Franco Laboratory Research Overview

Cancer is not a single disease, but a group of more than one hundred different diseases defined by abnormal cell growth. When cells no longer respond to the signals that tell them what to do, uncontrolled growth can result. Understanding the molecular and genetic regulation of cancer cells helps scientists develop therapeutics that selectively kill cancer cells and prevent metastasis. This work leads to more targeted therapies and improved outcomes for patients.

Scientists used to think that tumors comprised cancer cells growing uncontrollably, and that killing the cancer cells could cure the patient. But we know now that a tumor is more like a whole new, dysfunctional organ in the body that doesn’t respond normally to outside cues. In addition to containing cancer cells, tumors have blood vessels, fibroblasts, and immune cells that the cancer has hijacked for its own benefit. The Franco Lab team has done pioneering work to define stromal cells that are present in thyroid tumors, and demonstrate how these cells aid the tumor's progress. The goal is to manipulate the tumor microenvironment as a novel therapeutic approach to treat thyroid cancer.

Patients are the motivation for all cancer research in the Franco Lab, with the goal to improve patient care with a better understanding of the physiology and pathophysiology of the thyroid gland. Specifically, the team aims to understand how communication between normal and cancer cells in tumors change as patients age, and how different normal cells are recruited to tumors between pediatric and adult thyroid cancer patients. This work will have important implications in improving patient outcomes in thyroid cancer, and help to personalize care for pediatric and adult patients.

Any scientific question we ask in the laboratory can be patient-centric. Understanding how treatments for cancer cells affect normal cells can help researchers to identify potential side effects and consequences for patients being treated with these drugs. A greater understanding of patient experiences can contribute to the development of therapies that preserve quality of life. The Franco Lab team collaborates with patient advocacy groups as well as cancer survivors within our own lab to ask questions important to patients.

The team seeks answers to the following questions:

• What does long-term survivorship look like for survivors of pediatric thyroid cancer?
• Does age of diagnosis impact Quality of Life?
• How does age affect thyroid cancer development?
• What questions are we not asking that might impact patients?

Different driver mutations, even if they all activate MAPK signaling, can lead to the development of different subtypes of thyroid cancer. The lab team works with a variety of animal models and patient cell lines with different driving mutations to investigate how genetics impacts physiological remodeling.

The research team aims to answer the following questions:

• How do different driver mutations recruit different stromal cells?
• How does collagen crosslinking change tumor cell activation?
• How do tumor cells with different driver mutations activate or inhibit immune cells?
• Why do the same mutations confer different risks in pediatric versus adult thyroid cancer?
• Can we re-differentiate tumor cells with targeted therapy?

The Franco Lab collaborates with the Pediatric Thyroid Center at Children's Hospital of Philadelphia to investigate why pediatric thyroid cancers often present with larger, more aggressive tumors than adult tumors while maintaining a very favorable prognosis.

Research questions related to this work include:

• Do adult and pediatric tumors have the same microenvironment?
• How does age impact response to therapy?
• Do physical cues in the microenvironment change aging?
• Does age change the responsiveness of tumor cells to stimuli?

The lab team dissects the genetic and molecular events that drive pediatric thyroid cancer to identify novel therapeutic strategies that could improve quality of life outcomes for pediatric patients.

The research team investigates the following questions:

• Do pediatric and adult thyroid tumors have different driver mutations?
• Does age impact what mutations develop in a tumor?
• Can we develop curative therapies for pediatric patients with metastatic thyroid cancer?
• Can mutations in the KEAP1/NRF2 pathway drive thyroid tumor progression?