, which reduces growth, proliferation, and clonogenicity. Tumor growth and metastatic colonization are also reduced in orthotopic implantation models, with some KPCY-McucKO models failing to develop primary lesions. This suggests that MCU, and thus mitochondrial Ca2+, play an important role in tumor growth. Critically, we here elucidate a heretofore unknown relationship between ER-to-mitochondrial Ca2+ flux through Mcu and epithelial to mesenchymal transition (EMT), an important process that contributes to poor outcomes in PDAC. To this end, McucKO associates with reduced basal Snail expression and reduced TGFβ secretion, and McucKO clones have a more epithelial morphology than their isogenic, Mcu-expressing counterparts. Both stable expression of Snail and treatment with TGFβ are able to rescue growth, mobility, and clonogenic deficits in McucKO cell lines to levels comparable to isogenic, Mcu-expressing cell lines. Uptake assays, metabolomics, isotope tracing, and mRNA-Seq have enabled us to elucidate metabolic and transcriptional rewiring induced by Snail and TGFβ treatment which may promote cell survival and proliferation despite the lack of Mcu. This work has important implications for potential targeting of Ca2+ signaling in the context of PDAC. Citation Format: Jillian S. Weissenrieder, Jason Pitarresi, Natalie Weinmann, Rebecca Drager, Usha Paudel, Anil Rustgi, Ben Stanger, J. Kevin Foskett. The mitochondrial calcium uniporter supports epithelial to mesenchymal transition of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C113.

Circulating autoantibodies to alpha-enolase (ENO1) and far upstream element-binding protein 1 (FUBP1) are negative prognostic factors for pancreatic cancer patient survival

Pancreatic ductal adenocarcinoma (PDA) has a dismal prognosis due to a lack of early diagnostic markers and effective therapy. In PDA patients, the glycolytic enzyme and plasminogen receptor alpha-enolase (ENO1) and the transcription factor far upstream element-binding protein 1 (FUBP1) are upregulated and elicit the production of autoantibodies (aAb) that discriminate healthy subjects from PDA patients, with the latter mostly directed to post-translational phosphorylated isoforms. Here, the correlation of prognosis with circulating ENO1 and FUBP1aAb, and their protein tissue expression was analyzed in PDA patients. Circulating ENO1 and FUBP1 aAb was analyzed in two cohorts of PDA patients by ELISA (n = 470), while tissues expression was observed by immunohistochemistry (n = 45). Overall survival (OS) was estimated using the Kaplan–Meier method, while the Cox model was used to estimate the hazard ratios (HR) adjusted for the main prognostic factors. Logistic models were applied to assess associations between death and its risk indicators. All statistical analyses were performed with Stata version 15. Unlike ENO1 aAb, there was a significant correlation between FUBP1 aAb and FUBP1 expression in tumors (p = 0.0268). In addition, we found that high ENO1 (p = 0.016) and intermediate FUBP1 aAb levels (p = 0.013) were unfavorable prognostic factors. Notably, it was found that high anti-FUBP1 aAb level is a good prognostic marker for tail-body PDA (p = 0.016). Our results suggest that different levels of circulating aAb to ENO1 and FUBP1 predict a poor outcome in PDA patients and can be used to improve therapeutic strategies.

Identification of novel therapeutic target and prognostic biomarker in matrix metalloproteinase gene family in pancreatic cancer

