RESUMO
Pancreatic ductal adenocarcinoma (PDA) is a critical health issue in the field of cancer, with few therapeutic options. Evidence supports an implication of the intratumoral microenvironment (stroma) on PDA progression. However, its contribution to the role of neuroplastic changes within the pathophysiology and clinical course of PDA, through tumor recurrence and neuropathic pain, remains unknown, neglecting a putative, therapeutic window. Here, we report that the intratumoral microenvironment is a mediator of PDA-associated neural remodeling (PANR), and we highlight factors such as 'SLIT2' (an axon guidance molecule), which is expressed by cancer-associated fibroblasts (CAFs), that impact on neuroplastic changes in human PDA. We showed that 'CAF-secreted SLIT2' increases neurite outgrowth from dorsal root ganglia neurons as well as from Schwann cell migration/proliferation by modulating N-cadherin/ß-catenin signaling. Importantly, SLIT2/ROBO signaling inhibition disrupts this stromal/neural connection. Finally, we revealed that SLIT2 expression and CAFs are correlated with neural remodeling within human and mouse PDA. All together, our data demonstrate the implication of CAFs, through the secretion of axon guidance molecule, in PANR. Furthermore, it provides rationale to investigate the disruption of the stromal/neural compartment connection with SLIT2/ROBO inhibitors for the treatment of pancreatic cancer recurrence and pain.
Assuntos
Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neurônios/patologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Animais , Axônios/efeitos dos fármacos , Axônios/metabolismo , Caderinas/metabolismo , Comunicação Celular/efeitos dos fármacos , Compartimento Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Meios de Cultura/farmacologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Camundongos Nus , Modelos Biológicos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neoplasias Pancreáticas/genética , Células de Schwann/efeitos dos fármacos , Células de Schwann/metabolismo , Células de Schwann/patologia , Transdução de Sinais/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia , Transcriptoma/genética , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , beta Catenina/metabolismo , Neoplasias PancreáticasAssuntos
Metilação de DNA , Epigênese Genética , Histonas/genética , Leucemia Mieloide Aguda/genética , Família Multigênica , Idoso , Biomarcadores/metabolismo , Cromatina/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Proteínas Nucleares/genética , NucleofosminaRESUMO
Stem cells represent not only a potential source of treatment for degenerative diseases but can also shed light on developmental biology and cancer. It is believed that stem cells differentiation and fate is triggered by a common genetic program that endows those cells with the ability to differentiate into specialized progenitors and fully differentiated cells. To extract the stemness signature of several cells types at the transcription level, we integrated heterogeneous datasets (microarray experiments) performed in different adult and embryonic tissues (liver, blood, bone, prostate and stomach in Homo sapiens and Mus musculus). Data were integrated by generalization of the hematopoietic stem cell hierarchy and by homology between mouse and human. The variation-filtered and integrated gene expression dataset was fed to a single-layered neural network to create a classifier to (i) extract the stemness signature and (ii) characterize unknown stem cell tissue samples by attribution of a stem cell differentiation stage. We were able to characterize mouse stomach progenitor and human prostate progenitor samples and isolate gene signatures playing a fundamental role for every level of the generalized stem cell hierarchy.