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- Uncovering novel mechanical cell competition regulatorsPublication . Ferreira-Pinto, M.A.; Lampaya, Eduardo Moreno; Aguilar Aragón, Mario Alberto; Zilhão, RitaMechanical cell competition (MCC) is a quality control mechanism that regulates organ development and cancer growth. Despite separate publications showing the importance of mechanical forces and cell competition in biology, how these two processes are intertwined is still unclear. To study MCC, we used a well-established Drosophila pupal model of notum epithelium development where mechanical stress generated by increased tissue crowding triggers competition between cells with different mechanical resistance properties. Mechanical-resistant cells (winners) outcompete mechanical-sensitive cells (losers), largely through the downregulation of Egfr/Erk signalling and activation of the cell death regulator head involution defective (hid), ensuring losers’ elimination and preventing notum developmental defects. However, the MCC regulators found thus far do not explain the entire process, and how cells can sense and respond to high levels of mechanical stress remains unclear. Likewise, we set out to find new MCC regulators. We performed an unbiased genetic screen in the Drosophila notum and identified 47 potential MCC-regulating genes that could be studied in future experiments. We characterized the role of two promising candidates, roughest (rst) and hibris (hbs). Rst and Hbs cell adhesion proteins are selectively expressed in cells outside the midline (where elimination is low) and depleted in cells inside the midline (where elimination is high). Downregulating them or overexpressing hbs in the entire pupal notum prevents loser cells’ elimination inside the midline region. Inducing cell clones downregulating rst/hbs outside the midline region, where normally these genes are expressed, induces loser cells elimination. We also saw that Egfr can regulate Hbs but not Rst expression in most cells but not all. Altogether, our results suggest that Rst and Hbs might regulate MCC in a new cell competition mechanism, dependent or independent of Egfr/Erk signalling. Our work could ultimately lead to novel translational studies targeting rst and hbs in MCC and cancer.
- Sustained macrophage reprogramming is required for CD8+ T cell–dependent long-term tumor eradicationPublication . Jardim, Carolina; Bica, Marta; Reis-Sobreiro, Mariana; Mota, Afonso Teixeira da; Lopes, Raquel; Ferreira-Pinto, Miguel Alexandre; Sousa, Neuza S.; Mensurado, Sofia; Boekhoff, Henning; Scolaro, Tommaso; Reugebrink, Maud; Gonçalves-Sousa, Natacha; Kubo, Hiroshi; Leites, Elvira; Morais, Vanessa A.; Silva-Santos, Bruno; Barbosa-Morais, Nuno; Serre, KarineTumor-associated macrophages (TAM) exhibit a dual role in tumor progression and antitumor immunity. However, understanding the functional states and molecular mechanisms of antitumor TAMs remains a challenge. Herein, we show that intratumoral administration of a combination of agonists against TLR3 and CD40 [hereafter termed myeloid cell treatment (MCT)] reprogrammed TAMs in situ to adopt a protective antitumor phenotype in an orthotopic mouse breast cancer model, and that this led to tumor regression. Single-cell RNA sequencing of TAMs from different tumor stages and after MCT revealed a transient antitumor TAM phenotype, present at 12 hours after MCT and characterized by markers such as inducible nitric oxide synthase and CD38, which was replaced by TAMs coexpressing tumor-limiting and tumor-promoting features by 72 hours after MCT. Maintenance of antitumor TAMs required repeated MCT administration, and this promoted the activation of CD8+ T cells and long-term tumor eradication. Mechanistically, reactive oxygen species and TNF-α were pivotal in TAM-mediated tumor control. Our findings uncover the vulnerability of transient TAM reprogramming and show that it can be overcome by repeated MCT administrations to sustain efficient antitumor immune responses.