Heterogeneity of the tumor immune microenvironment and clinical interventions

The tumor immune microenvironment(TIME)is broadly composed of various immune cells,and its heterogeneity is characterized by both immune cells and stromal cells.During the course of tumor formation and progression and anti-tumor treatment,the composition of the TIME becomes heterogeneous.Such immunological heterogeneity is not only present between populations but also exists on temporal and spatial scales.Owing to the existence of TIME,clinical outcomes can differ when a similar treatment strategy is provided to patients.Therefore,a comprehensive assessment of TIME heterogeneity is essential for developing precise and effective therapies.Facilitated by advanced technologies,it is possible to understand the complexity and diversity of the TIME and its influence on therapy responses.In this review,we discuss the potential reasons for TIME heterogeneity and the current approaches used to explore it.We also summarize clinical intervention strategies based on associated mechanisms or targets to control immunological heterogeneity.

A miRNA-HERC4 pathway promotes breast tumorigenesis by inactivating tumor suppressor LATS1

The E3 ligase HERC4 is overexpressed in human breast cancer and its expression levels correlated with the prognosis of breast cancer patients. However, the roles of HERC4 in mammary tumorigenesis remain unclear. Here we demonstrate that the knockdown of HERC4 in human breast cancer cells dramatically suppressed their proliferation, survival, migration, and tumor growth in vivo, while the overexpression of HERC4 promoted their aggressive tumorigenic activities. HERC4 is a new E3 ligase for the tumor suppressor LATS1 and destabilizes LATS1 by promoting the ubiquitination of LATS1 miRNA-136-5p and miRNA-1285-5p, expression of which is decreased in human breast cancers and is inversely correlated with the prognosis of breast cancer patients, are directly involved in suppressing the expression of HERC4. In summary, we discover a miRNA-HERC4- LATS1 pathway that plays important roles in the pathogenesis of breast cancer and represents new therapeutic targets for human breast cancer.

Functions of p53 in pluripotent stem cells

Pluripotent stem cells(PSCs)are capable of unlimited self-renewal in culture and differentiation into all functional cell types in the body,and thus hold great promise for regenerative medicine.To achieve their clinical potential,it is critical for PSCs to maintain genomic stability during the extended proliferation.The critical tumor suppressor p53 is required to maintain genomic stability of mammalian cells.In response to DNA damage or oncogenic stress,p53 plays multiple roles in maintaining genomic stability of somatic cells by inducing cell cycle arrest,apoptosis,and senescence to prevent the passage of genetic mutations to the daughter cells.p53 is also required to maintain the genomic stability of PSCs.However,in response to the genotoxic stresses,a primary role of p53 in PSCs is to induce the differentiation of PSCs and inhibit pluripotency,providing mechanisms to maintain the genomic stability of the self-renewing PSCs.In addition,the roles of p53 in cellular metabolism might also contribute to genomic stability of PSCs by limiting oxidative stress.In summary,the elucidation of the roles of p53 in PSCs will be a prerequisite for developing safe PSC-based cell therapy.

A WNT7B-m^(6)A-TCF7L2 positive feedback loop promotes gastric cancer progression and metastasis

Dear Editor,Signal transduction takes the responsibility of translating extracellular information into specific cellular activities,enabling cells,including cancer cells,to respond exquisitely to extracellular guidance cues.N6-methyladenosine(m^(6)A),the most pervasive and abundant modification within eukaryotic mRNAs,is known to have specific effects on cellular activities relevant to cancer.1 Despite the fact that m^(6)A methylation is a dynamic event involving a series of enzymes,it remains unknown whether signal transduction,much less extracellular signaling molecules,uses m^(6)A methylation as an effector mechanism in cancer.