Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with a dismal 5-year survival rate at 12%. The fibrotic PDAC desmoplasia is a major contributor to chemoresistance and metastasis that drive this poor prognosis. Cancer-associated fibroblasts (CAFs) generate PDAC tumour fibrosis and have been identified as therapeutic targets to remodel the stroma to a more drug-permissive microenvironment. We assessed the therapeutic potential of inhibiting the collagen chaperone, heat shock protein 47 (HSP47) in PDAC cells and CAFs. Collagen is a key component of PDAC fibrosis and requires the activity of HSP47 to ensure correct maturation and secretion. Herein, we show that HSP47 knockdown inhibits both PDAC cells and CAF proliferation in vitro. In vivo, therapeutic HSP47 knockdown in orthotopic PDAC tumours significantly reduced intratumoural fibrosis and opened intratumoural blood vessels, while stable HSP47 knockdown specifically in CAFs additionally reduced PDAC tumour growth. We observed that HSP47 is highly expressed in the stroma of >80% of patients in a PDAC cohort (Australian Pancreatic Cancer Genome Initiative), but that it was only prognostic of poorer overall survival in the tumour compartment. Functional relevance in the tumour compartment was further validated in 3D human PDAC explants. Our work demonstrates that HSP47 is a potential therapeutic target in both PDAC cells and CAFs and represents a robust target to interfere with tumour collagen deposition.

Pancreatic ductal adenocarcinoma (PDAC) remains highly resistant to treatment, with mortality rates largely unchanged despite advances in cancer therapies. For ∼80% of borderline, non-resectable, or metastatic cases, chemotherapy is predominantly palliative, underscoring the need for improved drug delivery approaches. This study presents the development, characterization and in vivo evaluation of a novel polymeric implant loaded with 5-fluorouracil, irinotecan, and oxaliplatin (FIRINOX). Scanning electron microscopy of FIRINOX implants showed internal microstructure was preserved upon drug loading, while micro-CT and X-ray imaging revealed valuable insights into the morphology and degradation of implants retrieved from in vivo experiments. In murine PDAC models, dose-escalation identified 4 × FIRINOX implants as the maximum tolerated dose, while 2 × implants achieved significant therapeutic efficacy at lower doses than IV administration, without compromising animal safety. In healthy pigs, 20 × FIRINOX implants were well-tolerated, as confirmed by histopathology and blood analysis. Finally, laser ablation-inductively coupled plasma-mass spectrometry imaging and microbiome analysis confirmed localized drug perfusion within tissues, and minimal off-target effects, including preservation of gut microbiota diversity. These findings support the potential of this implantable platform to improve outcomes in borderline or non-resectable PDAC and enhance tolerability of cytotoxic chemotherapy through localized, controlled delivery, addressing a key gap where current treatment options are limited.

