New insights in the development of pancreatic cancer

Sinha, Smrita; Leach, Steven D.

doi:10.1097/mog.0000000000000295

“…Since we observed axons in close proximity to PanIN epithelial cells and showed that PDAC cells robustly recruited sensory axons, we hypothesized that nerves, like other stromal components (21,25), may communicate with and regulate the PanIN epithelium. The KPC Pdx1 PanIN epithelia were negative for expression of several nerve-responsive elements such as the neurotrophic receptors p75, TrkA, TrkB and TrkC that can be expressed in human PDAC (4) (data not shown).…”

Section: Resultsmentioning

confidence: 88%

“…Such time- and context-specific roles of oncogenic factors are well described in PanIN and PDAC tumorigenesis (for review see ref. ((25)).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

PanIN Neuroendocrine Cells Promote Tumorigenesis via Neuronal Cross-talk

Sinha

¹

,

Fu

²

,

Grimont

³

et al. 2017

Self Cite

View full text Add to dashboard Cite

Nerves are a notable feature of the tumor microenvironment in some epithelial tumors, but their role in the malignant progression of pancreatic ductal adenocarcinoma (PDAC) is uncertain. Here we identify dense innervation in the microenvironment of precancerous pancreatic lesions, known as pancreatic intraepithelial neoplasms (PanIN), and describe a unique subpopulation of neuroendocrine PanIN cells that express the neuropeptide substance P (SP) receptor Neurokinin 1-R (NK1-R). Using organoid culture, we demonstrated that sensory neurons promoted the proliferation of PanIN organoids via SP-NK1-R signaling and Stat3 activation. Nerve-responsive neuroendocrine cells exerted trophic influences and potentiated global PanIN organoid growth. Sensory denervation of a genetically engineered mouse model of PDAC led to loss of Stat3 activation, a decrease in the neoplastic neuroendocrine cell population, and impaired PanIN progression to tumor. Overall, our data provide evidence that nerves of the PanIN microenvironment promote oncogenesis, likely via direct signaling to neoplastic neuroendocrine cells capable of trophic influences. These findings identify neuroepithelial crosstalk as a potential novel target in PDAC treatment.

show abstract

“…Since we observed axons in close proximity to PanIN epithelial cells and showed that PDAC cells robustly recruited sensory axons, we hypothesized that nerves, like other stromal components (21,25), may communicate with and regulate the PanIN epithelium. The KPC Pdx1 PanIN epithelia were negative for expression of several nerve-responsive elements such as the neurotrophic receptors p75, TrkA, TrkB and TrkC that can be expressed in human PDAC (4) (data not shown).…”

Section: Panin Neuroendocrine Cells Express the Substance P Neuropeptmentioning

confidence: 99%

PanIN Neuroendocrine Cells Promote Tumorigenesis via Neuronal Cross-talk

Sinha

¹

,

Fu

²

,

Grimont

³

et al. 2017

Self Cite

View full text Add to dashboard Cite

Nerves are a notable feature of the tumor microenvironment in some epithelial tumors, but their role in the malignant progression of pancreatic ductal adenocarcinoma (PDAC) is uncertain. Here we identify dense innervation in the microenvironment of precancerous pancreatic lesions, known as pancreatic intraepithelial neoplasms (PanIN), and describe a unique subpopulation of neuroendocrine PanIN cells that express the neuropeptide substance P (SP) receptor Neurokinin 1-R (NK1-R). Using organoid culture, we demonstrated that sensory neurons promoted the proliferation of PanIN organoids via SP-NK1-R signaling and Stat3 activation. Nerve-responsive neuroendocrine cells exerted trophic influences and potentiated global PanIN organoid growth. Sensory denervation of a genetically engineered mouse model of PDAC led to loss of Stat3 activation, a decrease in the neoplastic neuroendocrine cell population, and impaired PanIN progression to tumor. Overall, our data provide evidence that nerves of the PanIN microenvironment promote oncogenesis, likely via direct signaling to neoplastic neuroendocrine cells capable of trophic influences. These findings identify neuroepithelial crosstalk as a potential novel target in PDAC treatment.

show abstract

“…Of note, PDAC is characterised by a hypoxic, immunosuppressive and highly fibrotic environment, with stromal components outnumbering pancreatic cancer cells [23,24]. Intricate communication between pancreatic cancer cells and their surrounding environment, driven by a dynamic signalling network of cellular and matrix remodelling enzymes, cytokines, chemokines and growth factors, collectively promotes tumour growth and treatment resistance [25][26][27][28].…”

Section: Introductionmentioning

confidence: 99%

Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

Parkin

¹

,

Man

²

,

Timpson

³

et al. 2019

View full text Add to dashboard Cite

Pancreatic cancer, a disease with extremely poor prognosis, has been notoriously resistant to virtually all forms of treatment. The dynamic crosstalk that occurs between tumour cells and the surrounding stroma, frequently mediated by intricate Src/FAK signalling, is increasingly recognised as a key player in pancreatic tumourigenesis, disease progression and therapeutic resistance. These important cues are fundamental for defining the invasive potential of pancreatic tumours, and several components of the Src and downstream effector signalling have been proposed as potent anticancer therapeutic targets. Consequently, numerous agents that block this complex network are being extensively investigated as potential antiinvasive and antimetastatic therapeutic agents for this disease. In this review, we will discuss the latest evidence of Src signalling in PDAC progression, fibrotic response and resistance to therapy. We will examine future opportunities for the development and implementation of more effective combination regimens, targeting key components of the oncogenic Src signalling axis, and in the context of a precision medicine‐guided approach.

show abstract

New insights in the development of pancreatic cancer

Cited by 10 publications

References 49 publications

PanIN Neuroendocrine Cells Promote Tumorigenesis via Neuronal Cross-talk

PanIN Neuroendocrine Cells Promote Tumorigenesis via Neuronal Cross-talk

PanIN Neuroendocrine Cells Promote Tumorigenesis via Neuronal Cross-talk

Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

Contact Info

Product

Resources

About