SUMMARY
Linda M. McAllister, M.D., Ph.D., is a pediatric oncologist physician-scientist who investigates the mechanisms by which dysregulated intracellular signaling drives neoplastic disease. In building her research program, Dr. McAllister chose to work with her husband, Peter C. Lucas, M.D., Ph.D., who is currently professor of laboratory medicine and pathology, Mayo Clinic College of Medicine and Science, and vice chair of Research for the Department of Laboratory Medicine and Pathology at Mayo Clinic. Their joint laboratory has been continuously supported by National Institutes of Health R01 funding since 2008.
During the early stages of her career, Dr. McAllister's team made a series of critical discoveries that led to a new understanding of the molecular mechanisms responsible for driving non-Hodgkin lymphoma. First, she identified a group of proteins known as the "CARMA family," which serve as scaffolds to recruit a multiprotein signaling complex that stimulates the pro-inflammatory, pro-survival 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 mediates antigen-receptor dependent NF-kB stimulation in lymphocytes. This discovery formed the basis of a large body of work by laboratories around the world, including her own, leading to the current understanding that the "CARMA1/BCL10/MALT1 (CBM) signalosome" plays a critical role in normal adaptive immune response by mediating antigen-induced NF-kB activation and proliferation in T and B cells.
Subsequent studies revealed that oncogenic gain-of-function mutations of CARMA, BCL10 or of upstream regulators of the CBM complex occur in a significant percentage of cases of activated B-cell diffuse large B-cell lymphoma (ABC-DLBCL) as well as multiple other subtypes of lymphoma and leukemia, highlighting the central role of this CBM complex in the pathogenesis of these cancers. Ongoing studies in the McAllister laboratory now focus on elucidating the mechanisms by which deregulation of CBM complex-dependent signaling occurs in lymphoid malignancies.
The McAllister-Lucas team also later discovered that a similar "CBM" signaling complex composed of CARMA3, BCL10 and MALT1 plays a key role in promoting cancer cell proliferation and survival 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, both promoting tumor cell proliferation through cancer cell-intrinsic effects, while also promoting an immunosuppressive tumor microenvironment through cancer cell-extrinsic effects within immune cells.
The McAllister-Lucas team is now investigating the possibility that pharmacologic targeting of MALT1 could therefore have a dual benefit in certain tumor types by acting within cancer cells to abrogate cell survival and proliferation, while also acting within immune cells to reprogram the tumor microenvironment and abrogate tumor immune suppression. Thus far, the team is focusing these investigations in two areas: breast cancers and brain tumors.
Focus areas
- Non-Hodgkin lymphoma. Dr. McAllister's team is investigating the molecular mechanisms by which MALT1 proteolytic activity can be regulated to abrogate tumor progression in non-Hodgkin lymphoma. Through studies led by team member Jing Cheng, Ph.D., the laboratory has identified a novel MALT1-binding protein, "GRK2," which inhibits MALT1 pro-tumorigenic signaling activity in lymphocytes. The team's recent studies suggest that GRK2 may function as a tumor suppressor in MALT1-dependent lymphoid malignancies.
- 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 (TNBC). Representing 15% of invasive breast cancer cases, with disproportionately high prevalence in African American and Hispanic women, TNBC is defined by the lack of expression of estrogen receptor, progesterone receptor and HER2. Due to the absence of these currently targetable molecular drivers, treatment for TNBC still relies on nonspecific toxic chemotherapeutics, and outcomes remain poor. As a result, there is a pressing need to develop molecularly informed, targeted therapies to treat TNBC. Team-member Dong Hu, Ph.D., leads a research program that investigates MALT1 protease as a potential new therapeutic target in a subset of TNBC.
- Brain tumors. The McAllister-Lucas laboratory's newest research program focuses on the role of MALT1 in the pathogenesis of gliomas. This new program, led by team member Juliana Hofstatter Azambuja, Ph.D., investigates how MALT1 activity within the unique brain tumor immune microenvironment impacts disease progression. Recent preclinical studies suggest that pharmacologic inhibition of MALT1 protease holds promise as a new and effective approach to abrogating immune suppression in the brain tumor microenvironment.
Significance to patient care
Dr. McAllister expects that her team's research will offer an important new understanding of how the molecular changes that occur within cancer cells and within the surrounding cells of the tumor microenvironment affect cancer progression. The ultimate goal of her research is to use this new understanding to help develop more effective and safer therapies for hard-to-treat cancers.
Professional highlights
- Elected member, American Pediatric Society, 2015-present.
- Elected member, The American Society of 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 member, Society of Pediatric Research Council, 2020-2023.
- Wheeler Family Charitable Foundation Endowed Chair, University of Pittsburgh School of Medicine, 2019-2023.
- Chief, Division of Pediatric Hematology Oncology, University of Pittsburgh School of Medicine, 2012-2023.
- Normal J. Siegel Outstanding Science Award, American Pediatric Society, 2015.
- Associate director, Medical Scientist Training Program, University of Michigan Medical School, 2011-2012.
- Doris Duke Clinical Scientist Development Award, 2002-2007.