This project seeks to investigate the role of nerves and other stromal cells in the development of digestive cancers, including stomach, esophageal, colon and pancreas. The project builds on previous work that suggests that these elements can regulate stem cells,a nd that inhibiting stromal cells in the microenvironment, it may be possible to inhibit the development of tumors.
Gastrointestinal cancers often arise in the setting of chronic inflammation, and thus involve early on close interactions between activated and mutated epithelial progenitors and accumulated stromal cells. Dr. Timothy Wang's laboratory has for several decades studied the pathogenesis of Helicobacter-dependent gastric cancer, and in previous studies defined clear roles for Helicobacter infection, myeloid cells and tumor-associated fibroblasts in the development of gastric tumors. Recent work from the lab has elucidated major contributions of cholinergic nerves, endothelial cells and innate lymphoid cells in modulating the gastric cancer niche. The PI has demonstrated a role for nerves both in direct control of normal stem cells and cancer cells, but also a role for nerves in regulating tumor immunity. The group now proposes to extend these findings to other gastrointestinal cancers, including esophageal, colon and pancreatic cancer. The laboratory will utilize its large collection of genetically engineered mouse models, inducible Cre-drivers and in vitro 3-D organoid cell models to better understand (1) the normal stem cell niche and the alterations that occur in the cancer cell niche which presumably contribute to tumor progression. Additional areas of investigation will include (2) the cross-talk that occurs between nerves and GI stem cells; (3) mechanisms for stem cell activation in regeneration and malignancy; (4) the potential contributions of nerves to the regulation of immunity in the cancer seting; (5) testing of possible strategies for modulation of neural regulation in preclinical models. The proposed studies will be carried out in collaboration with collaborators at MIT and the DFCI. The study of distinct models of digestive cancers will allow fundamental comparisons to be made in the evolution of the cancer niche and the control of cancer cell behavior. Building on a highly productive program and recent findings, the PI will explore the notion that there are a number of useful targets in the tumor microenvironment that will lead to improved therapy of gastrointestinal malignancies.
|Renz, Bernhard W; Tanaka, Takayuki; Sunagawa, Masaki et al. (2018) Cholinergic Signaling via Muscarinic Receptors Directly and Indirectly Suppresses Pancreatic Tumorigenesis and Cancer Stemness. Cancer Discov 8:1458-1473|
|Mannion, Anthony; Shen, Zeli; Fox, James G (2018) Comparative genomics analysis to differentiate metabolic and virulence gene potential in gastric versus enterohepatic Helicobacter species. BMC Genomics 19:830|
|Renz, Bernhard W; Takahashi, Ryota; Tanaka, Takayuki et al. (2018) ?2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer. Cancer Cell 33:75-90.e7|
|Renz, Bernhard W; Takahashi, Ryota; Tanaka, Takayuki et al. (2018) ?2 Adrenergic-Neurotrophin Feedforward Loop Promotes Pancreatic Cancer. Cancer Cell 34:863-867|
|Hayakawa, Yoku; Fox, James G; Wang, Timothy C (2017) Isthmus Stem Cells Are the Origins of Metaplasia in the Gastric Corpus. Cell Mol Gastroenterol Hepatol 4:89-94|
|Hayakawa, Yoku; Fox, James G; Wang, Timothy C (2017) The Origins of Gastric Cancer From Gastric Stem Cells: Lessons From Mouse Models. Cell Mol Gastroenterol Hepatol 3:331-338|
|Hayakawa, Yoku; Sakitani, Kosuke; Konishi, Mitsuru et al. (2017) Nerve Growth Factor Promotes Gastric Tumorigenesis through Aberrant Cholinergic Signaling. Cancer Cell 31:21-34|