New Diagnostic and Therapeutic Aspects of Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is devastating. Because of its silent nature, the disease is often only diagnosed once it has reached an advanced, frequently inoperable stage. To date, we have no biomarkers that facilitate earlier diagnosis, leaving sufficient time for curative therapy that effectively lowers the very high mortality rate of this cancer entity. Because of this, the life expectancy of patients with PDAC is low (i.e. ≤ 6% five-year survival rates). New data, including particular genetic signatures and features of the stromal architecture of PDAC tumors, may better explain their aggressiveness, their relatively long-lasting painless expansion, and why chemotherapy so frequently fails. The typical tumor-induced stromal desmoplasia is characterized by cancer-associated fibroblasts (CAFs), decreased immune surveillance, cancer-associated neural remodeling, and a very low vascular density. This stromal microenvironment generates hypoxia, nutrient deficiency, immune suppression, and chemoresistance. The combination of factors results in a vicious disease that begins with the long-lasting, asymptomatic development of a large tumor mass, followed by a delayed diagnosis with a high percentage of inoperable states, exhibiting a poor response to all conservative therapeutic options, including radiation, and which ends with metastasis resulting in a rapid fatal outcome. In this article, we review coherences on genetic, cellular, immunological, Nano medical and stromal characteristics of PDAC tissue, and discuss metabolic abnormalities associated with and/or preceding the tumor progression rate. A more comprehensive understanding of the underlying mechanisms can improve the diagnostic and therapeutic management of patients suffering from this devastating type of cancer.

Mangge H ，Niedrist T ，Renner W ，Lyer S ，Alexiou C ，Haybaeck J ... -  《-》

Unique metabolic features of pancreatic cancer stroma: relevance to the tumor compartment, prognosis, and invasive potential.

Knudsen ES ，Balaji U ，Freinkman E ，McCue P ，Witkiewicz AK ... -  《Oncotarget》

BNIP3+ fibroblasts associated with hypoxia and inflammation predict prognosis and immunotherapy response in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors that lacks effective treatment options. Cancer-associated fibroblasts (CAFs), an important component of the tumor microenvironment, associated with tumor progression, prognosis, and treatment response. This work aimed to explore the novel CAFs-associated target to improve treatment strategies in PDAC. The PDAC single-cell sequencing data (CRA001160, n = 35) were downloaded and integrated based on GSA databases to classify fibroblasts into fine subtypes. Functional enrichment analysis and coexpression regulatory network analysis were used to identify the functional phenotypes and biological properties of the different fibroblast subtypes. Fibroblast differentiation trajectories were constructed using pseudochronological analysis to identify initial and terminally differentiated subtypes of fibroblasts. The changes in the proportions of different fibroblast subtypes before and after PDAC immunotherapy were compared in responsive and nonresponding patients, and the relationships between fibroblast subtypes and PDAC immunotherapy responsiveness were determined based on GSA and GEO database. Using molecular biology methods to confirm the effects of BNIP3 on hypoxia and inflammation in CAFs. CAFs were co cultured with pancreatic cancer cells to detect their effects on migration and invasion of pancreatic cancer. Single-cell data analysis divided fibroblasts into six subtypes. The differentiation trajectory suggested that BNIP3+ Fibro subtype exhibited terminal differentiation, and the expression of genes related to hypoxia and the inflammatory response increased gradually with differentiation time. The specific overexpressed genes in the BNIP3+ Fibro subtype were significantly associated with overall and disease progression-free survival in the patients with PDAC. Interestingly, the greater the proportion of the BNIP3+ Fibro subtype was, the worse the response of PDAC patients to immunotherapy, and the CRTL treatment regimen effectively reduced the proportion of the BNIP3+ Fibro subtype. After knocking out BNIP3, the hypoxia markers and inflammatory factors of CAFs were inhibited. Co-culture of CAFs with pancreatic cancer cells can increase the migration and invasion of pancreatic cancer, but this could be reversed by knocking out BNIP3. This study revealed the BNIP3+ Fibro subtype associated with hypoxia and inflammatory responses, which was closely related to the poor prognosis of patients with PDAC, and identified signature genes that predict the immunotherapy response in PDAC.

Gao B ，Hu G ，Sun B ，Li W ，Yang H ... -  《Journal of Translational Medicine》

Targeting Aggressive Fibroblasts to Enhance the Treatment of Pancreatic Cancer.

Yu Y ，Schuck K ，Friess H ，Kong B ... -  《-》

A bioprinted sea-and-island multicellular model for dissecting human pancreatic tumor-stroma reciprocity and adaptive metabolism.

Pancreatic ductal adenocarcinoma (PDAC) presents a formidable clinical challenge due to its intricate microenvironment characterized by desmoplasia and complex tumor-stroma interactions. Conventional models hinder studying cellular crosstalk for therapeutic development. To recapitulate key features of PDAC masses, this study creates a novel sea-and-island PDAC tumor construct (s&i PTC). The s&i PTC consists of 3D-printed islands of human PDAC cells positioned within an interstitial extracellular matrix (ECM) populated by human cancer-associated fibroblasts (CAFs). This design closely mimics the in vivo desmoplastic architecture and nutrient-poor conditions. The model enables studying dynamic tumor-stroma crosstalk and signaling reciprocity, revealing both known and yet-to-be-discovered multicellular metabolic adaptations. Using the model, we discovered the orchestrated dynamic alterations of CAFs under nutrient stress, resembling critical in vivo human tumor niches, such as the secretion of pro-tumoral inflammatory factors. Additionally, nutrient scarcity induces dynamic alterations in the ECM composition and exacerbates poor cancer cell differentiation-features well-established in PDAC progression. Proteomic analysis unveiled the enrichment of proteins associated with aggressive tumor behavior and ECM remodeling in response to poor nutritional conditions, mimicking the metabolic stresses experienced by avascular pancreatic tumor cores. Importantly, the model's relevance to patient outcomes is evident through an inverse correlation between biomarker expression patterns in the s&i PTCs and PDAC patient survival rates. Key findings include upregulated MMPs and key ECM proteins (such as collagen 11 and TGFβ) under nutrient-avid conditions, known to be regulated by CAFs, alongside the concomitant reduction in E-cadherin expression associated with a poorly differentiated PDAC state under nutrient deprivation. Furthermore, elevated levels of hyaluronic acid (HA) and integrins in response to nutrient deprivation underscore the model's fidelity to the PDAC microenvironment. We also observed increased IL-6 and reduced α-SMA expression under poor nutritional conditions, suggesting a transition of CAFs from myofibroblastic to inflammatory phenotypes under a nutrient stress akin to in vivo niches. In conclusion, the s&i PTC represents a significant advancement in engineering clinically relevant 3D models of PDAC masses. It offers a promising platform for elucidating tumor-stroma interactions and guiding future therapeutic strategies to improve patient outcomes.

Li M ，Freeman S ，Franco-Barraza J ，Cai KQ ，Kim A ，Jin S ，Cukierman E ，Ye K ... -  《-》