Metastasis is a well-known poor prognostic factor in cancer. However, the mechanisms how long non-coding RNAs (lncRNAs) regulate metastasis in colorectal cancer (CRC) remain largely unknown. Besides, tumor-associated macrophages (TAMs) play an important role in tumor progression, yet the contribution of lncRNA-mediated crosstalk between TAMs and CRC cells to tumor progression is not well understood. In this study, we report that lncRNA RPPH1 was significantly upregulated in CRC tissues, and the RPPH1 overexpression was associated with advanced TNM stages and poor prognosis. RPPH1 was found to promote CRC metastasis in vitro and in vivo. Mechanistically, RPPH1 induced epithelial–mesenchymal transition (EMT) of CRC cells via interacting with β-III tubulin (TUBB3) to prevent its ubiquitination. Furthermore, CRC cell-derived exosomes transported RPPH1 into macrophages which mediate macrophage M2 polarization, thereby in turn promoting metastasis and proliferation of CRC cells. In addition, exosomal RPPH1 levels in blood plasma turned out to be higher in treatment-naive CRC patients but lower after tumor resection. Compared to CEA and CA199, exosomal RPPH1 in CRC plasma displayed a better diagnostic value (AUC = 0.86). Collectively, RPPH1 serves as a potential therapeutic and diagnostic target in CRC.

Conventional treatments for inflammatory bowel disease (IBD) have multiple potential side effects. Therefore, alternative treatments are desperately needed. This work demonstrated that systemic administration of exosomes from human bone marrow–derived mesenchymal stromal cells (MSC-Exos) substantially mitigated colitis in various models of IBD. MSC-Exos treatment downregulated inflammatory responses, maintained intestinal barrier integrity, and polarized M2b macrophages but did not favor intestinal fibrosis. Mechanistically, infused MSC-Exos acted mainly on colonic macrophages, and macrophages from colitic colons acquired obvious resistance to inflammatory restimulation when prepared from mice treated with MSC-Exos versus untreated mice. The beneficial effect of MSC-Exos was blocked by macrophage depletion. Also, the induction of IL-10 production from macrophages was partially involved in the beneficial effect of MSC-Exos. MSC-Exos were enriched in proteins involved in regulating multiple biological processes associated with the anticolitic benefit of MSC-Exos. Particularly, metallothionein-2 in MSC-Exos was required for the suppression of inflammatory responses. Taken together, MSC-Exos are critical regulators of inflammatory responses and may be promising candidates for IBD treatment.

Rationale: CD47 plays a vital role in the immune escape of tumor cells, but its role in regulating immune-unrelated biological processes such as proliferation and metastasis remains unclear. We seek to explore the immune-independent functions of CD47 in colorectal cancer (CRC).

Increasing studies indicated that circular RNAs (circRNAs) play important roles in cancer progression. However, the roles of circRNAs in colorectal cancer (CRC) remain largely unknown. In this study, we determined the circRNA expression profile by next-generation RNA sequencing from eight CRC and paired non-cancerous matched tissues. circCAMSAP1 (originating from exon 2 to exon 3 of the CAMSAP1 gene, hsa_circ_0001900) was significantly upregulated in CRC tissues. Increased circCAMSAP1 expression was significantly correlated with advanced tumor/node/metastasis (TNM) stage and shortened overall survival. An elevation of circCAMSAP1 expression was detected via droplet digital PCR in the serum of CRC patients prior to surgery. Functionally, circCAMSAP1 promoted the malignant behavior of CRC. Mechanism study of upstream biogenesis of circCAMSAP1 indicated that circCAMSAP1 cyclization in CRC was mediated by splicing factor epithelial-splicing regulatory protein 1. Moreover, circCAMSAP1 acted as a sponge for miR-328-5p and abrogated its suppression on transcription factor E2F1. Taken together, our data indicated an essential role of the circCAMSAP1/miR-328-5p/E2F1 axis in the progression of CRC, which implied that circCAMSAP1 could serve as a diagnostic and prognostic biomarker as well as a potential therapeutic target for CRC.

Histone lactylation is a novel epigenetic modification derived from lactate, but its role and mechanism in KRAS mutant colorectal cancer (CRC) progression remains to be fully elucidated. In this study, we first showed that mutant KRAS increased H3 lysine 9 lactylation (H3K9la) to promote CRC progression. We found that KRAS-mutant CRC tissues and cell lines exhibited higher lactylation and H3K9la levels compared to KRAS wild-type counterparts, driven by increased intracellular lactate. Elevated lactylation and H3K9la levels were associated with poor prognosis and advanced clinical stages. Inhibition of lactylation and H3K9la suppressed proliferation and migration of CRC cells. Mechanistically, mutant KRAS upregulated GRAMD1A expression by elevating H3K9la levels to increase chromatin accessibility. And increased GRAMD1A facilitated cholesterol metabolism to promote CRC growth and metastasis. Targeted inhibition of H3K9la or GRAMD1A reduced tumor growth in CRC patient-derived xenografts (PDX) models. Our study uncovered the critical role of H3K9la as a novel epigenetic modification in KRAS mutant CRC progression, suggesting H3K9la and its downstream gene GRAMD1A as promising targets for therapeutic intervention in KRAS mutant CRC and potential biomarkers for the prognosis of CRC patients.

Nutritional factors play crucial roles in immune responses. The tumor-caused nutritional deficiencies are known to affect antitumor immunity. Here, we demonstrate that pancreatic ductal adenocarcinoma (PDAC) cells can suppress NK-cell cytotoxicity by restricting the accessibility of vitamin B6 (VB6). PDAC cells actively consume VB6 to support one-carbon metabolism, and thus tumor cell growth, causing VB6 deprivation in the tumor microenvironment. In comparison, NK cells require VB6 for intracellular glycogen breakdown, which serves as a critical energy source for NK-cell activation. VB6 supplementation in combination with one-carbon metabolism blockage effectively diminishes tumor burden in vivo. Our results expand the understanding of the critical role of micronutrients in regulating cancer progression and antitumor immunity, and open new avenues for developing novel therapeutic strategies against PDAC. Significance: The nutrient competition among the different tumor microenvironment components drives tumor growth, immune tolerance, and therapeutic resistance. PDAC cells demand a high amount of VB6, thus competitively causing NK-cell dysfunction. Supplying VB6 with blocking VB6-dependent one-carbon metabolism amplifies the NK-cell antitumor immunity and inhibits tumor growth in PDAC models. This article is featured in Selected Articles from This Issue, p. 5