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JOYCE JOHANNA LAUSANNE LUDWIG Photo by Gilles Weber 12 THE TUMOR ECOLOGIST Her ongoing investigation of how noncancerous cells in the microenvironment of tumors contribute to malignant growth, drug resistance and metastasis is also revealing how such relationships might be disrupted to treat cancer. Johanna Joyce was puzzled. The cause of As Joyce and her team reported in Nature her befuddlement: positive results from an Medicine in 2013, the glioma cells were experiment in a mouse model of glioma, an producing factors that helped macrophages aggressive brain cancer. survive the therapy. But the loss of the receptors’ signal, rather than killing the The year was 2012, and it was already tumor-associated macrophages (TAMs), known that macrophages—immune cells had “reeducated” them, altering their gene that ordinarily gobble up cancer cells and expression programs to convert them back infectious agents—often turn traitor, multiply into cancer cell gourmands. within tumors and drive cancer progression. Joyce, who was at Memorial Sloan Kettering That study, with its scientific and Cancer Center (MSK) at the time, wanted therapeutic implications, put the Joyce to see what would happen if such turncoat laboratory on the map of tumor biology. macrophages in gliomas were targeted with In the years since, she and her lab have an inhibitor of the CSF-1 receptor (CSF-1R), continued to expose the intricate interplay whose activity is normally essential to their between cancer cells and a motley crew survival. of noncancerous cells in the tumor microenvironment. In 2017, she and her “The results were striking,” says Joyce, team at Ludwig Lausanne reported in who joined the Ludwig Branch in Lausanne, Oncogene how macrophages help gliomas Switzerland, in 2016, where she is a Member. resist targeted drug therapy and how such “Even after treatment of just one week, we resistance might be overcome with CSF-1R saw a pretty dramatic regression of the inhibition. Another Joyce lab publication in tumors.” But what puzzled her was that the Cell Reports described a similar macrophage tumors were still teeming with macrophages. role in chemotherapy resistance. Finally, a 13 “It was teaching as teaching should be done. They taught us how to think about science through stories of how the discoveries happened. That made it so fascinating that you just wanted to learn more and more.” Nature Cell Biology publication elucidated Joyce’s honors thesis at Trinity, on genomic how obesity, through its effects on another imprinting—the regulation of a subset of type of immune cell, the neutrophil, drives genes depending on which parent they’re the spread of breast tumors to the lungs. inherited from—led directly to doctoral research in clinical genetics at Cambridge Student days University, in the laboratory of Paul Schofield. When Joyce was 14 years old, her parents There she explored how the faulty regulation moved her and her four younger siblings of imprinted genes causes Beckwith- from London to a farm they bought outside Wiedemann syndrome, which predisposes Dublin. Joyce’s omnivorous appetite for children to cancer. science intensified under the influence of the teachers at her new school— Into the microenvironment particularly, she recalls, an enthusiastic An urge to go beyond cancer genetics chemistry instructor named Mr. Bennett. and plunge deeper into the multicellular After finishing school, she enrolled in an complexity of cancer took Joyce to Douglas honors program in the natural sciences Hanahan’s laboratory, then at the University at Trinity College, in Dublin, where she of California, San Francisco, where she ultimately focused on genetics. “I thought started her postdoctoral studies in 1999. the inherent logic of it was quite beautiful,” Collaborating with the chemical biologist she says. Matthew Bogyo, Joyce explored how cathepsins—a family of protein-snipping The professors of genetics at Trinity, she molecular scissors—participate in multiple says, were the best teachers she ever aspects of pancreatic cancer progression. had. “They instilled in us an absolute love for genetics of all types,” she says. “It was Their studies also revealed that immune cells teaching as teaching should be done. are notably avid expressers of cathepsins. They taught us how to think about science “That early result,” says Joyce, “ultimately led through stories of how the discoveries me to focus on the roles of TAMs in cancer happened. That made it so fascinating that initiation, progression, invasion and response you just wanted to learn more and more, to therapy, and so it set the stage for the and enjoyed going to the classes so much. whole program that I developed in my own It’s something I try, to the extent I can, to lab in New York and that continues here in bring into how I teach my own students.” Lausanne.” 