Matrix metalloproteinases (MMPs) play an essential role in various physiological events. Recent studies have revealed its carcinogenic effect in malignancies. However, the different expression patterns, prognostic value, and immunological value of MMPs in pancreatic ductal adenocarcinoma (PDAC) are yet to be comprehensively explored. We utilized Gene Expression Profiling Interactive Analysis (GEPIA) and Gene Expression Omnibus databases to explore the abnormal expression of MMPs in PDAC. Then, Kaplan–Meier survival curve and Cox regression analysis were performed to assess the prognostic value of MMPs. Association between MMPs expression and clinicopathological features was analyzed through UALCAN website. Functional annotations and GSEA analysis were performed to excavate the possible signaling pathways involving prognostic-related MMP. TIMER and TISCH database were used to performed immune infiltration analysis. The expression of prognostic-related MMP in pancreatic cancer cell lines and normal pancreatic cells was detected by Real time quantitative PCR. We observed that 10 MMP genes were consistently up-regulated in GEPIA and GSE62452 dataset. Among them, five highly expressed MMPs (MMP1, MMP3, MMP11, MMP14, MMP28) were closely related to poor clinical outcomes of PDAC patients. Cox regression analysis indicated MMP28 was a risk factor influencing the overall survival of patients. In the clinicopathological analysis, up-regulated MMP28 was significantly associated with higher tumor grade and the mutation status of TP53. GSEA analysis demonstrated that high expression of MMP28 was involved in “interferon_alpha_response” and “P53_pathway”. Immune infiltration analysis showed that there was no correlation between MMP28 expression and immune cell infiltration. Single-cell sequencing analysis showed MMP28 has strong correlations with malignant cells and stromal cells infiltration in the tumor microenvironment. And MMP28 was highly expressed in various pancreatic cancer cell lines. In conclusion, MMP28 may represent a potential prognosis biomarker and novel therapeutic molecular targets for PDAC.

Reversible promoter demethylation of PDGFD confers gemcitabine resistance through STAT3 activation and RRM1 upregulation

Drug resistance is a major problem in cancer treatment with traditional or targeted therapeutics. Gemcitabine is approved for several human cancers and the first line treatment for locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC). However, gemcitabine resistance frequently occurs and is a major problem in successful treatments of these cancers and the mechanism of gemcitabine resistance remains largely unknown. In this study, we identified 65 genes that had reversible methylation changes in their promoters in gemcitabine resistant PDAC cells using whole genome Reduced Representation Bisulfite Sequencing analyses. One of these genes, PDGFD, was further studied in detail for its reversible epigenetic regulation in expression and shown to contribute to gemcitabine resistance in vitro and in vivo via stimulating STAT3 signaling in both autocrine and paracrine manners to upregulate RRM1 expression. Analyses of TCGA datasets showed that PDGFD positively associates with poor outcome of PDAC patients. Together, we conclude that the reversible epigenetic upregulation plays an important role in gemcitabine resistance development and targeting PDGFD signaling alleviates gemcitabine resistance for PDAC treatment.

The role of BHLHE40 in clinical features and prognosis value of PDAC by comprehensive analysis and in vitro validation.

Pancreatic ductal adenocarcinoma (PDAC) is the leading cause of cancer-related mortality, primarily due to the abundance of cancer-associated fibroblasts (CAFs), depleted effector T cells, and increased tumor cell stemness; hence, there is an urgent need for efficient biomarkers with prognostic and therapeutic potential. Here, we identified BHLHE40 as a promising target for PDAC through comprehensive analysis and weighted gene coexpression network analysis of RNA sequencing data and public databases, taking into account the unique characteristics of PDAC such as cancer-associated fibroblasts, infiltration of effector T cells, and tumor cell stemness. Additionally, we developed a prognostic risk model based on BHLHE40 and three other candidate genes (ITGA2, ITGA3, and ADAM9) to predict outcomes in PDAC patients. Furthermore, we found that the overexpression of BHLHE40 was significantly associated with T stage, lymph node metastasis, and American Joint Committee on Cancer (AJCC) stage in a cohort of 61 PDAC patients. Moreover, elevated expression levels of BHLHE40 were validated to promote epithelial-mesenchymal transition (EMT) and stemness-related proteins in BXPC3 cell lines. Compared to the parent cells, BXPC3 cells with BHLHE40 overexpression showed resistance to anti-tumor immunity when co-cultured with CD8+ T cells. In summary, these findings suggest that BHLHE40 is a highly effective biomarker for predicting prognosis in PDAC and holds great promise as a target for cancer therapy.

