The Sweet-Cordero Lab at UCSF
The Sweet-Cordero Lab at UCSF is focused on identifying novel therapeutic approaches for cancer that target the genetic mutations and altered signaling networks that are specific to cancer cells, with a focus on two primary disease interests: lung cancer and pediatric sarcomas. The lab uses functional genomics applied to mouse and human systems (genetically engineered models, patient derived xenografts) to understand the transcriptional networks that regulate the outcome of specific oncogenic mutations and to identify new approaches for cancer therapy. Their research spans the continuum from basic discovery to clinical application in a dynamic, interactive, and highly collaborative environment.
We asked Alejandro Sweet-Cordero, MD, Chief, Division of Pediatric Oncology and Director, Molecular Oncology Initiative at Benioff Professor of Children’s Health, University of California San Francisco to share insights from his lab and how his team Makes It Better.
The Sweet-Cordero Lab focuses on lung cancer and pediatric sarcomas, and many projects are focused on osteosarcoma specifically. How did you decide to focus on these disease areas and how does your work in both these disease areas inform each other?
I did my postdoctoral research training in a laboratory that specialized in using genetically engineered mouse models to study cancer. At the time I joined that lab the most interesting mouse model available was a lung cancer model. So I got my start in cancer biology research studying lung cancer. Since lung cancer is the most common cause of cancer death, I decided to keep studying that when I started my own lab. Once I had my own lab, I also started to develop projects in pediatric cancer but these took many years to establish. It's only been in the last 4-5 years that our pediatric cancer projects have matured to where well over half the lab studies pediatric cancer. But cancer has many similarities across subtypes, so studying both types of cancer together means we have a stronger skill set in the lab and we can share tools and resources that help advance all of our work.
One of the lab's focus areas is integrative genomic analysis, using both whole genome sequencing (WGS) and RNA sequencing, of advanced pediatric cancer cases to identify novel drivers of relapse and metastasis in pediatric cancer and to develop new tools that can help guide therapy for patients with high-risk disease. Can you discuss patterns you see across disease types?
Some of the common patterns we see have to do with “drivers” that are present in more than one cancer. For example, many cancers upregulate genes in a family of genes called “tyrosine kinases.” We also see that many relapsed cancers show evidence of injury in the DNA of the tumor caused by the chemotherapy that was given to the patient (for example, cisplatin).
The Sweet-Cordero lab has an impressive library of patient derived xenografts (PDX) mouse models and cell lines which are an incredibly valuable resource. Generating osteosarcoma PDX and cell lines can be challenging. What are some of the lab's key learnings based on your experience that you would share with other labs?
The main learning is patience. It takes a lot of dedication and patience to develop these models. It's also important to be very careful to make sure these lines don’t change over time or get cross-contaminated from one to another. The lab has staff that are very dedicated to patiently making these models over many years. Another thing we always emphasize is sharing these models freely. These models came from patients who suffered because of these tumors, we feel it's important to make sure that their suffering wasn’t in vain and we share these models with any labs that want them. We have shared them with over 20 labs worldwide.
Another key area the Sweet-Cordero lab is focused on is studying chemotherapy resistance which is a huge challenge in a disease like osteosarcoma for which there are limited therapy options. Can you share some of your findings to date on drivers of chemo resistance?
This is a relatively newer interest in the laboratory so we don’t have as much data yet, but we do feel it is important to study chemoresistance in animal models and not just in tissue culture because mechanisms of resistance in an organism are different from those in a tissue culture dish.
In addition to studying genomics to identify potential targeted therapies for osteosarcoma, your lab is also investigating immunotherapy approaches for osteosarcoma. Can you tell us about your active research projects in this area?
We are very interested in a pathway called the STING pathway which in normal cells is used to signal that a cell has been infected with a virus. Tumor cells often also activate STING and this can recruit immune cells to kill tumors. But many tumors also “turn off” STING as a way to silence immune surveillance . We are trying to understand how this “turning off” works and what can be done to reactivate STING to make tumors more responsive to immunotherapy.
You have a large team of talented young investigators and mentorship is so important in career development, particularly in a rare disease that gets less funding than more common diseases. What are your key tenets for mentoring YIs?
First is finding the right people and recruiting them to the lab. The key to that is to have a collaborative, positive atmosphere in the lab that people feel attracted to. Then once they join the lab, you need to give them the resources and tools to succeed and encourage them to help each other and collaborate. I also try to foster their own creativity and encourage them to explore areas that may be “high risk” but exciting. It's also important to help young investigators to make sure they have opportunities to present their work at meetings and develop networks of their own through exposure to other scientists, etc.
The Sweet-Cordero lab has received support from the MIB Agents OutSmarting Osteosarcoma grant program. What has been the impact of this funding?
MIB has been an incredibly important partner for us. Grants from MIB have helped young investigators develop their most innovative ideas which might not be funded by more risk-averse foundations or government agencies. It is also important for young investigators to know that people care about their research and that it has potential for impact.
What recent developments in osteosarcoma and/or cancer research are you most excited about?
The ability to study tumors at “high resolution” using new spatial analysis technologies has huge potential to help us understand osteosarcoma and especially why the immune system isn’t always successful at getting rid of tumor cells.
Warriors, Giants, or 49ers?
Love them all, but the Warriors and Giants are close by so they feel more like part of the SF family, but then again, excited to watch the Niners crush Kansas (sorry Taylor).