14 Photo by Eric Déroze After joining MSK in 2004, Joyce expanded about half of the gliomas in mice became her studies to investigate TAMs in breast resistant to the CSF-1R inhibitor and every cancer and, later, in gliomas, ultimately tumor that recurred did so in the context of leading to the Nature Medicine paper on a scar. “We identified a prominent and quite CSF-1R inhibition and TAM reprogramming. complex resistance mechanism involving many different cell types within these “That was a different way of thinking about treated lesions that ultimately led to the targeting the tumor microenvironment,” says reemergence of glioma cell proliferation and Joyce. “You don’t necessarily want to deplete invasion,” says Joyce. these and other immune cells in cancers because they have critical housekeeping Prolonged treatment with the anti-CSF-1R functions. But by re-educating them so that drug in the context of recurrent disease they can again execute those functions we prompted macrophages to adopt a wound could potentially get better therapeutic healing response. That includes secreting outcomes.” growth factors such as insulin-like growth factor-1 (IGF-1), which they do in response to Resolving resistance another factor (interleukin-4) produced by But would the effect last? Or would gliomas, infiltrating T cells of the immune system. IGF- among the wiliest of malignancies, develop 1, for its part, activates a signaling pathway resistance? in the cancer cells that drives their growth—a pathway mediated by a protein named PI-3 In a 2016 paper published in Science after kinase (PI3K). The CSF-1R resistance, the Joyce joined Ludwig Lausanne, she and researchers showed, could be overcome with her colleagues addressed those questions. drugs that block the receptor for IGF-1 or They found that after prolonged treatment, PI3K activity. Combining either with 15 Photo by Gilles Weber CSF-1R blockade extended survival in a susceptible to the cancer cell-targeted mouse model. inhibitors. Restorative interventions “We used the knowledge we had of Like many other cancers, gliomas are driven macrophages and of CSF-1R signaling in large part by the unbridled activity of a and inhibition to overcome this diverse and ubiquitous clan of signaling microenvironment-mediated resistance to enzymes known as tyrosine kinases. But therapy—something we and others are finding drugs that inhibit various kinases have had is extremely important to the efficacy of little or no effect on gliomas. Joyce and her multiple therapies in many different cancers,” team noticed, however, that tyrosine kinase says Joyce. inhibitors were nonetheless very effective in killing glioma cells in culture. “Whenever Indeed, she and her group had already shown you see something like that, it grabs your in 2011 that treating breast cancer with Taxol attention,” says Joyce. tends to boost TAM numbers, which drives resistance to chemotherapy. In 2017, her It suggested, for one thing, that the observed laboratory demonstrated in a Cell Reports drug resistance might stem from the tumor paper that macrophages also secrete factors microenvironment. In 2017, Joyce and her that interfere directly with Taxol’s effects on team reported in Oncogene that inhibiting cancer cells—which is to force an extended CSF-1R with a drug could restore sensitivity arrest during cell division that prompts their to other tyrosine kinase inhibitors in mouse suicide. TAMs, Joyce and her colleagues models. In this case, they showed, the found, shortened the duration of the mitotic reprogramming of TAMs by CSF-1R inhibition arrest induced by Taxol. They also showed was directly involved in making gliomas that inhibiting a signaling pathway involved 16 in this interference, mediated by a protein named MEK, could restore sensitivity to Taxol. “We have established Prep work some fantastic While at MSK, Joyce’s team had held joint meetings with the laboratory of Andrew collaborations with CHUV Dannenberg, a colleague at Weill Cornell Medical College in New York. Dannenberg and his team were interested in the link between to perform immune cell obesity and different cancers, including breast cancer; Joyce and her team were landscaping in every particularly intrigued by the effects of obesity on systemic inflammation and potential brain malignancy that connections to metastasis. With a shared expertise in TAMs, the is operated on in the researchers looked at the effects of obesity on these cells first. But they quickly hospital.” noticed that neutrophils—another type of immune cell—were more intimately linked to inflammation in the obese. “We found that in the normal lung, outside of the context be incorporated into the ambitious cancer

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