PhD Public Seminar: SUMEDHA PAREEK, MS
When & Where
November 21
10:00 AM - 11:00 AM
UTH MD Anderson Cancer Center, SCRB1/2, SCR1.1025 (View in Google Map)
Contact
- Joy A. Lademora
- 713-500-9872
- [email protected]
Event Description
Host-intrinsic Factors Determine Anti-Tumor Efficacy of Exercise in Pancreatic Ductal Adenocarcinoma
Sumedha Pareek, MS (Advisor: Keri Schadler, PhD)
Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths with a low 5-year relative survival rate of approximately 13.3% for all stages combined. We have previously shown that exercise can improve quality of life and enhance functional capacity among patients with PDAC. Exercise induces a variety of changes in the tumor microenvironment with beneficial effects in several tumor types. However, our understanding of the clinical effects of exercise and the mechanisms that mediate anti-tumor effects are limited in pancreatic cancer.
In this project, using C57BL/6 mice from Taconic Biosciences (Tac) and Jackson Laboratories (Jax), we established a pre-clinical mouse model of orthotopic PDAC with multiple exercise interventions. We demonstrated that gut microbiome differences between Tac and Jax result in differential exercise capacity with an intensity- dependent effect of exercise on tumor infiltrating immune cells.
We interrogated tumor stromal composition changes with exercise and observed a gut microbiome dependent reduction in alpha smooth muscle actin (αSMA+) cells and Il6 expressing inflammatory cancer associated fibroblasts (iCAFs). Similar analysis of tumors from patients in the PancFit trial demonstrated an exercise induced reduction in αSMA+ cells. We subsequently identified Cholic Acid (CA), a microbial bile acid that was increased in both patients and murine models with exercise, as a likely mediator of exercise induced reduction in iCAFs. Consistent with these findings, patients that exercised more also exhibited fewer iCAFs and lower tumor IL6 gene expression, supporting a stromal remodeling effect of physical activity.
In conclusion, this project demonstrates the role of host-intrinsic differences in regulation of exercise capacity, exercise-induced immune cell infiltration and activation, tumor growth, and stromal composition. Future work will evaluate the role of microbial metabolites such as CA as a biomarker of anti-tumor effect of exercise for patients with PDAC and as therapy for stromal remodeling to improve patient outcomes.
Advisory Committee:
- Keri Schadler, PhD, Chair
- Florencia McAllister, MD
- Nancy Gordon, MD
- Matthew Gubin, PhD
- Emily LaVoy, PhD
- Seyed Javad Moghaddam, MD
Host-intrinsic Factors Determine Anti-Tumor Efficacy of Exercise in Pancreatic Ductal Adenocarcinoma
Sumedha Pareek, MS (Advisor: Keri Schadler, PhD)
Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths with a low 5-year relative survival rate of approximately 13.3% for all stages combined. We have previously shown that exercise can improve quality of life and enhance functional capacity among patients with PDAC. Exercise induces a variety of changes in the tumor microenvironment with beneficial effects in several tumor types. However, our understanding of the clinical effects of exercise and the mechanisms that mediate anti-tumor effects are limited in pancreatic cancer.
In this project, using C57BL/6 mice from Taconic Biosciences (Tac) and Jackson Laboratories (Jax), we established a pre-clinical mouse model of orthotopic PDAC with multiple exercise interventions. We demonstrated that gut microbiome differences between Tac and Jax result in differential exercise capacity with an intensity- dependent effect of exercise on tumor infiltrating immune cells.
We interrogated tumor stromal composition changes with exercise and observed a gut microbiome dependent reduction in alpha smooth muscle actin (αSMA+) cells and Il6 expressing inflammatory cancer associated fibroblasts (iCAFs). Similar analysis of tumors from patients in the PancFit trial demonstrated an exercise induced reduction in αSMA+ cells. We subsequently identified Cholic Acid (CA), a microbial bile acid that was increased in both patients and murine models with exercise, as a likely mediator of exercise induced reduction in iCAFs. Consistent with these findings, patients that exercised more also exhibited fewer iCAFs and lower tumor IL6 gene expression, supporting a stromal remodeling effect of physical activity.
In conclusion, this project demonstrates the role of host-intrinsic differences in regulation of exercise capacity, exercise-induced immune cell infiltration and activation, tumor growth, and stromal composition. Future work will evaluate the role of microbial metabolites such as CA as a biomarker of anti-tumor effect of exercise for patients with PDAC and as therapy for stromal remodeling to improve patient outcomes.
Advisory Committee:
- Keri Schadler, PhD, Chair
- Florencia McAllister, MD
- Nancy Gordon, MD
- Matthew Gubin, PhD
- Emily LaVoy, PhD
- Seyed Javad Moghaddam, MD