ABSTRACT Background Pancreatic ductal adenocarcinoma (PDAC) is a particularly lethal malignancy with few treatment options available. Extensive remodelling of extracellular matrix (ECM) generates a highly fibrotic tumour landscape, which impairs therapeutic response. Objective We investigated whether stromal priming via the highly specific Focal Adhesion Kinase (FAK) inhibitor narmafotinib (AMP945) in combination with the two major standard-of-care chemotherapies in PDAC, gemcitabine/Abraxane and FOLFIRINOX, reduces fibrosis and enhances treatment efficacy. Design 3D organotypic matrices, intravital imaging, and in vivo subcutaneous and orthotopic PDAC models were used to provide a rationale for a first-line priming regimen of narmafotinib prior to chemotherapy. Results Neoadjuvant chemotherapy induces fibrosis in PDAC indicating a need for upfront first-line priming of the ECM to normalise the stroma for optimal treatment response. Narmafotinib is a new potent small molecule FAK inhibitor. Phase I safety data shows excellent safety, tolerability, and pharmacokinetics following oral administration in humans. We reveal that narmafotinib treatment during early ECM remodelling (‘priming’) reduces fibrosis, while limiting subsequent PDAC invasion. Moreover, intravital imaging demonstrates real-time FAK inactivation and cell cycle stalling, leading to improved chemotherapeutic efficacy upon narmafotinib priming in vivo . Long-term assessment in patient-derived models shows that narmafotinib priming prior to gemcitabine/Abraxane or FOLFIRINOX reduces PDAC progression and extends survival in both chemotherapy settings. Conclusions Our results using these Phase II-ready drug combinations strongly support the clinical assessment of narmafotinib in PDAC. Narmafotinib is currently in Phase Ib/IIa trials, assessing a pulsed dosing regimen prior to gemcitabine/Abraxane, and warrants further clinical assessment in combination with FOLFIRINOX. SIGNIFICANCE OF THIS STUDY What is already known on this topic Pancreatic cancer (PC) is one of the most lethal malignancies and is characterised by a dense, fibrotic stroma, which impairs chemotherapy efficacy. The non-receptor tyrosine kinase FAK is known to promote cancer fibrosis and therefore represents a therapeutic target to normalise the PC stroma and to improve chemotherapy performance. What this study adds Neoadjuvant chemotherapy induces early fibrosis indicating a need for upfront first-line priming of the ECM to blunt or normalise stromal fibrosis for optimal response to therapy. The small molecule inhibitor narmafotinib (which is currently under Phase Ib/IIa clinical trial assessment) shows high specificity towards FAK as well as desirable pharmacokinetics and pharmacodynamics in healthy human volunteers. Early short-term narmafotinib priming reduces fibrosis and improves the efficacy of subsequent standard-of-care gemcitabine/Abraxane chemotherapy. FOLFIRINOX (oxaliplatin, irinotecan, leucovorin and 5-fluorouracil) is a multi-agent chemotherapy preferentially used in PDAC patients with good performance status. Our results demonstrate that narmafotinib priming also improves FOLFIRINOX efficacy, leading to extended survival in patient-derived PDAC models. How this study might affect research, practice, or policy This study supports the clinical development of narmafotinib in combination with both gemcitabine/Abraxane (ACCENT trial) and further FOLFIRINOX standard-of-care chemotherapies for PDAC patient treatment. The first-line priming strategy and early ECM normalisation used in this study may also be applicable to other combination therapy settings and warrants further investigation in ongoing clinical studies.

The microtubule protein βIII-tubulin is a prognostic, pro-survival, and chemoresistance factor in multiple malignancies, including pancreatic ductal adenocarcinoma (PDAC). However, the precise survival mechanisms controlled by βIII-tubulin in cancer remain unknown. Here, we discovered a link between βIII-tubulin and the activation of caspase 8-mediated extrinsic apoptosis. Silencing βIII-tubulin in PDAC cells activated caspase 8, leading to decreased cell viability and growth both in vitro and in vivo. βIII-tubulin knockdown also increased the sensitivity of PDAC cells to extrinsic cell death signals, including TNF-related apoptosis-inducing ligand (TRAIL), TNFα, and FasL. Furthermore, we demonstrated that βIII-tubulin knockdown in PDAC cells, in the absence or presence of TRAIL, increased diffusion and clustering of the TRAIL death receptor DR5 at the cell membrane, inducing extrinsic apoptosis. Nanoparticle delivery of βIII-tubulin siRNA to mouse PDAC tumours reduced tumour growth and increased responsiveness to TRAIL therapy. In patient-derived human PDAC explants, βIII-tubulin silencing reduced tumour cell frequency and improved sensitivity to TRAIL. Finally, we showed that high βIII-tubulin expression in the human PDAC stroma was independently prognostic for poor overall survival. Taken together, silencing βIII-tubulin represents an innovative strategy to activate a suicide signal in PDAC cells and render them more sensitive to microenvironment- and chemotherapy-derived death signals.