Phosphoproteomics guides effective low-dose drug combinations against pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with a limited set of known driver mutations but considerable cancer cell heterogeneity. Phosphoproteomics provides a readout of aberrant signaling and has the potential to identify new targets and guide treatment decisions. Using two-step sequential phosphopeptide enrichment, we generate a comprehensive phosphoproteome and proteome of nine PDAC cell lines, encompassing more than 20,000 phosphosites on 5,763 phospho-proteins, including 316 protein kinases. By using integrative inferred kinase activity (INKA) scoring, we identify multiple (parallel) activated kinases that are subsequently matched to kinase inhibitors. Compared with high-dose single-drug treatments, INKA-tailored low-dose 3-drug combinations against multiple targets demonstrate superior efficacy against PDAC cell lines, organoid cultures, and patient-derived xenografts. Overall, this approach is particularly more effective against the aggressive mesenchymal PDAC model compared with the epithelial model in both preclinical settings and may contribute to improved treatment outcomes in PDAC patients.

Abstract 378: Ferritin regulates oxaliplatin sensitivity and immunosuppression in pancreatic ductal adenocarcinoma

Abstract Oxaliplatin, a third-generation of platinum analog, has been used for the treatment of colorectal, gastric, and advanced pancreatic ductal adenocarcinoma (PDAC); however, its relatively high toxicity reduced its efficacy in clinical use. Recently, we found that organic cation transporter 2 (OCT2) expression is positively correlated to Oxaliplatin sensitivity in PDAC cells and better survival outcomes in PDAC patients with chemotherapy, suggesting that OCT2 level is important not only in predicting sensitivity to oxaliplatin but also in guiding dose adjustments to minimize toxicity. Here, we observed the significance of serum Ferritin as a prognostic marker for pancreatic cancer, and further identified Ferritin heavy chain (FTH1) down-regulated OCT2 level and reduced Oxaliplatin sensitivity of advanced PDAC cells in vitro and in vivo. Our study reveals the negative correlation between FTH1 and OCT2 levels in PDAC database analysis and reducing FTH1 expression with Deferasirox (DFX), which is an agent that has been widely used for patients with iron overload, reversed OCT2 expression and Oxaliplatin sensitization in metastatic PDAC cells. Additionally, we identified that exosomal Ferritin/FTH1 from PDAC cells may enhance M1-type to M2-type macrophage polarization to build up immunosuppression in the tumor microenvironment. Citation Format: Ching-Feng Chiu. Ferritin regulates oxaliplatin sensitivity and immunosuppression in pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 378.

Abstract 6515: Pancreatic ductal adenocarcinoma (PDAC) early detection

Abstract Introduction Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer and is one of the deadliest cancer in the U.S., with a 5-year survival rate of just 11%. It is expected that ~62,000 new cases will be diagnosed in the US in 2023 and &amp;gt;70% of those will be at the regional or distant state, when curative resection is no longer an option. It is imperative that tools enabling early disease detection (stages I and II) are developed to improve patient survival outcomes. Here, we report the results of a study on the utility of extracellular vesicles (EVs) for early PDAC detection. Methods Our case-control training set was comprised of 75 pathologically confirmed PDAC cases (Stage I = 31, Stage II = 44) and 640 controls (including 11 subjects with pancreatitis) for EV biomarker and algorithm selection via machine learning. EVs from plasma were isolated using a proprietary technology, then EV-bound proteins of interest were analyzed via an immunoassay. A second independently collected cohort of 20 confirmed PDAC cases (Stage I = 10, Stage II = 10) and 27 controls (including 9 patients newly diagnosed with diabetes) was used for validation. Results The machine learning analysis using EV-isolated proteins generated a signature that utilized 8 different biomarkers, with an AUC of 0.989 (95% CI: 0.980 - 0.998) in the training set and an AUC of 0.987 (CI: 0.964 - 1.000) in the validation set. For the validation set, the sensitivity was 95% (CI: 76.4% - 99.1%) and the specificity was 92.6% (CI: 76.6% - 97.9%), with 10 out of 10 stage I cases and 9 out of 10 stage II cases correctly classified. Conclusions The ability to alter the future outcomes of PDAC patients will be predicated on development of a new generation of early-detection biomarkers and technologies. The use of EV protein signatures, a new class of cell-free biomarker, permits detection at high sensitivity and specificity, as demonstrated for the independently collected validation cohort. Studies aimed to assess this test for high-risk patients (family history of PDAC, known germline mutations, precursor lesions, hereditary pancreatitis, new onset diabetes will continue towards the establishment of real-world evidence. Citation Format: Juan P. Hinestrosa, Harmeet Dhani, Gregor Schroeder, Jean M. Lewis, Heath I. Balcer, Razelle Kurzrock, Dove Keith, Rosalie Sears, Paul Billings. Pancreatic ductal adenocarcinoma (PDAC) early detection. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6515.

