Jim McCarthy’s career reflects the rise and value of PhD scientists in pathology

There are lots of stories about how established biomedical scientists have influenced college graduates who are pursuing a career in the field.  In the case of LMP professor Jim McCarthy, who is retiring this month, two fortuitous encounters were coupled with superb timing: The rapid rise of the PhD scientist in academic pathology starting around 1980, and the beginning of what became a surge in research on the extracellular matrix (ECM). 

The ECM forms a three-dimensional network of proteins, glycoproteins, and polysaccharides that surrounds cells.  It provides mechanical stability and maintains tissue architecture. Extensive research has revealed that ECM composition is unique for each tissue, and the components are critically important for allowing each tissue to perform its function. 

It turns out that ECM is a lot more than a structural support network, as we will see.

A Connecticut native, McCarthy attended Susquehanna University (Selinsgrove, PA) as an undergraduate biology major and earned a PhD in microbiology and immunology from Catholic University of America in Washington, DC in 1981. During his doctoral studies, McCarthy worked in the immunology laboratory of Sharon Wahl at the National Institute of Dental Research (NIDR), a leading investigator exploring the role of inflammation in periodontal disease.  Wahl’s research clearly demonstrated that inflammation, which is important for fighting infections, can also lead to the destruction ECM in tissues. While at NIDR, McCarthy met George R. Martin, who was a section laboratory chief at NIDR. Martins’ focus at the time was on identifying ECM structural proteins such as collagens and understanding the role they play in normal and diseased tissue functions. As McCarthy was completing his graduate thesis, Martin suggested he contact Leo Furcht, then an associate professor at the University of Minnesota who was doing research on other ECM components, such as laminin and fibronectin.

Prior to 1980, faculty in academic pathology departments were physician-scientists.   There were few PhD scientists.  McCarthy’s hiring by the University’s Department of Laboratory Medicine and Pathology (LMP) in 1981 coincided with the beginning of a steep growth trend in those numbers.   Today, a quarter of faculty in academic pathology departments are PhD scientists, reflecting the incorporation of basic research into anatomic and clinical pathology. “It’s a brand-new dimension,” McCarthy said.  “It’s allowed PhD scientists to contribute to the study of disease diagnosis and therapy, and it has enriched physician scientists in pathology departments and enabled them to move fields of discovery forward toward clinical application.  It’s a terrific collaboration between the two areas.”

As the table above shows, when McCarthy joined the laboratory of physician-scientist Leo Furcht, studies of ECM were about to take off.  “George Martin was fundamentally involved in taking apart and characterizing ECM components and structures,” McCarthy said. “He was the first to identify a protein called laminin, which is a protein in basement membranes—thin, dense sheets of ECM that are used by the body to define boundaries between different tissue types. Laminin is very important for the structure of those membranes and how they function.” 

ECM:  Conducting a cellular symphony 

What many regarded as merely a physiological ‘filler material’ and a ‘research backwater topic' soon came to the fore. ECM has been described as a “multitasking marvel.”  One of its virtues is its variability.  Its composition of fibrous proteins, carbohydrates, and water has countless variations depending on the function of a given body part.  ECM is a dynamic, physiologically active component of all our tissues.

“People would ask at the time, what does ECM have to do with disease?” McCarthy said.  “The fact is, ECM has everything to do with disease.”  

At the time (early 80’s and 90’s), it was known that ECM is important for maintaining tissue architecture and structure. However, studies also started to reveal how critical it is at regulating how cells in the body depend on the ECM for regulating their normal function. “These studies led to the idea that it isn’t just an inert interaction – that cells just ‘stick’ to these structural proteins—rather that there’s biological information in the ECM,” McCarthy said.  “It became clear that cells can ‘sense’, and get information from, the ECM which causes them to act accordingly. In the case of tissue damage, inflammation, and fibrosis, cells may make proteases [enzymes that break down proteins] or make new ECM components to repair damaged tissue. Cell-ECM interactions also lead to activation of cellular growth pathways, which can help replenish cells within damaged tissues.”

The bottom line, McCarthy said, is that “ECM is critically important for how tissues form, how they function, and how they fail to function when the matrix is damaged/disorganized and cells lose the information they need to maintain normal tissue function.”   

Some ECM proteins, particularly the different forms of collagen, had been well studied at the time McCarthy began his research career.  One that had not was fibronectin, a circulating protein found in blood serum plasma and in many tissues of the body.  It was the first protein studied for its ability to promote cell adhesion and alter their behavior. When scientists first purified fibronectin, put it on a culture dish and put cells on top, the cells would stick to it and then begin to move across it, revealing that fibronectin contains cell-signaling information. Investigators would subsequently identify key peptides—short chains of amino acids in the complex protein molecule—that are responsible for the signaling.  It would become evident that disease is a dysfunction involving both cells and ECM, but there was still work do.

“When I came to the lab, monoclonal antibodies had just been introduced,” McCarthy said.  “Leo was using them to map out the biologically active domains of fibronectin, domains that bind the cells. Leo and his graduate student used monoclonals to take these regions of fibronectin apart and map them out on the fibronectin molecule.”  These experiments laid the groundwork for the subsequent identification of specific peptides (strings of amino acids) in fibronectin and other ECM molecules that are responsible for promoting cell adhesion, differentiation, and cell migration. These structures are known to bind multiple types of cellular receptors (known as integrins or cell surface proteoglycans), which transmit information into cells to regulate their behavior.  It became apparent that ECM components conduct a sort of cellular symphony, a symphony that keeps us healthy -- until it goes out of tune. Furcht’s lab was in the middle of it all.