Atypical chemokine receptors (ACKRs) are a subclass of chemokine receptors that internalise and degrade chemokines instead of eliciting chemotaxis. Scavenging by ACKRs reduces the local bioavailability of chemokines and can thus reshape chemokine gradients that direct leukocyte trafficking during inflammation and anticancer responses. In pancreatic ductal adenocarcinoma (PDAC), chemokine axes, such as CXCL12-CXCR4, are co-opted by cancer-associated fibroblasts (CAFs) for tumour growth and escape, and immunosuppression. Here, we explore the use of ACKRs to reshape chemokine gradients within the PDAC tumour microenvironment. ACKR2, previously only known to scavenge inflammatory CC chemokines, was recently shown to be able to interact with CXCL10 and CXCL14. Here, using a chemokine binding assay and cytometric bead arrays, we reveal that ACKR2 scavenges additional CXC chemokines CXCL12 and CXCL1. ACKR2 scavenges CXCL12 with reduced efficiency compared to ACKR3, previously reported to bind CXCL12. Finally, we demonstrate that the overexpression of ACKR2 on bystander cells protects primary murine cytotoxic T lymphocytes from PDAC CAF-mediated chemoattraction. These findings reveal new CXC chemokine ligands of ACKR2 and indicate that ACKR overexpression may protect T cells from misdirection by CAFs.

Pancreatic cancer (PC) patients have a dismal 11% 5-year survival rate. Therapy personalization has significant potential to improve this. Our team developed a world-first model to maintain and treat 3D pieces of human PC tissue in a dish (Kokkinos et al, Scientific Reports, 2021). To examine potential translation to precision medicine, this project aimed to: (1) assess explant response to PC chemotherapies; (2) develop a secretions-based approach for rapid measurement of explant response; (3) demonstrate the utility of our model to identify chemoresistance pathways. 27 patient-derived pancreatic tumor samples were obtained from surgical resections (Prof Haghighi; Prince of Wales hospital), then processed into 1-8mm3 explants. Explants were treated every 72h over 12 days, with the following drug combinations (used in neoadjuvant/adjuvant clinical setting): (i) Gemcitabine+5-fluorouracil (5-FU), (ii) Gemcitabine+Abraxane, (iii) 5-FU+Oxaliplatin+Irinotecan. Secretions were collected at endpoint for analysis of cancer and CAF-secreted markers by multiplex ELISA. Explants were fixed at endpoint for immunohistochemistry analysis of tumor cell/cancer-associated fibroblast (CAF) populations, cell death and proliferation, collagen content and spatial transcriptomics. (1) Patient/regimen-dependent responses in tumor cell and CAF populations were observed. FOLFIRINOX was the most effective treatment (based on >50% reduction in tumor cells), followed by Gemcitabine+Abraxane and Gemcitabine+5FU, consistent with clinical trends. Patient/regimen-dependent explant responses to chemotherapy were also observed for CAF, cell death and proliferation markers, and collagen content. Follow up of patient overall survival is ongoing. (2) CA19-9 and IL6 were the most highly secreted markers and could follow changes in tumor and CAF populations. (3) Spatial transcriptomics identified differentially expressed genes in treatment-resistant tumor cells. Patient-derived explants demonstrate patient heterogeneity in response to standard chemotherapies and can be used to identify drug resistance pathways. Explant secretions can also be utilized to obtain an early indication of therapeutic response in culture. George Sharbeen, Janet Youkhana, Keilah G. Netto, Aparna S. Raina, Shannon Chiang, Koroush S. Haghighi, John Kokkinos, Omali Pitiyarachchi, Jessica Yang, Tony Wang, Alexander Swarbrick, David Goldstein, Phoebe A. Phillips. Assessing the response of 3D human pancreatic tumor explants to standard chemotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B080.