The Role of Exosomes in Pancreatic Ductal Adenocarcinoma Progression and Their Potential as Biomarkers

Pancreatic ductal adenocarcinoma (PDAC), the most common pancreatic malignancy, is an aggressive and lethal cancer with a dismal five-year survival rate. Despite remarkable improvements in cancer therapeutics, the clinical outcome of PDAC patients remains poor due to late diagnosis of the disease. This highlights the importance of early detection, wherein biomarker evaluation including exosomes would be helpful. Exosomes, small extracellular vesicles (sEVs), are cell-secreted entities with diameters ranging from 50 to 150 nm that deliver cellular contents (e.g., proteins, lipids, and nucleic acids) from parent cells to regulate the cellular processes of targeted cells. Recently, an increasing number of studies have reported that exosomes serve as messengers to facilitate stromal-immune crosstalk within the PDAC tumor microenvironment (TME), and their contents are indicative of disease progression. Moreover, evidence suggests that exosomes with specific surface markers are capable of distinguishing patients with PDAC from healthy individuals. Detectable exosomes in bodily fluids (e.g., blood, urine, saliva, and pancreatic juice) are omnipresent and may serve as promising biomarkers for improving early detection and evaluating patient prognosis. In this review, we shed light on the involvement of exosomes and their cargos in processes related to disease progression, including chemoresistance, angiogenesis, invasion, metastasis, and immunomodulation, and their potential as prognostic markers. Furthermore, we highlight feasible clinical applications and the limitations of exosomes in liquid biopsies as tools for early diagnosis as well as disease monitoring. Taking advantage of exosomes to improve diagnostic capacity may provide hope for PDAC patients, although further investigation is urgently needed.

PLA2G2A+ cancer-associated fibroblasts mediate pancreatic cancer immune escape via impeding antitumor immune response of CD8+ cytotoxic T cells

Our previous research defined a novel metabolic cancer associated fibroblasts subset (meCAFs) enriched in loose-type pancreatic ductal adenocarcinoma (PDAC) and related to CD8+ T cells accumulation. Consistently, the abundance of meCAFs was associated with poor prognosis but better immunotherapy responses in PDAC patients. However, the metabolic characteristic of meCAFs and its cross-talk with CD8+ T cells remain to be elucidated. In this study, we identified PLA2G2A as a marker of meCAFs. In particular, the abundance of PLA2G2A+ meCAFs was positively related to the accumulation of total CD8+ T cells and negatively correlated with clinical outcomes of PDAC patients and infiltration of intratumoral CD8+ T cells. We demonstrated that PLA2G2A+ meCAFs substantially attenuated the antitumor ability of tumor infiltrating CD8+ T cells and facilitated tumor immune escape in PDAC. Mechanistically, PLA2G2A regulated the function of CD8+ T cells as a pivotal soluble mediator via MAPK/Erk and NF-κB signaling pathways. In conclusion, our study identified the unrecognized role of PLA2G2A+ meCAFs in promoting tumor immune escape by impeding the antitumor immune function of CD8+ T cells, and strongly suggested PLA2G2A as a promising biomarker and therapeutic target for immunotherapy in PDAC.

