Biology of Cancer

Publications and presentations that deepen our understanding of pancreatic cancer biology.

β2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer
PanCAN article: Grantee’s Work Explains Stress in Disease Progression
Journal: Cancer Cell
Institution(s): Columbia University Medical Center, New York, NY, and others
Corresponding author(s): Timothy Wang
PanCAN-affiliated authors: Kenneth Olive and Timothy Wang
Major finding: The authors’ findings suggest that catecholamines drive a feedforward loop, whereby upregulation of neurotrophins increases sympathetic innervation and local norepinephrine accumulation.

The Pancreatic Cancer Microbiome Promotes Oncogenesis by Induction of Innate and Adaptive Immune Suppression
PanCAN article: Grantee’s Study Suggests Bacteria Can Influence Tumor Growth and Immune Response
Journal: Cancer Discovery
Institution(s): New York University School of Medicine, New York, NY, and others
Corresponding author(s): George Miller or Deepak Saxena
PanCAN-affiliated author: George Miller
Major finding: The authors’ data suggest that endogenous microbiota promote the crippling immune-suppression characteristic of pancreatic ductal adenocarcinoma and that the microbiome has potential as a therapeutic target in the modulation of disease progression.

Association of Alterations in Main Driver Genes With Outcomes of Patients With Resected Pancreatic Ductal Adenocarcinoma
PanCAN article: Tumor’s Genetic Changes Can Impact Patient Outcomes
Journal: JAMA Oncology
Institution(s): Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, and others
Corresponding author(s): Brian Wolpin
PanCAN-affiliated author: Andrew Aguirre, Jennifer Tseng, David Linehan, Aram Hezel and Brian Wolpin
Major finding: Although patients with resected pancreatic adenocarcinoma are at high risk for disease recurrence, few biomarkers are available to inform patient outcomes. The authors conclude that patient outcomes are associated with alterations of the 4 main driver genes in resected pancreatic adenocarcinoma.

Transcriptional Regulation by NR5A2 Links Differentiation and Inflammation in the Pancreas
Journal: Nature
Institution(s): Spanish National Cancer Research Centre-CNIO, Madrid, Spain, and others
Corresponding author(s): Francisco Real
PanCAN-affiliated author: Gloria Petersen
Major finding: These findings support the notion that, in the pancreas, the transcriptional networks involved in differentiation-specific functions also suppress inflammatory programs. Under conditions of genetic or environmental constraint, these networks can be subverted to foster inflammation.

Evolutionary Routes and KRAS Dosage Define Pancreatic Cancer Phenotypes
Journal: Nature
Institution(s): Technische Universität München, Munich, Germany, and others
Corresponding author(s): Roland Rad
Major finding: Evolutionary constraints and contingencies direct oncogenic dosage gain and variation along defined routes to drive the early progression of pancreatic ductal adenocarcinoma and shape its downstream biology. The authors’ study uncovers universal principles of Ras-driven oncogenesis that have potential relevance beyond pancreatic cancer.

Immune Cell Production of Interleukin 17 Induces Stem Cell Features of Pancreatic Intraepithelial Neoplasia Cells
PanCAN article: Grantee Explains Inflammation Driving Cancer Growth
Journal: Gastroenterology
Institution(s): The University of Texas MD Anderson Cancer Center. Houston, TX, and others
Corresponding author(s): Florencia McAllister
PanCAN-affiliated authors: Huamin Wang, Paul Chiao, Anirban Maitra, Steven Leach, Timothy Wang, Jennifer Bailey and Florencia McAllister
Major finding: In studies of mouse and human pancreatic tumors and precursors, the authors found immune cell-derived interleukin 17 (IL17) to regulate development of tuft cells and stem cell features of pancreatic cancer cells via increased expression of DCLK1, POU2F3, ALDH1A1, and IL17RC. Strategies to disrupt this pathway might be developed to prevent pancreatic tumor growth and progression.

Breast and Pancreatic Cancer Interrupt IRF8-Dependent Dendritic Cell Development to Overcome Immune Surveillance
Journal: Nature Communications
Institution(s): Washington University School of Medicine, St. Louis, MO, and others
Corresponding author(s): David DeNardo
PanCAN-affiliated authors: William Hawkins, David Linehan and David DeNardo
Major finding: The authors’ data suggest immune surveillance can be impaired by tumor-induced alterations in conventional dendritic cell development.

Autophagy Sustains Pancreatic Cancer Growth through Both Cell-Autonomous and Nonautonomous Mechanisms
Journal: Cancer Discovery
Institution(s): Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, and others
Corresponding author(s): Alec Kimmelman
PanCAN-affiliated authors: Alec Kimmelman
Major finding: The authors’ study supports autophagy inhibition in pancreatic ductal adenocarcinoma may have future utility in the treatment of pancreatic cancer and illustrates the importance of assessing complex biological processes in relevant autochthonous models.

Loss of KDM6A Activates Super-Enhancers to Induce Gender-Specific Squamous-like Pancreatic Cancer and Confers Sensitivity to BET Inhibitors
Journal: Cancer Cell
Institution(s): George Washington University (GWU) School of Medicine and Health Sciences, Washington, DC
Corresponding author(s): Alexandros Tzatsos
Major finding: KDM6A, an X chromosome-encoded histone demethylase and member of the COMPASS-like complex, is frequently mutated in a broad spectrum of malignancies and contributes to oncogenesis with poorly characterized mechanisms. The authors also demonstrate that KDM6A-deficient pancreatic cancer is selectively sensitive to BET inhibitors, which reversed squamous differentiation and restrained tumor growth in vivo, highlighting a therapeutic niche for patient tailored therapies.

Recapitulating the Clinical Scenario of BRCA‐Associated Pancreatic Cancer in Pre‐Clinical Models
Journal: International Journal of Cancer
Institution(s): Sheba Medical Center, Tel Hashomer, Israel, and others
Corresponding author(s): Talia Golan
Major finding: The authors’ results demonstrate heterogeneous responses to DNA damaging agents/PARP inhibitors in BRCA-associated patient-derived xenogfrafts thus reflecting the wide clinical spectrum.

Saa3 Is a Key Mediator of the Protumorigenic Properties of Cancer-Associated Fibroblasts in Pancreatic Tumors
Journal: PNAS
Institution(s): Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain, and others
Corresponding author(s): Carmen Guerra or Mariano Barbacid
Major finding: These findings support the concept that selective inhibition of SAA1, a member of the serum amyloid A (SAA) apolipoprotein family, in cancer-associated fibroblasts may provide potential therapeutic benefit to pancreatic ductal adenocarcinoma patients.

Pancreatic Cancer in 2017: Rebooting Pancreatic Cancer Knowledge and Treatment Options
Journal: Nature Reviews Gastroenterology & Hepatology
Institution(s): UT MD Anderson Cancer Center, Houston, TX
Corresponding author(s): Anirban Maitra
PanCAN-affiliated authors: Anirban Maitra
Major finding: High stromal cellularity in pancreatic cancer is an important factor for ineffective treatment and molecular studies. In 2017, major advancements were made in transcriptional characterization, treatment delivery and clinical regimes, raising hope for a breakthrough against this deadly disease.

Establishment of the First Well-Differentiated Human Pancreatic Neuroendocrine Tumor Model
Journal: Molecular Cancer Research
Institution(s): University Medical Center Hamburg-Eppendorf, Hamburg, Germany, and others
Corresponding author(s): Joerg Schrader
Major finding: High expression of somatostatin receptors and a well-differentiated phenotype as well as a slow growth rate qualify the new cell line as a relevant model to study neuroendocrine tumor biology and to develop new tumor treatments.