Pancreatic ductal adenocarcinoma (PDAC) has a poor 5-year survival rate of just 13 %. Conventional therapies fail due to acquired chemoresistance. We previously identified MutY-Homolog (MYH), a protein that repairs oxidative DNA damage, as a therapeutic target that induces apoptosis in PDAC cells. However, we did not understand the mechanism driving these anti-PDAC effects, nor did we have a means to therapeutically inhibit MYH. In this study, we demonstrated that MYH inhibition induces DNA damage and checkpoint activation in PDAC cells. Using a clinically-relevant PDAC mouse model, we showed that therapeutic MYH-siRNA delivery using Star 3 nanoparticles increased intratumoural PDAC cell death, but did not inhibit tumour growth. Finally, we showed that MYH knockdown in PDAC cells sensitised them to the anti-proliferative and anti-clonogenic effects of oxaliplatin and olaparib. Our findings identify a potential novel therapeutic approach for PDAC that induces a therapeutically exploitable DNA repair vulnerability.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy that urgently needs more effective therapies. Cancer-associated fibroblasts (CAFs) contribute to the aggressive and chemo-resistant nature of the disease by creating a drug-impeding fibrotic microenvironment. We developed novel compounds, the racemate CRO-05 and its active enantiomer CRO-67, which target both pancreatic tumor and CAF cells with robust anti-cancer activity. These compounds were designed using rational medicinal chemistry based on chromans, a class of anti-cancer drugs. Their therapeutic potential and efficacy were assessed in a clinically relevant patient-derived PDAC tumor explant model, which mimics the disease's 3-dimensional complexity. CRO-67 treatment in these explants significantly reduced tumor cell and αSMA+ CAF frequency, decreased cell proliferation and increased cell death. CRO-67 also significantly decreased cell proliferation and enhanced apoptosis by inhibiting cell cycle progression through G2/M phase in PDAC cells and patient-derived CAFs in vitro. CRO-67 treatment of orthotopic PDAC tumors in mice significantly reduced tumor growth in tumors with active growth (> 150% growth at endpoint), and remodeled tumor stroma (reduced αSMA+ CAF frequency, loosened tumor fibrosis and normalized tumor vasculature). Finally, CRO-67 sensitized PDAC cells to multiple standard-of-care chemotherapeutics in vitro, paving the way for future combination therapy development and validation.

Extracellular vesicles (EVs) play a crucial role in intercellular communication. While the effects of EVs released from living or non-dying cancer cells are well characterized, the impact of EVs released from chemotherapy-treated or apoptotic cancer cells is less understood. This study investigated the effects of the chemotherapy agent cisplatin on EV release and miRNA content in apoptotic medulloblastoma cells, as well as their influence on the growth of drug-naïve recipient cancer cells. EVs were isolated from cisplatin-treated and untreated SHH and group 3 medulloblastoma cells, as well as from the blood of mice with orthotopic medulloblastoma tumors. EVs were characterized using nanoparticle tracking analysis, cryo-TEM, and western blotting, and their impact on the growth of recipient medulloblastoma cells in 2D and 3D cultures was assessed. EV-miRNAs were analyzed using small RNA sequencing and qPCR, and the effects of candidate miRNA overexpression on medulloblastoma cell growth and apoptosis were evaluated. We demonstrate that apoptotic SHH and group 3 medulloblastoma cells secrete increased numbers of EVs (size range 150–600 nm) both in vitro and in vivo. EVs isolated from cisplatin-treated SHH and group 3 medulloblastoma cells were internalized by recipient medulloblastoma cells and exhibited distinct effects on their growth. EVs from cisplatin-treated SHH medulloblastoma cells reduced clonogenic growth in recipient drug-naïve medulloblastoma cells, whereas EVs from cisplatin-treated group 3 medulloblastoma cells enhanced the clonogenic and sphere-forming capacity of recipient cells. These contrasting effects were associated with significant alterations in EV-miRNA expression profiles between untreated and cisplatin-treated SHH and group 3 medulloblastoma cells. Notably, miR-449a was found to be upregulated in EVs from cisplatin-treated SHH medulloblastoma cells, and its overexpression in medulloblastoma cells led to potent inhibition of growth. Our findings demonstrate, for the first time, that cisplatin-treated medulloblastoma cells from distinct molecular subgroups secrete EVs with altered miRNA expression profiles that either inhibit or promote the growth of recipient cancer cells. This underscores the potential of targeting EV-mediated communication as a novel therapeutic strategy in medulloblastoma.

