Biology subjects

Luchini, C.

Publications and source records attributed to Luchini, C..

6 recordsLinked to original sources

bioRxiv2026

Diet-induced macrophage-driven inflammation fuels pancreatic plasticity and aggressiveness

High-fat diet (HFD) and obesity are increasingly recognized as risk factors of pancreatic ductal adenocarcinoma (PDAC), yet the mechanisms by which dietary fat contribute to oncogenic transformation remain elusive. Using an inducible acinar-specific KrasG12V/Trp53-loss genetically-engineered mouse model of PDAC, we established early-and late-onset protocols to assess age-dependent susceptibility to HFD. Specifically, HFD accelerated tumorigenesis with poorer prognosis in early-onset mice and, strikingly, enabled full PDAC development in late-onset adult mice otherwise resistant to oncogenic transformation. Tumors arising under HFD activated a distinct transcriptional and epigenetic state enriched in pathways or genes related to stemness, plasticity, and metastatic competence, which was maintained even in tumor-derived cell lines. Mechanistically, fatty acid-educated macrophages secreted the cathelicidin antimicrobial peptide (CAMP), activating P2X purinoceptor 7 (P2RX7) signaling in tumor cells to drive a highly plastic, immune-evasive phenotype reinforced by the expression of the peptidoglycan recognition protein 1 (PGLYRP1), further shielding tumor cells from macrophage phagocytosis. Functionally, HFD-induced tumors displayed enhanced metastatic potential independent of host context. Analysis of 164 human PDAC samples revealed that elevated body-mass index (BMI) was associated to a conserved CAMP-P2RX7-CXCR4 signature, maintained despite weight loss during disease progression. Together, these findings uncover a diet-imprinted macrophage-tumor cell circuit that promotes transformation and accelerates PDAC progression, positioning it as a therapeutic vulnerability in obesity-associated pancreatic cancer. Statement of significanceHigh-fat diet induces pancreatic tumorigenesis in adult tissue, driving metastatic competence and a plastic state, and ultimately engages a macrophage-derived CAMP-P2RX7 circuit that reinforces immune evasion and accelerates PDAC progression.

cancer biology↗

bioRxiv2024

An integrative RNA spliceosomic landscape of pancreatic neuroendocrine tumors unveils novel clinicomolecular associations

Alterations in alternative splicing are emerging as a novel hallmark in cancer biology, offering new insights. However, integrative analyses of splicing are still scarce, particularly in rare cancers such as pancreatic neuroendocrine tumors (PanNETs). These tumors are highly heterogeneous, complicating diagnosis and treatment. This study is the first to comprehensively investigate the RNA splicing landscape in PanNETs, identifying distinct spliceosomic profiles correlated with unique clinical and molecular characteristics. We analyzed RNA-seq data from 174 samples, identifying three distinct spliceosomic groups (SPN1, SPN2, SPN3) with unique clinical and molecular characteristics. SPN1 exhibited intermediate clinical features and specific splicing machinery profile, SPN2 was associated with frequent mutations in MEN1 and DAXX/ATRX genes, and SPN3 showed a prevalence of well-differentiated tumors with distinct splicing patterns. These groups were linked to different clinical outcomes and activated key biological processes like mTOR signaling and hormone secretion pathways. Our findings underscore the significant impact of RNA splicing on PanNET heterogeneity and suggest that detailed splicing profiles could serve as valuable tools for identifying novel biomarkers and therapeutic targets. This study provides crucial insights into PanNET molecular biology and paves the way for personalized therapies based on splicing features.

cancer biology↗

bioRxiv2024

Clonal evolutionary analysis reveals patterns of malignant transformation in pancreatic cancer from Intraductal Papillary Mucinous IPMN Neoplasms (IPMN)

Intraductal papillary mucinous neoplasms (IPMNs) are critical precursors to pancreatic ductal adenocarcinoma (PDAC), a highly lethal cancer due to late detection and rapid progression. Using multi-region whole-genome and transcriptome sequencing, we traced the evolution of PDAC from IPMN, constructing detailed phylogenetic trees to provide insights into subclonal architectures and progression pathways. Our analysis identified two distinct evolutionary trajectories: one driven by a single ancestral clone, and another involving multiple independent ancestral clones, potentially influencing the timing and nature of PDAC onset. We further explored the roles of mutational signatures and structural variants (SVs) in promoting clonal evolution. Complementing these genomic findings, our transcriptomic analysis revealed unique gene expression profiles and variations in the immune landscape, correlating with the different progression stages from IPMN to PDAC. These insights reveal the complex molecular dynamics of IPMN progression to PDAC, highlighting the need to refine early detection and treatment strategies.

