Coexisting morpho-biotypes unveil the regulatory bases of phenotypic plasticity in pancreatic ductal adenocarcinoma

Chiaro, Pierluigi Di; Nacci, Lucia; Brandini, Stefania; Polletti, Sara; Donati, Benedetta; Gualdrini, Francesco; Frigè, Gianmaria; Mazzarella, Luca; Ciarrocchi, Alessia; Zerbi, Alessandro; Scocco, Paola; Barozzi, Iros; Diaferia, Giuseppe R.; Natoli, Gioacchino

doi:10.1101/2022.12.12.520054

Cited by 4 publications

(4 citation statements)

References 86 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, Krebs and colleagues showed the enrichment of axon guidance-associated gene sets in basal-like as well as high grade PDAC [15]. Furthermore, neuronal-like progenitor cell states have been reported in undifferentiated tumors [16] and positively selected in post-treatment tumors [17]. Most of the previous studies have focused on investigating the role of members of the Slit/Robo axis on the PDAC malignant traits of PDAC as well as its cell identity [15, 18, 19, 20, 21].…”

Section: Introductionmentioning

confidence: 99%

The axon guidance cue SEMA3A promotes the aggressive phenotype of basal-like PDAC

Lupo

Pezzini

Fiorini

et al. 2023

Preprint

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with few available therapeutic options. Two transcriptional cancer cell states have been consistently reported in PDAC, with the basal-like/squamous phenotype displaying a more aggressive biological behavior. Genetic and epigenetic dysregulation of the axon guidance pathway are common in PDAC, yet our understanding of its biological relevance is limited. Here, we investigated the functional role of the axon guidance cue SEMA3A in sustaining the progression of PDAC. We integrated available transcriptomic datasets of human PDAC with in situ hybridization analyses of patients' tissues to find that SEMA3A is expressed by stromal cells and selectively enriched in epithelial cells of the basal-like/squamous subtype. We found that both cell-intrinsic and cell extrinsic factors instructing the basal-like/squamous subtype induce expression of SEMA3A in PDAC cells. In vitro, SEMA3A promoted cell migration as well as anoikis resistance. At molecular level, these phenotypes were associated with increased FAK signaling and enrichment of gene programs related to cytoskeleton remodeling. Accordingly, SEMA3A provided mouse PDAC cells with greater metastatic competence. In mouse orthotopic allografts, SEMA3A remodeled the TME by favoring infiltration of tumor-associated macrophages and exclusion of T cells. Mechanistically, SEMA3A functioned as chemoattractant for macrophages and favored their polarization towards an M2-like phenotype. In SEMA3Ahigh tumors, depletion of macrophages resulted in greater intratumor infiltration by CD8+ T cells and increased sensitivity of these tumors to chemotherapy. Overall, we show that SEMA3A contributes to the malignant phenotype of basal-like PDAC.

show abstract

Section: Introductionmentioning

confidence: 99%

The axon guidance cue SEMA3A promotes the aggressive phenotype of basal-like PDAC

Lupo

Pezzini

Fiorini

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…For pancreatic cancer we employed a new classification of TCGA samples using a multi- class classifier already implemented to classify three novel PDAC subtypes (Glandular, GL; Transitional, TR; Undifferentiated, UN) obtained from the transcriptional profiles of multiple morphological distinguishable tumor areas isolated by laser micro-dissection (LMD) in primary PDACs of treatment-naïve patients 52 . Briefly, a random Forest (RF) classification method was used to build the model setting the number of trees to 500.…”

Section: Methodsmentioning

confidence: 99%

“…Transitional, TR; Undifferentiated, UN) obtained from the transcriptional profiles of multiple morphological distinguishable tumor areas isolated by laser micro-dissection (LMD) in primary PDACs of treatment-naïve patients 52 . Briefly, a random Forest (RF) classification method was used to build the model setting the number of trees to 500.…”