4120 Background: The genomic and prognostic characteristics of recurrent (R, from curative surgery) v de novo (D) presentation in metastatic PDAC patients (pt) requiring systemic therapy (rx) remain underexplored. We examined the difference in genomic alterations (alts), overall survival (OS), and outcome to matched rx according to disease presentation (DP). Methods: The PDAC cohorts from the Australian Molecular Screening and Therapeutics (MoST) and Cancer Screening Programs (CaSP) completed sequencing from 2016 to July 2024 were analysed; archival tissue was sequenced using genomic profiling platforms (mainly TSO500 and FoundationOne CDx). Frequencies of genomic alts were compared between R and D groups; significance was assessed using Chi-square tests with the Benjamini-Hochberg method (q < 0.05). OS was calculated from the start of initial rx using Kaplan-Meier method, with hazard ratios (HR) from Cox regression used for comparison. OS outcomes were stratified by matched versus unmatched rx in pts harbouring genomic alts within clinically actionable Tier 1-3 categories per TOPOGRAPH knowledge base criteria. Results: 949 pts with PDAC with valid genomic results across both programs were included. The KRAS alts were numerically more frequent in D (n = 434/491, 88%, p = 0.02) than R (n = 380/458, 82%) groups. Both CDKN2A and SMAD4 alts were enriched in the D group ( CDKN2A , D: 248, 51% v R: 157, 34%; SMAD4 , D: 139, 29% v R: 85, 19%, p < 0.001 both). Among the 821 pts who started systemic rx, those with R PDAC (n = 411) showed longer median OS compared to those with D PDAC (n = 410, 18.9 v 13.0 months, mo; HR 0.59, 95% CI 0.49-0.69, p < 0.001). Genomic CDKN2A alts were associated with worse OS (median 13.4 v 16.5 mo, HR 1.34, 95% CI 1.14-1.58); most favourable prognosis was seen in 267 pts with CDKN2A wildtype in the R group (median 22.1 mo, 95% CI 17.4-25.9). After adjusting for both CDKN2A and SMAD4 alts, R group remained associated with a lower risk of death than D group (HR 0.61, 95% CI: 0.51-0.72, p < 0.001). Pts who received active matched rx (n = 23) showed longer OS than those who received unmatched rx (n = 314) in both D (30.1 v unmatched 14.0 mo) and R groups (34.6 v 24.1 mo). The prevalence of specific KRAS mutations showed no significant differences between D and R groups, including G12D (D: 192, 39% v R: 167, 36%, p = 0.44), G12V (D: 126, 26% v R: 113, 25%, p = 0.78), G12R (D: 59, 12% v R: 50, 11%, p = 0.67), G12C (D: 6, 1% v R: 10, 2%, p = 0.37), and Q61 mutations (D: 37, 8% v R: 26, 6%, p = 0.31). There were no differences in alts in TP53 , ARID1A, BRCA1/2, or other DNA repair pathway genes. Conclusions: Genomic and prognostic differences were seen in metastatic PDAC according to presentation, with CDKN2A alts enriched in de novo cases and associated with poor OS, emphasising the need to consider stratification of DP in trials and observational studies.

