Molecular drivers and cells of origin in pancreatic ductal adenocarcinoma and pancreatic neuroendocrine carcinoma

Gao, Heli; Wang, Wenquan; Lei, Yu; Liu, Liang

doi:10.1186/s40164-020-00184-0

Cited by 22 publications

(18 citation statements)

References 73 publications

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“…Arising from either ductal or acinar cells of the exocrine portion, pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all pancreatic cancers, while the remainder chiefly evolves from Langerhans islets ( Gao et al, 2020 ). While this latter subtype is typically linked to an abnormal hormone secretion even at the early stage, facilitating its detection and diagnosis, PDAC is almost a symptom-free disease until metastases, or rather when the advanced stage leaves no longer chances of recovery ( Mpilla et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Integrating Gemcitabine-Based Therapy With AdipoRon Enhances Growth Inhibition in Human PDAC Cell Lines

et al. 2022

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Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all pancreatic cancers. Albeit its incidence does not score among the highest in cancer, PDAC prognosis is tremendously fatal. As a result of either aggressiveness or metastatic stage at diagnosis, chemotherapy constitutes the only marginally effective therapeutic approach. As gemcitabine (Gem) is still the cornerstone for PDAC management, the low response rate and the onset of resistant mechanisms claim for additional therapeutic strategies. The first synthetic orally active adiponectin receptor agonist AdipoRon (AdipoR) has recently been proposed as an anticancer agent in several tumors, including PDAC. To further address the AdipoR therapeutic potential, herein we investigated its pharmacodynamic interaction with Gem in human PDAC cell lines. Surprisingly, their simultaneous administration revealed a more effective action in contrasting PDAC cell growth and limiting clonogenic potential than single ones. Moreover, the combination AdipoR plus Gem persisted in being effective even in Gem-resistant MIA PaCa-2 cells. While a different ability in braking cell cycle progression between AdipoR and Gem supported their cooperating features in PDAC, mechanistically, PD98059-mediated p44/42 MAPK ablation hindered combination effectiveness. Taken together, our findings propose AdipoR as a suitable partner in Gem-based therapy and recognize the p44/42 MAPK pathway as potentially involved in combination outcomes.

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Section: Introductionmentioning

confidence: 99%

Integrating Gemcitabine-Based Therapy With AdipoRon Enhances Growth Inhibition in Human PDAC Cell Lines

et al. 2022

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“…Smoking (2), obesity (3), diabetes (4), alcohol consumption (5), and Helicobacter pylori infection (6) are the major risk factors linked to this malignancy. Pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine neoplasm (PanNEN) are the two primary histological subtypes of pancreatic cancer of which the former accounts for 90% of all pancreatic cancer cases, whereas PanNEN accounts for only 3-5% of all cases (7). Surgical resection, chemotherapy, and radiotherapy are the major conventional therapeutic approaches; however, surgical excision is the only current therapy that can be potentially curative in comparison to other clinical approaches (8).…”

Section: Introductionmentioning

confidence: 99%

A cancer-associated fibroblast gene signature predicts prognosis and therapy response in patients with pancreatic cancer

et al. 2022

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Pancreatic cancer is a lethal malignancy with a 5-year survival rate of about 10% in the United States, and it is becoming an increasingly prominent cause of cancer death. Among pancreatic cancer patients, pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of all cases and has a very poor prognosis with an average survival of only 1 year in about 18% of all tumor stages. In the past years, there has been an increasing interest in cancer-associated fibroblasts (CAFs) and their roles in PDAC. Recent data reveals that CAFs in PDAC are heterogeneous and various CAF subtypes have been demonstrated to promote tumor development while others hinder cancer proliferation. Furthermore, CAFs and other stromal populations can be potentially used as novel prognostic markers in cancer. In the present study, in order to evaluate the prognostic value of CAFs in PDAC, CAF infiltration rate was evaluated in 4 PDAC datasets of TCGA, GEO, and ArrayExpress databases and differentially expressed genes (DEGs) between CAF-high and CAF-low patients were identified. Subsequently, a CAF-based gene expression signature was developed and studied for its association with overall survival (OS). Additionally, functional enrichment analysis, somatic alteration analysis, and prognostic risk model construction was conducted on the identified DEGs. Finally, oncoPredict algorithm was implemented to assess drug sensitivity prediction between high- and low-risk cohorts. Our results revealed that CAF risk-high patients have a worse survival rate and increased CAF infiltration is a poor prognostic indicator in pancreatic cancer. Functional enrichment analysis also revealed that “extracellular matrix organization” and “vasculature development” were the top enriched pathways among the identified DEGs. We also developed a panel of 12 genes, which in additional to its prognostic value, could predict higher chemotherapy resistance rate. This CAF-based panel can be potentially utilized alone or in conjunction with other clinical parameters to make early predictions and prognosticate responsiveness to treatment in PDAC patients. Indeed, it is necessary to conduct extensive prospective investigations to confirm the clinical utility of these findings.

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“…The origin of EP-PD-NECs remains elusive. Accumulating evidence from clinical observations, genomic and transcriptomic studies suggests a distinct pathogenesis and, in some anatomical sites, cell of origin for WD-NETs and PD-NECs (122)(123)(124). WD-NETs are thought to develop from mature NE cells or pluripotent precursors primed for a NE lineage commitment (122,123).…”

Section: Origin and Ne Lineage Plasticitymentioning

confidence: 99%

Expanding Therapeutic Opportunities for Extrapulmonary Neuroendocrine Carcinoma

Frizziero

Kilgour

Simpson

et al. 2022

Clinical Cancer Research

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Poorly differentiated neuroendocrine carcinomas (PD-NEC) are rare cancers garnering interest as they become more commonly encountered in the clinic. This is due to improved diagnostic methods and the increasingly observed phenomenon of “NE lineage plasticity,” whereby nonneuroendocrine (non-NE) epithelial cancers transition to aggressive NE phenotypes after targeted treatment. Effective treatment options for patients with PD-NEC are challenging for several reasons. This includes a lack of targetable, recurrent molecular drivers, a paucity of patient-relevant preclinical models to study biology and test novel therapeutics, and the absence of validated biomarkers to guide clinical management. Although advances have been made pertaining to molecular subtyping of small cell lung cancer (SCLC), a PD-NEC of lung origin, extrapulmonary (EP)-PD-NECs remain understudied. This review will address emerging SCLC-like, same-organ non-NE cancer-like and tumor-type–agnostic biological vulnerabilities of EP-PD-NECs, with the potential for therapeutic exploitation. The hypotheses surrounding the origin of these cancers and how “NE lineage plasticity” can be leveraged for therapeutic purposes are discussed. SCLC is herein proposed as a paradigm for supporting progress toward precision medicine in EP-PD-NECs. The aim of this review is to provide a thorough portrait of the current knowledge of EP-PD-NEC biology, with a view to informing new avenues for research and future therapeutic opportunities in these cancers of unmet need.

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Molecular drivers and cells of origin in pancreatic ductal adenocarcinoma and pancreatic neuroendocrine carcinoma

Cited by 22 publications

References 73 publications

Integrating Gemcitabine-Based Therapy With AdipoRon Enhances Growth Inhibition in Human PDAC Cell Lines

Integrating Gemcitabine-Based Therapy With AdipoRon Enhances Growth Inhibition in Human PDAC Cell Lines

A cancer-associated fibroblast gene signature predicts prognosis and therapy response in patients with pancreatic cancer

Expanding Therapeutic Opportunities for Extrapulmonary Neuroendocrine Carcinoma

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