cancer biology↗

bioRxiv2024

Multi-omic profiling of intraductal papillary neoplasms of the pancreas reveals distinct expression patterns and potential markers of progression

In order to advance our understanding of precancers in the pancreas, 69 pancreatic intraductal papillary neoplasms (IPNs), including 64 intraductal papillary mucinous neoplasms (IPMNs) and 5 intraductal oncocytic papillary neoplasms (IOPNs), 32 pancreatic cyst fluid samples, 104 invasive pancreatic ductal adenocarcinomas (PDACs), 43 normal adjacent tissues (NATs), and 76 macro-dissected normal pancreatic ducts (NDs) were analyzed by mass spectrometry. A total of 10,246 proteins and 22,284 glycopeptides were identified in all tissue samples, and 756 proteins with more than 1.5-fold increase in abundance in IPMNs relative to NDs were identified, 45% of which were also identified in cyst fluids. The over-expression of selected proteins was validated by immunolabeling. Proteins and glycoproteins overexpressed in IPMNs included those involved in glycan biosynthesis and the immune system. In addition, multiomics clustering identified two subtypes of IPMNs. This study provides a foundation for understanding tumor progression and targets for earlier detection and therapies. SignificanceThis multilevel characterization of intraductal papillary neoplasms of the pancreas provides a foundation for understanding the changes in protein and glycoprotein expression during the progression from normal duct to intraductal papillary neoplasm, and to invasive pancreatic carcinoma, providing a foundation for informed approaches to earlier detection and treatment.

cancer biology↗

bioRxiv2023

Differential Activity of MAPK signalling Defines Fibroblast Subtypes in Pancreatic Cancer

Fibroblast heterogeneity is increasingly recognised across cancer conditions. Given their important contribution to disease progression, mapping out fibroblasts heterogeneity is critical to devise effective anti-cancer therapies. Cancer-associated fibroblasts (CAFs) represent the most abundant cell population in pancreatic ductal adenocarcinoma (PDAC). Whether CAF phenotypes are differently specified by PDAC cell lineages remains to be elucidated. Here, we reveal an important role for the MAPK signalling pathway in the definition of PDAC CAF phenotypes. We identify the myCAF transcriptional phenotype as uniquely dependent on proficient MAPK signalling. In addition, CAFs displaying elevated MAPK activity are specifically anchored to basal-like/squamous PDAC cells and define tumour subdomains with reduced frequency of CD8+ T cells. We characterize the single-cell transcriptome of mouse PDAC tumours in response to MAPK inhibition and identify gene expression signatures of MAPKhigh CAFs, which suggest immunoregulatory functions. Accordingly, a gene expression signature of MAPKhigh CAFs correlates with poor prognosis in several human cancer conditions, including PDAC, and with reduced response to immune checkpoint inhibition in immune-reactive solid tumours. Altogether, our data expand our knowledge on CAF phenotype heterogeneity and reveal a new strategy for targeting of myofibroblastic CAFs in vivo.

cancer biology↗

bioRxiv2023

ecDNA amplification of MYC drives intratumor copy-number heterogeneity and adaptation to stress in PDAC

Intratumor heterogeneity and phenotypic plasticity drive tumour progression and therapy resistance. Oncogene dosage variation contributes to cell state transitions and phenotypic heterogeneity, thereby providing a substrate for somatic evolution. Nonetheless, the genetic mechanisms underlying phenotypic heterogeneity are still poorly understood. Here, we show that extrachromosomal DNA (ecDNA) is a major source of high-level focal amplification in key oncogenes and a major contributor of MYC heterogeneity in pancreatic ductal adenocarcinoma (PDAC). We demonstrate that ecDNA can drive exceptionally high dosage of MYC and afford cancer cells rapid adaptation to microenvironmental changes. The continued maintenance of extrachromosomal MYC is uniquely ensured by the presence of the selective pressure. We also show that MYC dosage affects cell morphology and dependence of cancer cells on stromal niche factors, with the highest MYC levels correlating with squamous-like phenotypes. Our work provides the first detailed analysis of ecDNAs in PDAC and describes a new genetic mechanism driving MYC heterogeneity in PDAC.

cancer biology↗