Root meristem controls: The plant meristem, a small cluster of stem cells generates all of the cell types necessary for the plant’s indeterminate growth pattern. Roszak et al . use single-cell analyses to follow development from the stem cell to the enucleated cell of the phloem vasculature. In the root of the small mustard plant Arabidopsis , this process takes just over 3 days, and the developmental trajectory spans more than a dozen different cell states. A transcriptional program initially held under repressive control is released as those initial repressors dissipate. Reciprocal repression by regulators early and late in the developmental trajectory control a rapid switch in the differentiation program. —PJH

Primary thyroid lymphomas comprise largely extranodal marginal zone lymphoma of mucosa‐associated lymphoid tissue (EMZL) and diffuse large B‐cell lymphoma (DLBCL), followed by follicular lymphoma (FL). They commonly develop from a background of Hashimoto's thyroiditis (HT), where dysregulated immune responses trigger autoreactive infiltrates and drive clonal B‐cell evolution. To understand how these lymphomas and their relapse evolve, we investigated 10 cases by mutation profiling, including five with metachronous lymphomas [primary lymphoma (EMZL = 4, DLBCL = 1) with local relapse (EMZL = 3, DLBCL = 2)], one composite EMZL and Epstein–Barr virus (EBV)‐positive DLBCL, and four lymphomas (EMZL = 3, FL = 1) with prior or subsequent biopsy showing HT. In four cases with metachronous lymphomas, both common and distinct variants were seen in the paired lesions, indicating their divergent evolution from clonally related lymphoma precursor (CLP) cells. In the remaining case with metachronous lymphomas, the relapsed lesion was progressed from the initial lymphoma. In the case with composite lymphoma, the EBV‐positive DLBCL was transformed from EMZL. Finally, in the four cases with paired lymphoma and HT biopsies, two showed shared mutations between the paired lesions, indicating involvement and divergent evolution from CLP cells. Thyroid lymphoma relapse may frequently develop via divergent evolution from a CLP cell, which is likely premalignant. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

The receptor-interacting protein kinase 4 (RIPK4) plays an important role in the development and maintenance of various tissues including skin, but its role in melanoma has not been reported. Using patient-derived cell lines and clinical samples, we show that RIPK4 is expressed in melanomas at different levels. This heterogenous expression, together with very low level of RIPK4 in melanocytes, indicates that the role of this kinase in melanoma is context-dependent. While the analysis of microarray data has revealed no straightforward correlation between the stage of melanoma progression and RIPK4 expression in vivo, relatively high levels of RIPK4 are in metastatic melanoma cell lines. RIPK4 down-regulation by siRNA resulted in the attenuation of invasive potential as assessed by time-lapse video microscopy, wound-healing and transmigration assays. These effects were accompanied by reduced level of pro-invasive proteins such as MMP9, MMP2, and N-cadherin. Incubation of melanoma cells with phorbol ester (PMA) increased PKC-1β level and hyperphosphorylation of RIPK4 resulting in degradation of RIPK4. Interestingly, incubation of cells with PMA for short and long durations revealed that cell migration is controlled by the NF-κB signaling in a RIPK4-dependent (RIPK4^high) or independent (RIPK4^low) manner depending on cell origin (distant or lymph node metastasis) or phenotype (mesenchymal or epithelial).

Melanoma cells remain resistant to chemotherapy with cisplatin (CisPt) and doxorubicin (DOX). The abnormal expression of Receptor-Interacting Protein Kinase 4 (RIPK4) in certain melanomas contributes to tumour growth through the NFκB and Wnt/β-catenin signalling pathways, which are known to regulate chemoresistance and recurrence. Despite this, the role of RIPK4 in response to chemotherapeutics in melanoma has not been reported. In this study, we examined how the downregulation and overexpression of RIPK4 affect the sensitivity of BRAF-mutated melanoma cells (A375 and WM266.4) to CisPt and DOX along with determining the underlying mechanism. Using two RIPK4 silencing methods (siRNA and CRISPR/Cas9) and overexpression (dCas9-VPR), we assessed CisPt and DOX-induced apoptosis using caspase 3/7 activity, annexin V/7AAD staining, and FASC analysis. In addition, qRT-PCR and Western blotting were used to detect apoptosis-related genes and proteins such as cleaved PARP, p53, and cyclin D1. We demonstrated that the overexpression of RIPK4 inhibits, while its downregulation enhances, CisPt- or DOX-induced apoptosis in melanoma cells. The effects of downregulation are similar to those observed with pre-incubation with cyclosporin A, an ABCG2 inhibitor. Additionally, our findings provide preliminary evidence of crosstalk between RIPK4, BIRC3, and ABCG2. The results of these studies suggest the involvement of RIPK4 in the observed resistance to CisPt or DOX.

In the present study, we investigated the influence of resveratrol on PhIP treated human colon cancer cells and compared the effect to HaCaT cells considered as normal, human keratinocytes. Our results show that resveratrol decreases DNA damage in both cell types, it increases the sensitivity of LoVo cells to apoptosis and has no effect on PhIP-treated HaCaT cells. We confirm that PhIP-induced apoptosis is p53 and caspase 3/7 dependent. Interestingly, normal cells such as HaCaT, which lack functional p53 are more resistant to PhIP treatment.