Challenges and opportunities in 2021

viewpoint Challenges and opportunities in 2021 Twelve early-career investigators share their thoughts on the challenges faced by their teams and communities during the past year, and look ahead to new opportunities for 2022. Leila Akkari, Stacey D. Finley, Ping-Chih Ho, Misty Jenkins, Barbara B. Maier, Nicholas McGranahan, Miriam Mutebi, Rushika M. Perera, Carla Daniela Robles-Espinoza, Santosha Vardhana, Liling Wan and Meng Michelle Xu Leila Akkari: plasticity — where challenges and solutions lie Choosing a career in academic research always involves the development of a remarkable capacity to accept challenging situations and adapt to them, whether it is when planning and performing experiments or building novel lines of research as a junior principal investigator (PI). It involves passion, commitment and patience — in all steps of this journey, we grow, learn and evolve. This process of growth and change is not unlike the one observed within tumors, in which the plasticity of tumor and immune cells is a crucial source of heterogeneity underlying the dynamic features of malignancy. Tumor-associated macrophages (TAMs), the most abundant immune cells in nearly all solid cancers, exhibit a beguiling level of versatility. This past year further revealed the layers of complexity underlying TAM heterogeneity, ontogeny and education, which we now appreciate are far from static and orchestrated in a tumorand tissue-specific manner. TAMs co-evolve with cancer cells often to the advantage of the tumor — all thanks to the tremendous plastic nature of what are, originally, housekeeper cells of organ homeostasis. This hallmark of macrophage biology is now at the core of myeloid checkpoint blockade approaches and the therapeutic potential may be tremendous, although several challenges remain in understanding how to best equip these cells to boost anti-tumor immunity rather than support malignancy. Thus, enduring harsh environments requires plasticity, which, in the case of macrophages, often leads to thriving. This concept very much applies to our experience of the past 18 months, when we had to wield a lot of flexibility to keep 1278 ourselves sane, physically and mentally healthy and somewhat productive. These unprecedented challenges fostered different forms of bounds — more focused, personal and caring. We appreciated that that every lab member had different needs to cope with the sudden halt of regular lab life. To support each other, we made use of online casual meetings and remote celebrations, and kept a more attentive eye to each other’s mindsets and vulnerabilities. It took time, but altogether this experience allowed us to grow into a more united and efficient group. It taught us that we could still be scientists without being at the bench all day; and in the case of early-career PIs, such as myself, it showed that being a leader did not only entail directing the pace of our research, but also keeping the team connected and reassured. Consequently, we forged forward and grew scientific networks enriching our research questions, taking more time to think and discuss, while slowly re-initiating experiments. The resilience we had to build will eventually be a formidable asset to the careers of the next generation of scientists, and we now relish the simple joys of sharing lunches and coffees, strengthened by the challenges we turned into opportunities. Stacey D. Finley: resilience in research and life I work in the area of computational systems biology, leading a research group that develops mechanistic mathematical models. My group applies such models to answer unresolved questions about how cells behave, and to identify new ways to control their behavior. We particularly look to these models to help us better understand pathological conditions, with a focus on predicting tumor growth and response to treatment. Collectively, we are engineers and computational biologists that get really excited about modeling approaches that allow us to generate new insights about biological systems. Understandably, excitement about my science has waxed and waned over the past 18 months. I readily admit that leading a research group during a global pandemic has been hard. As a group, we faced health challenges, experienced the loss of loved ones, dealt with mental health issues and handled dependent-care responsibilities, all while trying to make progress towards research and career goals. More personally, it has been hard to lead my research group while managing home life that includes a spouse who is also in academia and three young children. Additionally, as a Black woman in the United States, I acutely felt the burden of the racial unrest in this country. At one point, the goal became to just make it through 2020. Then I realized that many of the difficulties from last year would (literally and figuratively) bleed into 2021. At the same time, I am prouder of myself and my trainees than I have ever been. We have displayed great strength, fortitude and courage. We grew together as a group and worked to sustain a welcoming and healthy lab culture. We talked about diversity and equity issues that individuals from minoritized groups face. For the first time, we connected with cancer patient advocates, who give purpose and urgency to our research. We also celebrated amazing feats this year — three PhD students graduated in the spring (all now gainfully employed!), two students passed their qualifying exams and an undergraduate researcher submitted a first-author paper, just to name a few. The circumstances of 2021 magnified the highs and lows of leading a research group, but it allowed me to witness firsthand how resilient we can be. As a perennially optimistic person, I believe that both the difficulties and successes of this year will propel us to greater heights. Nature Cancer | VOL 2 | December 2021 | 1278–1282 | www.nature.com/natcancer viewpoint Ping-Chih Ho: metabolic crosstalk in the tumor microenvironment Our understanding of immunometabolism and how the metabolic stress imposed by the tumor microenvironment (TME) disarms anti-tumor immunity has increased dramatically in recent years. Building on the lessons we learned from the success and failure of cancer immunotherapies, including checkpoint blockade and cell therapy, we now enter a new era of unraveling the complexity of metabolic crosstalk between immune, stromal and tumor cells in the TME. Although, we gained a tremendous understanding of how metabolic stress imposed by the TME hampers anti-tumor functions and orchestrates differentiation of tumor-infiltrating T cells and natural killer cells by perturbing their metabolic program, it remains challenging to therapeutically target metabolic machineries in cancer cells and alleviate the microenvironmental stress. Adapting engineered cell therapies, including T cell receptors and CAR-T cells, by rewiring their metabolic program may allow immune cells to better handle (...truncated)