Functional reprogramming of tumor-associated macrophages (TAMs) is crucial to their potent tumor-supportive capacity. However, the molecular mechanism behind the reprogramming process remains poorly understood. Here, we identify engulfment and cell motility protein 1 (ELMO1) as a crucial player for TAM reprogramming in colorectal cancer (CRC). The expression of ELMO1 in stromal but not epithelial tumor cells was positively associated with advanced clinical stage and poor disease-free survival in CRC. An increase in ELMO1 expression was specifically found in TAMs, but not in other multiple nonmalignant stromal cells. Gain- and loss-of-function assays indicated ELMO1 reprogrammed macrophages to a TAM-like phenotype through Rac1 activation. In turn, ELMO1-reprogrammed macrophages were shown to not only facilitate the malignant behaviors of CRC cells but exhibited potent phagocytosis of tumor cells. Taken together, our work underscores the importance of ELMO1 in determining functional reprogramming of TAMs and could provide new insights on potential therapeutic strategies against CRC.

Frailty, a common, multifaceted, and significant geriatric condition, involves crucial roles of inflammation and metabolic factors in its onset and progression. Nevertheless, the ambiguities and complexities in earlier observational studies make current research into their interactions somewhat insufficient. Our goals were to clarify the causal link between inflammatory cytokines and frailty and to explore the potential mediating effect of metabolites using Mendelian randomization (MR) analysis. Utilizing detailed summary-level data from genome-wide association studies, we conducted two-sample Mendelian randomization analyses to evaluate the potential causal connection between 91 inflammatory cytokines and the frailty index, along with the possible mediating pathways that involve 1400 metabolites. For our main analysis, we applied the inverse variance weighted method. To evaluate the potential mediating pathways of metabolites, a two-step MR analysis was utilized. We identified 8 inflammatory cytokines that were genetically associated with the frailty index, we subsequently identified 2 mediated relationships, with 2 metabolites acting as potential mediators between 2 inflammatory cytokines and frailty index. The 8 inflammatory cytokines were fractalkine (CX3CL1), interleukin-33 (IL-33), leukemia inhibitory factor receptor (LIF-R), monocyte chemoattractant protein-1 (CCL8), CC motif chemokine 4 (CCL4), C-X-C motif chemokine 10 (CXCL10), fibroblast growth factor 5 (FGF-5), and TNF-beta (TNFB) levels. The findings of this study demonstrate a direct connection between inflammatory cytokines and the frailty index, as well as two pathways mediated by metabolites. These biomarkers contribute valuable insights into the foundational mechanisms of frailty, presenting a novel research avenue for upcoming clinical studies.

Although observational studies have revealed a link between frailty and serum micronutrient levels, it remains unclear whether these 2 states are directly connected. Thus, Mendelian randomization (MR) was used to investigate the causal relationship between frailty and blood micronutrient levels. Summary-level data for 15 blood micronutrients (copper, selenium, zinc, calcium, iron, magnesium, potassium, folate, carotene, vitamin A, vitamin B6, vitamin B12, vitamin C, vitamin D, and vitamin E) were obtained from people of European ancestry from the Integrative Epidemiology Unit. Single nucleotide polymorphisms associated with the frailty index were extracted from a published meta-analysis study in the UK Biobank and Swedish TwinGene. We used the inverse variance weighted (IVW) method for the primary analysis. We employed pleiotropy residual sum and outlier (MR-PRESSO) tests, MR-Egger intercepts, Cochran Q tests, and leave-one-out analysis to assess causality validity and robustness. Reverse MR analysis was used to determine reverse causation. The IVW results revealed that vitamin D (odds ratio [OR] = 1.096; 95% confidence interval [CI]: 1.019–1.178; P = .014) increased the likelihood of a high risk of frailty, whereas the frailty index had a protective effect on selenium (OR = 0.622; 95% CI: 0.396–0.977; P = .039), carotene (OR = 0.916; 95% CI: 0.858–0.979; P = .009), vitamin C (OR = 0.895; 95% CI: 0.837–0.957; P = .001), iron (OR = 0.921; 95% CI: 0.859–0.988; P = .022), and vitamin E (OR = 0.907; 95% CI: 0.847–0.971; P = .005). The reverse IVW analysis revealed no significant correlation between micronutrient levels and frailty indices. The study revealed causal links between vitamin D and the risk of frailty. Notably, our findings highlight the necessity of adjuvant vitamin D in frailty management.

N6-methyladenosine (m6A) modification serves as a crucial regulator of diverse biological processes and disease progression. A central player in m6A regulation is YT521-B homology domain family member 2 (YTHDF2), a well-characterized m6A-binding protein primarily involved in mRNA stabilization. This study identifies lysine 542 (K542) as a critical acetylation site on YTHDF2, regulated by p300 as the acetyltransferase and SIRT2 as the deacetylase. Notably, while K542 acetylation has minimal effects on YTHDF2's protein stability or subcellular localization, it significantly enhances the protein's binding affinity for m6A-modified mRNAs. This enhanced binding affinity has profound biological implications, as K542 acetylation promotes malignant phenotypes in colorectal cancer (CRC) cells in vitro and in vivo. Supporting its clinical relevance, analysis of CRC tissues reveals elevated levels of YTHDF2 acetylation in primary tumors, strongly associating this modification with CRC pathology. Collectively, these findings highlight K542 acetylation as a key enhancer of YTHDF2's m6A recognition and a critical driver of its oncogenic activity.

Background Functional reprogramming of tumor-associated macrophages (TAMs) is crucial to their potent tumor-supportive capacity. However, the molecular mechanism behind the reprogramming process remains poorly understood. This work aimed to investigate the involvement of engulfment and cell motility protein 1 (ELMO1) in TAM reprogramming in colorectal cancer (CRC).Methods The expression of ELMO1 in CRC was determined by western blots and immunohistochemistry. The biological effects of ELMO1 on TAM reprogramming were evaluated in vitro. The dependence of these effects on Rac1 was assessed using a Rac1 inhibitor (NSC23766). Cell function assays were performed to determine the role of ELMO1-reprogrammed macrophages in the context of CRC progression.Results The expression of ELMO1 in stromal but not epithelial tumor cells was positively associated with advanced clinical stage and poor disease-free survival in CRC. An increase in ELMO1 expression was specifically found in TAMs, but not in other multiple non-malignant stromal cells. Gain- and loss-of-function assays indicated ELMO1 reprogrammed macrophages to a TAM-like phenotype via Rac1 activation. In turn, ELMO1-reprogrammed macrophages were shown to not only facilitate the malignant behaviors of CRC cells but exhibited potent phagocytosis of tumor cells.Conclusion ELMO1 was shown to be a crucial player for TAM reprogramming in CRC. Our work underscores the importance of ELMO1 in determining functional reprogramming of TAMs and may provide new insights on potential therapeutic strategies against CRC.