Inflammatory Cytokines and Radiotherapy in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains a therapeutic challenge in clinical oncology. Surgery is the only potentially curative treatment. However, the majority of PDAC patients present with locally advanced/unresectable or metastatic disease, where palliative multiagent chemotherapy is the first-line treatment with the therapeutic intent to delay progression and prolong survival. For locally advanced/unresectable pancreatic cancer patients who are treated with chemotherapy, consolidative radiotherapy in the form concurrent chemoradiation or stereotactic ablative radiotherapy improves locoregional control and pain/symptom control. To improve clinical outcomes of PDAC patients, there is a dire need for discoveries that will shed more light on the pathophysiology of the disease and lead to the development of more efficacious treatment strategies. Inflammatory cytokines are known to play a role in mediating tumor progression, chemoresistance, and radioresistance in PDAC. A PubMed search on published articles related to radiotherapy, inflammatory cytokines, and pancreatic cancer patients in the English language was performed. This article primarily focuses on reviewing the clinical literature that examines the association of inflammatory cytokines with clinical outcomes and the effects of radiotherapy on inflammatory cytokines in PDAC patients.

Abstract C061: Alternative polyadenylation regulates gene expression within the pancreatic cancer tumor microenvironment

Abstract A characteristic of pancreatic ductal adenocarcinoma (PDAC) is that about 90% of its tumor volume can be made up of dense, fibrotic stroma. Multiple studies have shown that this dense stroma strongly influences disease progression and drug delivery. Amongst the cells that make up the stroma, Cancer Associated Fibroblasts (CAFs) are important regulators directly affecting cancer progression and therapeutic resistance. CAFs are a heterogeneous population, including inflammatory, myofibroblastic, and antigen-presenting CAFs, each with specific functional contributions to the cancer phenotype. While we have been able to define CAFs phenotypically, we lack a deeper understanding of the mechanisms underlying their transcriptional heterogeneity and ultimately their contribution in driving PDAC progression. Our lab has previously shown that 3’UTR-Alternative Polyadenylation (APA) is a key mechanism underlying gene dysregulation in PDAC. APA machinery makes use of multiple Poly A Sites (PAS) in a transcript and leads to the formation of distinct isoforms of mRNA with varying lengths, commonly referred to as short or long isoforms. This lengthening and shortening of mRNA modulates mRNA stability, protein expression, and localization, thus directly affecting cellular processes including proliferation, metastasis, and migration. We have now extended these findings to an analysis of APA events within the tumor microenvironment (TME). We find that 3’ UTR shortening is significantly associated with inflammatory CAFs (iCAFs), and that these APA events are correlated with gene expression changes in iCAF marker genes. We hypothesize that APA is a crucial driver of heterogeneity within the tumor microenvironment of PDAC. We have begun to elucidate the mechanisms underlying these gene regulatory changes in vitro using human-derived CAF cell lines via genetic and pharmacological inhibition of APA. Understanding these mechanisms may help us find druggable targets that may eventually affect the overall outcomes of PDAC patients. Citation Format: Aditi H Chaubey, Michael E Feigin. Alternative polyadenylation regulates gene expression within the pancreatic cancer tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C061.

Association between remotely-monitored activity, patient-reported outcomes, and physical function in patients with advanced pancreatic cancer.

1572 Background: Patients with pancreatic ductal adenocarcinoma (PDAC) experience significant functional decline over the course of their treatment, which can negatively impact their quality of life (QOL) and clinical outcomes. There are currently no standardized methods to monitor physical function (PF) in PDAC patients outside the clinic setting. The use of wearable technology to obtain continuous and objective activity data combined with routine collection of patient-reported outcomes (PROs) provides an opportunity to monitor PF and intervene in a timely matter. Methods: We conducted a single-site, single-arm prospective study in advanced stage 3 and 4 PDAC patients between 2019 and 2/2022. Patients used a wrist-worn wearable activity monitor (Fitbit) continuously for 8 weeks and completed NIH PROMIS surveys (PF, pain, fatigue, sleep disturbance, and emotional distress) at baseline, week 4 and week 8. ECOG performance status (PS), hand grip strength, and timed 15-foot walk test were also assessed at each timepoint. Pearson correlation coefficients were calculated for activity data (step counts, distance, stairs, time spent sedentary and in light, moderate, or vigorous activity, sleep), PROs, and functional outcomes. Multivariable regression models, adjusted for age, sex, and cancer stage, were fit to evaluate associations between activity metrics, PROs, and functional outcomes. Multivariable cox proportional hazard models were fit to evaluate the impact of activity levels on survival. Results: A total of 40 patients consented onto study: 50% female, median age: 67 years (range 47-85), 92% ECOG 1. Baseline activity data are summarized in Table. Statistically significant correlations between step counts and PF T-scores (coeff: 0.6, p = 0.001) and lower pain scores (coeff: -0.53, p = 0.002) were observed. Increased stairs count and time spent in moderate and high physical activity were also positively correlated with increased PF (p&lt;0.001). No statistically significant correlations were observed between hand grip strength, activity metrics or PROs. Fewer average step counts and worse PF scores were significantly associated with poor survival with hazard ratios (HR) of 1.44 per 1000 steps (95% CI 1.06, 1.97, p = 0.02) and 1.69 (95% CI 1.1-2.56, p = 0.017), respectively, after adjusting for age, sex, stage, and ECOG PS. Conclusions: Findings from this research suggest that the use of wearable technology for remote monitoring of daily activity is feasible and may be used to supplement functional assessment and predict outcomes in PDAC patients. Larger trials are needed to validate findings. [Table: see text]