Section: Transcriptomics Datasetmentioning

confidence: 99%

The landscape of cancer rewired GPCR signaling axes

Raimondi

Arora

Matic

et al. 2023

Preprint

Self Cite

View full text Add to dashboard Cite

We explored the dysregulation of GPCR ligand signaling systems in cancer transcriptomics datasets. We derived a network of interacting ligands and biosynthetic enzymes from public databases, that we combined with cognate GPCRs and downstream effectors to quantify GPCR signaling pathways. We found multiple GPCRs differentially regulated together with their ligands across cancers, suggesting a widespread perturbation of these signaling axes in specific cancer molecular subtypes. We showed that biosynthetic pathway enrichment from enzyme expression recapitulates pathway activity signatures from metabolomics datasets, therefore providing valuable surrogate information for receptor-organic ligand systems. The expression of several GPCRs signaling components is significantly associated with either lower or higher patient survival in a cancer subtype specific fashion. In particular, the expression of both receptor-ligand (or biosynthetic enzyme) interaction partners improves the stratification of patients based on survival, suggesting a potential synergistic role for the activation of certain receptor axes in modulating cancer phenotypes. Strikingly, we have found that receptors from these actionable axes are the targets of several drugs displaying anti-growth effects in large, drug repurposing screens in cancer cell lines. This study provides a comprehensive map to exploit GPCR signaling axes as actionable targets for personalized cancer treatments. We have made the results generated in this study freely available for further exploration to the community through a webapp (gpcrcanceraxes.bioinfolab.sns.it).

show abstract

“…[14][15][16] Recently, Krebs et al showed the enrichment of axon guidance-associated gene sets in basal-like as well as high-grade PDAC. 17 Furthermore, neuronal-like progenitor cell states have been reported in undifferentiated tumours 18 and are positively selected in posttreatment tumours. 12 Most of the previous studies have focused on investigating the role of members of the Slit/Robo axis on the PDAC malignant traits as well as its cell identity.…”

Section: Pancreasmentioning

confidence: 99%

Axon guidance cue SEMA3A promotes the aggressive phenotype of basal-like PDAC

Lupo,

Pezzini,

Pasini

et al. 2024

Gut

View full text Add to dashboard Cite

ObjectiveThe dysregulation of the axon guidance pathway is common in pancreatic ductal adenocarcinoma (PDAC), yet our understanding of its biological relevance is limited. Here, we investigated the functional role of the axon guidance cue SEMA3A in supporting PDAC progression.DesignWe integrated bulk and single-cell transcriptomic datasets of human PDAC with in situ hybridisation analyses of patients’ tissues to evaluate SEMA3A expression in molecular subtypes of PDAC. Gain and loss of function experiments in PDAC cell lines and organoids were performed to dissect how SEMA3A contributes to define a biologically aggressive phenotype.ResultsIn PDAC tissues, SEMA3A is expressed by stromal elements and selectively enriched in basal-like/squamous epithelial cells. Accordingly, expression of SEMA3A in PDAC cells is induced by both cell-intrinsic and cell-extrinsic determinants of the basal-like phenotype.In vitro, SEMA3A promotes cell migration as well as anoikis resistance. At the molecular level, these phenotypes are associated with increased focal adhesion kinase signalling through canonical SEMA3A-NRP1 axis. SEMA3A provides mouse PDAC cells with greater metastatic competence and favours intratumoural infiltration of tumour-associated macrophages and reduced density of T cells. Mechanistically, SEMA3A functions as chemoattractant for macrophages and skews their polarisation towards an M2-like phenotype. In SEMA3Ahightumours, depletion of macrophages results in greater intratumour infiltration by CD8+T cells and better control of the disease from antitumour treatment.ConclusionsHere, we show that SEMA3A is a stress-sensitive locus that promotes the malignant phenotype of basal-like PDAC through both cell-intrinsic and cell-extrinsic mechanisms.

show abstract

Coexisting morpho-biotypes unveil the regulatory bases of phenotypic plasticity in pancreatic ductal adenocarcinoma

Cited by 4 publications

References 86 publications

The axon guidance cue SEMA3A promotes the aggressive phenotype of basal-like PDAC

The axon guidance cue SEMA3A promotes the aggressive phenotype of basal-like PDAC

The landscape of cancer rewired GPCR signaling axes

Axon guidance cue SEMA3A promotes the aggressive phenotype of basal-like PDAC

Contact Info

Product

Resources

About