Loss of FGFR4 promotes the malignant phenotype of PDAC

D’Agosto, Sabrina; Pezzini, Francesco; Veghini, Lisa; Delfino, Pietro; Fiorini, Claudia; Tane, Gael D. Temgue; Curatolo, Anais Del; Vicentini, Caterina; Ferrari, G.; Pasini, Davide; Andreani, Silvia; Lupo, Fabio; Fiorini, Elena; Lorenzon, G; Lawlor, Rita T.; Rusev, Borislav; Malinova, Antonia; Luchini, Claudio; Milella, Michèle; Sereni, Elisabetta; Pea, Antonio; Bassi, Claudio; Bailey, Peter J.; Scarpa, Aldo; Bria, Emilio; Corbo, Vincenzo

doi:10.1038/s41388-022-02432-5

Cited by 8 publications

(9 citation statements)

References 55 publications

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“…Therefore, we decided to focus on SEMA3A and SEMA3C. In keeping with the correlative analyses, we identified higher SEMA3A expression in whole cell lysates from cells with prominent squamous features including expression of TP63/ΔNp63 (Colo357, L3.6pl, BxPC3) or CK5 (Hs766t, see D’Agosto et al [27]) ( Figure 1C ). SEMA3C showed a more promiscuous pattern of expression in human cell lines ( Figure S1C ).…”

Section: Resultssupporting

confidence: 55%

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

Lupo

Pezzini

Fiorini

et al. 2023

Preprint

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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.

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Section: Resultssupporting

confidence: 55%

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

Lupo

Pezzini

Fiorini

et al. 2023

Preprint

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“…The HNF1A gene encodes hepatocyte nuclear factor-1 alpha (HNF-1α), which is important in the pancreas and liver. It acts as a transcription factor to regulate insulin, controls genes that regulate cell growth and survival, and acts as a tumor suppressor [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Association of the rs1966265 and rs351855 FGFR4 Variants with Colorectal Cancer in a Mexican Population and Their Analysis In Silico

Carrillo-Dávila,

Garibaldi-Ríos,

Figuera

et al. 2024

Biomedicines

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The aim of this study was to associate FGFR4 rs1966265 and rs351855 variants with colorectal cancer (CRC) in a Mexican population and to perform in silico analysis. Genomic DNA from 412 healthy individuals and 475 CRC patients was analyzed. In silico analysis was performed using the PolyPhen-V2, GEPIA, GTEx, and Cytoscape platforms. The GA genotype dominant model (GAAA) of rs1966265 and the AA genotype dominant and recessive models of rs351855 were identified as CRC risk factors (p < 0.05). CRC patients aged ≥ 50 years at diagnosis who consumed alcohol had a higher incidence of the rs351855 GA genotype than the control group (p < 0.05). Associations were observed between the rs1966265 GA genotype and patients with rectal cancer and stage III–IV disease. The rs351855 AA genotype was a risk factor for partial chemotherapy response, and the GA + AA genotype for age ≥ 50 years at diagnosis and rectal cancer was associated with a partial response to chemotherapy (p < 0.05). The AA haplotype was associated with increased susceptibility to CRC. In silico analysis indicated that the rs351855 variant is likely pathogenic (score = 0.998). Genotypic expression analysis in blood samples showed statistically significant differences (p < 0.05). EFNA4, SLC3A2, and HNF1A share signaling pathways with FGFR4. Therefore, rs1966265 and rs351855 may be potential CRC risk factors.

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“…We have previously shown that querying bulk transcriptional datasets from tissues with different neoplastic cell content is a viable strategy to localise the cellular compartment contributing to gene expression differences between molecular subtypes 74 . Using the same approach, we show that MAPK transcriptional signatures were particularly elevated in basal-like tumours from the TCGA cohort 16 .…”

Section: Discussionmentioning

confidence: 99%

“…Our results are in line with previous observation from Miyabayashi and colleagues showing that RAS signalling hyperactivation is not fundamental for the definition of the basal-like/squamous subtype in the epithelial compartment 27 . We have previously shown that querying bulk transcriptional datasets from tissues with different neoplastic cell content is a viable strategy to localise the cellular compartment contributing to gene expression differences between molecular subtypes 74 . Using the same approach, we show that MAPK transcriptional signatures were particularly elevated in basal-like tumours from the TCGA cohort 16 .…”

Section: Discussionmentioning

confidence: 99%

“…mPSC4 was provided by the Tuveson’s laboratory (Cold Spring Harbor Laboratory, NY, USA) and cultivated as previously described 8 . Human PDAC cell lines (PANC-1, HPAF-II, hT1, hM1, hF2, and Hs766T), human primary PDAC monolayer cell lines (VR2-2D (PDA2-2D), VR6-2D (PDA6-2D), VR9-2D (PDA9-2D), VR20-2D (PDA20-2D), and VR23-2D (PDA23-2D)) and human PDAC organoids (hT3, VR1-O (PDA1-O), VR2-O (PDA2-O), VR9-O (PDA9-O), and VR20-O (PDA20-O)) were obtained and cultivated as previously described 74 . Cell lines and organoids were routinely screened for Mycoplasma contamination using MycoAlert Mycoplasma Detection Kit (Lonza).…”

Section: Methodsmentioning

confidence: 99%

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Differential Activity of MAPK signalling Defines Fibroblast Subtypes in Pancreatic Cancer

Veghini,

Pasini,

Delfino

et al. 2023

Preprint

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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 MAPKhighCAFs, which suggest immunoregulatory functions. Accordingly, a gene expression signature of MAPKhighCAFs 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 CAFsin vivo.

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Loss of FGFR4 promotes the malignant phenotype of PDAC

Cited by 8 publications

References 55 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

Association of the rs1966265 and rs351855 FGFR4 Variants with Colorectal Cancer in a Mexican Population and Their Analysis In Silico

Differential Activity of MAPK signalling Defines Fibroblast Subtypes in Pancreatic Cancer

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