Asymmetric division of stem cells and its cancer relevance.

Asymmetric division is a fundamental process for generating cell diversity and maintaining the stem cell population. During asymmetric division, proteins, organelles, and even RNA are distributed unequally between the two daughter cells, determining their distinct cell fates. The mechanisms orchestrating this process are extremely complex. Dysregulation of asymmetric division can potentially trigger cancer progression. Cancer stem cells, in particular, undergo asymmetric division, leading to intra-tumoral heterogeneity, which contributes to treatment refractoriness. In this review, we delve into the cellular and molecular mechanisms that govern asymmetric division and explore its relevance to tumorigenesis.

Targeting intratumor heterogeneity suppresses colorectal cancer chemoresistance and metastasis.

Intratumor heterogeneity (ITH) is a barrier to effective therapy. However, it is largely unknown how ITH is established at the onset of tumor progression, such as in colorectal cancer (CRC). Here, we integrate single-cell RNA-seq and functional validation to show that asymmetric division of CRC stem-like cells (CCSC) is critical for early ITH establishment. We find that CCSC-derived xenografts contain seven cell subtypes, including CCSCs, that dynamically change during CRC xenograft progression. Furthermore, three of the subtypes are generated by asymmetric division of CCSCs. They are functionally distinct and appear at the early stage of xenografts. In particular, we identify a chemoresistant and an invasive subtype, and investigate the regulators that control their generation. Finally, we show that targeting the regulators influences cell subtype composition and CRC progression. Our findings demonstrate that asymmetric division of CCSCs contributes to the early establishment of ITH. Targeting asymmetric division may alter ITH and benefit CRC therapy.

Fusobacterium nucleatum Promotes Colorectal Cancer Cell to Acquire Stem Cell-Like Features by Manipulating Lipid Droplet-Mediated Numb Degradation.

Fusobacterium nucleatum is a critical microbe that contributes to colorectal cancer progression and chemoresistance. However, whether and how F. nucleatum regulates colorectal cancer stem-like cells (CCSCs) remains unknown. Here, the authors show that F. nucleatum promotes CCSC self-renewal, and non-CCSCs to acquire CCSC features by manipulating cellular lipid accumulation. F. nucleatum infection decreases lipid accumulation in CCSCs by enhancing fatty acid oxidation, thus promoting CCSC self-renewal. In contrast, F. nucleatum increases lipid accumulation in non-CCSCs by promoting fatty acid formation. Lipids are deposited as lipid droplets, which recruits Numb, a key cell fate regulator, through the AP2A/ACSL3 complex, and MDM2, an E3 ubiquitin ligase, though VCP and UBXD8. On lipid droplets, Numb is degraded by MDM2, activating Notch signaling, thus promoting gain of stem-like cell features. Their findings demonstrate that F. nucleatum directly manipulates colorectal cancer cell fate and reveal the mechanism of lipid droplet-mediated Numb degradation for activating Notch signaling.

miR-34a is a microRNA safeguard for Citrobacter-induced inflammatory colon oncogenesis.

Inflammation often induces regeneration to repair the tissue damage. However, chronic inflammation can transform temporary hyperplasia into a fertile ground for tumorigenesis. Here, we demonstrate that the microRNA miR-34a acts as a central safeguard to protect the inflammatory stem cell niche and reparative regeneration. Although playing little role in regular homeostasis, miR-34a deficiency leads to colon tumorigenesis after Citrobacter rodentium infection. miR-34a targets both immune and epithelial cells to restrain inflammation-induced stem cell proliferation. miR-34a targets Interleukin six receptor (IL-6R) and Interleukin 23 receptor (IL-23R) to suppress T helper 17 (Th17) cell differentiation and expansion, targets chemokine CCL22 to hinder Th17 cell recruitment to the colon epithelium, and targets an orphan receptor Interleukin 17 receptor D (IL-17RD) to inhibit IL-17-induced stem cell proliferation. Our study highlights the importance of microRNAs in protecting the stem cell niche during inflammation despite their lack of function in regular tissue homeostasis.

mTOR masters monocyte development in bone marrow by decreasing the inhibition of STAT5 on IRF8.

Monocytes and macrophages play a key role in defending pathogens, removing the dead cells or cell debris, and wound healing. The mammalian target of rapamycin (mTOR) inhibitor rapamycin (RPM) is widely used in clinics to treat patients with organ transplantation or tumors. The role of mTOR in monocyte/macrophage development remains to be clarified. Here we found that mTOR intrinsically controls monocyte/macrophage development, as evidenced by the decreased percentages and cell numbers of CD11b+F4/80+ cells resulting from mTOR inhibition in SCID mice, mTOR-deficient mice, and mixed chimera mice, and the in vitro colony formation and monocyte/macrophage induction assays. However, Lyzs-mTOR knockout mice displayed normal levels of monocytes/macrophages, indicating that mTOR is not essential for the survival and maturation of monocytes/macrophages. Further studies showed that mTOR deficiency significantly reduced macrophage colony-stimulating factor receptor CD115 expression at the transcriptional and translational levels. The molecular mechanism studies indicate that the impaired monocyte/macrophage development caused by mTOR deficiency is mainly a result of the overactivated STAT5 and subsequent downregulation of IRF8, but not the altered cell metabolism and autophagy. Therefore, our work identifies that mTOR is an intrinsic master for monocyte/macrophage development at the early stages through regulating STAT5-IRF8-dependent CD115-expressing pathway. Long-term usage of RPM may cause a defect of myeloid progenitors in bone marrow.