SUMMARY
Linda M. McAllister, M.D., Ph.D., is a pediatric oncologist and physician-scientist who investigates the mechanisms by which dysregulated intracellular signaling drives neoplastic disease. Dr. McAllister also is co-director of the Oncoimmune Signaling and Therapeutics Laboratory along with her husband, Peter C. Lucas, M.D., Ph.D.
Early in her career, Dr. McAllister and her research team made a series of crucial discoveries that led to a new understanding of the molecular mechanisms responsible for driving non-Hodgkin lymphoma.
First, they identified a group of proteins known as the CARMA family. These proteins serve as a scaffold to recruit a multiprotein signaling complex that stimulates the proinflammatory, prosurvival transcription factor, NF-kB. The McAllister-Lucas team identified two proteins, BCL10 and MALT1, as components of this complex and provided the initial evidence that a CARMA family protein links antigen-receptor activation to stimulation of NF-kB in lymphocytes.
Their discovery formed the basis of a large body of work by laboratories around the world, including their own. This work led to the current understanding that the CARMA1/BCL10/MALT1 (CBM) complex plays a critical role in normal adaptive immune response by mediating NF-kB activation and proliferation in response to antigen stimulation in T and B cells.
Subsequent studies revealed that oncogenic gain-of-function mutations of CARMA1, BCL10, MALT1 or upstream regulators of the CBM complex occur in a significant percentage of cases of activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) and multiple other subtypes of lymphoma and leukemia. These findings highlight the central role of the CBM complex in the pathogenesis of this group of cancers. Ongoing studies in the McAllister-Lucas laboratory now focus on elucidating the mechanisms by which deregulation of CBM complex signaling promotes lymphoid malignancies.
The McAllister-Lucas Oncoimmune Lab team also discovered that a similar CBM signaling complex composed of CARMA3, BCL10 and MALT1 plays a key role in certain solid tumors. One particularly exciting new area of investigation is the evaluation of a potential dual role for MALT1 proteolytic activity in solid tumor pathogenesis. This activity promotes tumor cell proliferation through cancer cell-intrinsic effects while also promoting an immunosuppressive tumor microenvironment through cancer cell-extrinsic effects within immune cells.
Focus areas
- Non-Hodgkin lymphoma. Dr. McAllister and her team are investigating the molecular mechanisms by which MALT1 proteolytic activity can be regulated to stop tumor progression in non-Hodgkin lymphoma. The Oncoimmune Lab has identified a novel MALT1-binding protein called GRK2 that inhibits MALT1 protumorigenic activity in lymphocytes. Recent studies suggest that GRK2 may function as a tumor suppressor in MALT1-dependent lymphoma.
- Breast cancer. The McAllister-Lucas laboratory team is investigating the dual function of MALT1 protease in breast cancer cells and immune cells in the tumor microenvironment in triple-negative breast cancer as a potential new therapeutic target. There is a pressing need to develop molecularly informed, targeted therapies to treat triple-negative breast cancer because current treatments rely on nonspecific toxic chemotherapeutics, and outcomes remain poor.
- Brain tumors. The McAllister-Lucas lab's newest research area focuses on the role of MALT1 in the pathogenesis of glioma. The team is investigating how MALT1 activity within the unique brain tumor immune microenvironment affects disease progression. Recent preclinical studies suggest that pharmacological inhibition of MALT1 protease holds promise as a new and effective approach to stopping immune suppression in the brain tumor microenvironment.
Significance to patient care
Dr. McAllister thinks her team's research will help explain how some cancers grow and change, like lymphoma, breast cancer, and brain tumors. By learning this, healthcare professionals can make better and safer treatments for cancers that can be hard to treat.
Professional highlights
- American Pediatric Society:
- Elected member, 2015-present.
- Norman J. Siegel Outstanding Science Award, 2015.
- Elected member, The American Society for Clinical Investigation, 2014-present.
- Co-director, The American Society of Pediatric Hematology/Oncology Division Director Community, 2020-2024.
- Founding director, Mario Lemieux Institute for Pediatric Cancer Research, 2022-2023.
- Elected council member, Society for Pediatric Research, 2020-2023.
- University of Pittsburgh School of Medicine:
- Endowed chair, Wheeler Family Charitable Foundation, 2019-2023.
- Chief, Division of Pediatric Hematology-Oncology, 2012-2023.
- Associate director, Medical Scientist Training Program, University of Michigan Medical School, 2011-2012.
- Clinical Scientist Development Award, Doris Duke Foundation, 2002-2007.