Harvard Catalyst Profiles

The overall goal of our research is to understand the role of the tumor microenvironment in tumor growth and response to therapy, to develop novel strategies to manipulate the tumor microenvironment, and to translate these strategies into improved cancer detection, prevention and treatment in humans. The tumor microenvironment includes the tumor vasculature, the stromal compartment such as cancer-associated fibroblasts, extracellular matrix and immune cells, and also the lymphatic vasculature.

To unravel the complex biology of tumors, we have developed an array of imaging technologies, mathematical models, and animal preparations. These include multiphoton microscopy and genetically engineered mice with surgically implanted transparent windows, which permit in vivo visualization of gene expression and function in tumors and their surrounding host stroma. This undertaking has provided powerful molecular, cellular, anatomical and functional insights into the barriers to cancer treatment.

Our work has revealed that the abnormal vasculature in solid tumors often thwarts the effectiveness of both conventional and novel therapies. Our laboratory is known for a new hypothesis that antiangiogenic therapy can "normalize" the abnormal tumor vasculature and improve both the delivery and efficacy of therapeutics. We have validated this concept in mice and patients receiving antiangiogenic therapy and in the process, discovered potential biomarkers for tailoring individual therapies.

Our lab has also shown that the dense extracellular matrix of tumors leads to high mechanical forces known as solid stress within tumors. This solid stress compresses/collapses blood vessels in the tumor, leading to poor delivery of conventional therapeutics. We have shown that the use of losartan, an angiotensin receptor blocker (ARB) commonly used to treat high blood pressure, can reduce extracellular matrix in tumors, leading to decreased solid stress within tumors, decompressing blood vessels and improving drug delivery.

This preclinical work has led to a clinical trial at MGH where losartan is given to patients with pancreatic ductal adenocarcinoma (PDAC) together with conventional chemotherapy, and it has been shown that losartan increases the R0 resection rate in resectable and borderline resectable PDAC patients. Other projects in the lab include reprogramming the immune microenvironment of tumors to improve the efficacy of immunomodulatory drugs such as immune checkpoint blockers; lymphatic function and lymphangiogenesis; dissection of steps in hematologic and lymphatic metastasis; drug screening for treatment of metastasis; and translation of these findings to the clinic.

Our laboratory is truly multidisciplinary spanning expertise in molecular and cellular biology, physiology, bioengineering, optics, mathematics to radiation, medical and surgical oncology. A tight integration between bench and bedside guides our research.