Co‐expression of Zeb‐1 and K17 provides new insights into the role of EMT in pancreatic cancer progression

INTRODUCTIONDespite improvements in screening and therapeutic options, pancreatic ductal adenocarcinoma (PDAC) has the third‐worst mortality rate, highlighting the need for better diagnostic and therapeutic approaches. Epithelial‐mesenchymal transition (EMT) has been conferred with a greater likelihood of metastasis in multiple cancers, specifically identified through markers like Zeb‐1 and Twist‐1. Zeb‐1 (Zinc Finger E‐Box Binding Homeobox 1) was shown to repress E‐cadherin expression, consequently inducing EMT.Our lab has previously identified K17 (Keratin 17) as an independent prognostic biomarker of poor outcomes in PDAC patients. While increasing evidence has suggested that EMT drives pancreatic cancer migration and metastasis, there have not been any well‐established connections between K17 expression and EMT. This study aims to provide new insights into the role of K17 in EMT by evaluating the co‐expression of K17 and Zeb‐1 in human PDAC biopsies. We hypothesized that tumor cells co‐express K17 and Zeb‐1 as a hallmark of EMT in PDAC. In addition, our study aims to establish a novel method of scoring Zeb‐1 expression in stromal fibroblasts via immunofluorescence to remove variability in the stromal constituency.METHODSPDAC tissues obtained from patients who underwent surgical resection between 2013 and 2017 at Stony Brook University (n=20) were selected for serial sectioning. Double immunofluorescence and single immunohistochemical staining were achieved by incubation with Zeb‐1 and K17 antibodies followed by incubation of fluorescent or biotin conjugated secondary antibodies, respectively. Histologic examination was performed using immunofluorescence staining along with H&amp;E and immunohistochemical staining (IHC) to determine concordance.RESULTS● IHC for Zeb‐1 was detected predominantly in the nuclei of centroacinar cells, benign proliferative ducts, and stromal fibroblasts. Focal nuclear staining in tumor epithelial was also detected in some cases.● High levels of K17 and but decreased expression of Zeb‐1 were detected in diffusely infiltrative cells with morphologic features of EMT.● Both high Zeb‐1 and high K17 protein expression were associated with poor survival of PDAC patients.● Using confocal immunofluorescence microscopy, we detected co‐localization of Zeb‐1 and K17 in PDAC.● We quantified Zeb‐1 protein expression in PDAC samples from 20 patients and confirmed significantly higher expression in the tumor‐associated stroma of high‐grade tumors compared to stromal fibroblasts in areas devoid of tumor.CONCLUSIONOur results provide evidence that K17 is upregulated in tumor epithelial cells that show morphologic immunohistochemical properties of EMT. The loss of Zeb‐1 in diffusely infiltrative, K17‐positive tumor cells suggests that EMT upregulates K17, driving tumor aggression. Our results suggest that K17 may enhance PDAC aggression by mediating EMT. Hence, novel therapeutic agents targeting K17 may improve clinical care for this biologically distinct patient subgroup.