An eye for emerging technologies

PhD scientists are key for implementing advanced technologies in biomedical research.  That McCarthy joined Leo Furcht’s laboratory when he came to Minnesota in 1981 was fortunate because Furcht had a sharp eye for emerging technologies that could be adopted for advancing biomedical research.  “One of Leo’s strengths was his knack for identifying key emerging technologies,” McCarthy said.  “He was always talking to people from diverse areas of research, clinical practice, and technology. 

“He could understand how things can move forward based on those discussions, on how he thinks about pathology. He has a sense of how technology will develop moving into the future, he said, adding that there are many examples of his adopting new technologies “to dissect the complexities of normal tissue function and disease.”

McCarthy cites LMP's recent initiatives in spatial transcriptomics and digital pathology / artificial intelligence (AI) as recent examples of Furcht's foresight.

For McCarthy himself, the most amazing laboratory technology is the CRISPR/Cas 9 gene editing system, a system discovered in bacteria that use it as a molecular defense against viruses, a system that is now being used to save people’s lives.  “Understanding the mechanisms involved in this shuttling of DNA that are involved in clipping DNA and stitching it back together, that’s a game changer, McCarthy said. “Now that we can take a given gene that we want to study and take it out or put it in and ask questions about what that does to a cell.” 

Identifying and tracking a cell-surface molecule in cancer

As noted above, McCarthy’s studies focused on how cells interact with ECM components.  “In the case of cancer, how does that gene influence the ability of cancer cells to invade and metastasize?  My early studies identified a cell-surface receptor on melanoma cells, termed CSPG4 (chondroitin sulfate proteoglycan 4), that promoted their adhesion and motility to fibronectin coated on cell culture dishes.” Over the years, McCarthy demonstrated that CSPG4 expression and function also stimulated melanoma cell invasion and metastasis in animal models of cancer.

“What was unexpected is that CSPG4, which we first identified many years ago on melanoma cells, is also found on multiple types of tumor cells and appears to be important for also stimulating their malignant potential,” he said.

McCarthy was senior author of a 2021 study that identified CPSG4 as an independent risk factor and predictor of poor outcomes for patients with multiple types of ovarian cancer.   Along with other technologies, the investigators used CRISPR/Cas9 to knock out CPSG4 in human ovarian cancer cell lines. Deleting CSPG4 expression using CRISPR/Cas9 decreased tumor cell invasion, tumor growth in animals, and promoted increased sensitivity to chemotherapy. Targeting tumors that express CPSG4, the authors concluded, could improve outcomes for patients.  “The idea is, if you can reduce the level of CPSG4-positive cells in a patient, you could push the patient into a more favorable prognosis,” McCarthy said. 

Towards this end, collaborative work is underway with Jeffrey Miller and Martin Felices of the Masonic Cancer Center to use natural killer (NK) cells to target ovarian cancer cells that express CPSG4. “We have utilized an animal model system that supports the idea that we can take antibodies against CSPG4 that we’ve designed, pair them up with NK cell activation pathways, and improve the survival of animals that are carrying ovarian cancer,” McCarthy said.  “Jeff and Martin have developed the NK cell tumor-targeting technology from the ground up.  So, this is Minnesota born and raised.”

Technology transfer and trainees

Technology transfer is commonly understood as the moving of scientific findings, knowledge, and intellectual property from creators—such as universities, research institutions, or federal labs—to public or private users.  But technology transfer also occurs in education, in the use of tools by educators and mentors.  In the case of cutting-edge biomedical research, especially where it interacts with information systems and software, now and then it’s the students and trainees who do the transfer.

“These new technologies are continuously developing,” McCarthy said.  “Trainees, through their coursework, (which has also obviously changed over the years) can bring these technologies into their research projects.  I may not fully understand these technologies at first, but they bring them in and suggest different approaches, which I’m in favor of them doing. It’s all about looking at problems and suggesting new ways to solve them.”

That attitude has paid dividends for McCarthy, as his experience with his last trainee illustrates.  Allison RK Macaulay was lead author along with then Medical School Dean Jakub Tolar of a 2024 paper studying tumors from patients with a rare genetic skin-blistering disorder called Recessive Dystrophic Epidermolysis Bullosa (RDEB). Tolar is a leading researcher in developing treatments for RDEB. Patients with RDEB are unable to make one of the collagens present in skin ECM, which leads to extensive blistering and disfiguring skin wounds. In addition to their other problems, these patients are at high risk for developing squamous cell carcinoma cancers at the REDB wound sites. 

“What Allison did with Tolar was to identify the same melanoma and ovarian cancer-associated CSPG4 molecule is also expressed in RDEB squamous cell carcinomas,” McCarthy said.  She demonstrated that, as with other tumors, CSPG4 functioned to promote the invasive and malignant potential of these patient tumor cells.”   

As is the case with the CSPG4 immune targeting studies in ovarian cancer, “CSPG4 in RDEB squamous cell carcinomas could also be targeted someday by immunotherapy,” McCarthy said. “The RDEB study did a great job of identifying the molecule and included collaborators from LMP.” [McCarthy, his lab lead Matt Price, and LMP associate professor Alessio Giubellino, a dermatopathologist].   

Macaulay was his McCarthy’s last trainee, and the experience “couldn’t have been more rewarding,” he said.

Pathology is a complex area with different subspecialities, McCarthy said, reflecting on his 45 years as a departmental research scientist.  “Because of the highly collaborative way in which the clinical and molecular expertise within LMP has been structured, our ability to contact somebody who has expertise in the complexities of a particular disease and associated tissues allows us to refine the questions we want to ask at a molecular level. 

“Moving forward, it is this organization that will continue to support our ability to develop better diagnostics and therapy for patients.”