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to therapy. Stromal cancer-associated fibroblasts (CAFs) play a key role in promoting tumor progression and chemoresistance, by creating a fibrotic microenvironment that impedes drug access and feeds PDAC cells nutrients and pro-tumor signals. CRO-67 (Patent PCT/AU2023/050505) is a novel drug developed with Noxopharm Ltd using a rational medicinal chemistry design to improve bioavailability of chromans which have potent anti-cancer activity. Using our patient-derived PDAC tumor in a dish model (explants; maintain multicellular architecture and fibrosis) we previously showed that CRO-67 has both anti-tumor and CAF reprogramming capacity in 4 patient explants [Cancer Res (2022) 82 (22_Supplement):C073]. Aims: 1) To expand evaluation of CRO-67 in additional patient-derived PDAC tumor explants given PDAC heterogeneity. 2) Assess the effect of CRO-67 on PDAC cell and CAF function. 3) Validate the therapeutic potential of CRO-67 on PDAC growth in vivo. Methods: 1) PDAC tumor samples collected from 7 patients undergoing pancreatic resection. Tumor explants (1–2mm diameter) were cultured on gelatin sponges, treated with CRO-67 (0–50μg/mL) every 3 days and fixed on day 12. Therapeutic response assessed by immunohistochemistry for cytokeratin (PDAC cells), α-smooth muscle actin (CAFs), bromodeoxyuridine (proliferation) and TUNEL (cell death). 2) PDAC cells (MiaPaCa-2) and patient-derived CAFs were treated with CRO-67 (1.5μM) for 48h before proliferation analysis (IncuCYTE S3) and for 24h before apoptosis (Annexin V/DAPI staining; flow cytometry) and cell cycle (DAPI staining; flow cytometry) analysis. 3) Subcutaneous PDAC (BxPC3 human cells) tumors in mice were treated with CRO-67 (2.5mg/kg Intraperitoneally, twice a day) for 21 days and tumor volume measured (calipers). Results: 1) CRO-67 treatment decreased tumor and CAF cell frequency in 6/6 (no quantifiable tumor in patient 7 explants) and 7/7 patient PDAC explants, respectively. It also decreased explant cell proliferation and increased cell death versus controls. 2) CRO-67 completely abolished proliferation of MiaPaCa-2 and reduced the average growth rate of CAFs by 81.3±8.8% (p=0.0025; n=5), increased apoptosis in MiaPaCa-2 by 455.7±21.4% (p=0.003; n=3) and in CAFs by 172.6±13.1% (p=0.0067; n=5) and increased the fraction of cells in G2/M cell cycle phase by 163.8±12.8% (p<0.0001; n=3) in MiaPaCa-2 and by 74.6±8.6% (p=0.0015; n=5) in CAFs versus controls. 3) CRO-67 reduced PDAC tumors in vivo by 56.7±6.6% (p=0.0013; n=9 mice/group) versus controls. Conclusions: CRO-67: 1) reduced PDAC cells and CAFs in human PDAC explants via reduced proliferation and increased death; 2) reduced proliferation of PDAC cells and CAFs in vitro, increased apoptosis and disrupted cell cycle progression through G2/M phase; 3) reduced PDAC tumor growth in vivo. Implication: We predict CRO-67 is a potential ‘dual cell’ therapy with direct anti-tumor effects and CAF reprogramming capacity, warranting further investigation in vivo. Citation Format: Keilah Garcia Netto, Shannon Chiang, John Kokkinos, Koroush S. Haghighi, Aparna Raina, Omali Pitiyarachchi, Janet Youkhana, Quach Truong, Daniel Wenholz, Xiang Li, Olivier Laczka, Naresh Kumar, John Wilkinson, David Goldstein, George Sharbeen, Phoebe A. Phillips. CRO67 has therapeutic potential against pancreatic tumor cells and cancer associated fibroblasts [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 B062.

Incidence of endometrial cancer (EC) is rising in the developed world. The current standard of care, hysterectomy, is often infeasible for younger patients and those with high body mass index. There are limited non-surgical treatment options and a lack of biologically relevant research models to investigate novel alternatives to surgery for EC. The aim of the present study was to develop a long-term, patient-derived explant (PDE) model of early-stage EC and demonstrate its use for investigating predictive biomarkers for a current non-surgical treatment option, the levonorgestrel intra-uterine system (LNG-IUS). Fresh tumour specimens were obtained from patients with early-stage endometrioid EC. Tumours were cut into explants, cultured on media-soaked gelatin sponges for up to 21 days and treated with LNG. Formalin-fixed, paraffin embedded (FFPE) blocks were generated for each explant after 21 days in culture. Tumour architecture and integrity were assessed by haematoxylin and eosin (H&E) and immunohistochemistry (IHC). IHC was additionally performed for the expression of five candidate biomarkers of LNG resistance. The developed ex vivo PDE model is capable of culturing explants from early-stage EC tumours long-term (21 Days). This model can complement existing models and may serve as a tool to validate results obtained in higher-throughput in vitro studies. Our study provides the foundation to validate the extent to which EC PDEs reflect patient response in future research.

This chapter encompasses the principles of the management of patients with pancreatic adenocarcinoma from a surgical, systemic therapy and radiation oncology perspective, but also highlights the importance of multidisciplinary team discussion in guiding appropriate diagnostic investigations and interventions, and the early involvement of palliative care. A succinct summary of the latest guidelines in the radiological and pathological diagnosis of this disease is outlined. As the key to guiding future therapeutic breakthroughs in this poor prognosis cancer is through clinician-scientist collaboration and translational research, the key points for facilitation of this are also highlighted.

<p>Patient characteristics of UoL serum sample cohorts.</p>

Differentially expressed transcripts (mRNA and microRNA) between disease-associated fibroblasts and normal activated (NA) or normal fibroblasts (NF).