Cancer Cell De-Differentiation: Plasticity-Driven Stratagem For Tumor Metastasis and Recurrence.

Tumor recurrence is a colossal challenge in clinical oncology. This multifactorial problem is attributed to the emergence of additional genetic mutations and the presence of dormant cancer cells. However, the plasticity of non-stem cancer cells and the acquisition of cancer stem cell (CSC) functionality is another contributing factor to tumor recurrence. Herein, I focus attention on the mechanisms that fuel cancer cell de-differentiation and the interplay between intra-cellular regulators and tumor microenvironment (TME) landscape that promotes cancer cell stemness. Our understanding of the mechanisms underlying tumor cell de-differentiation is crucial for developing innovative therapeutic strategies that prevent cancer from ever recurring.

Whole-genome analysis reveals unexpected dynamics of mutant subclone development in a patient with JAK2-V617F-positive chronic myeloid leukemia.

We report here the first use of whole-genome sequencing (WGS) to examine the initial clonal dynamics in an unusual patient with chronic myeloid leukemia (CML), who presented in chronic phase (CP) with doubly marked BCR-ABL1+/JAK2V617F-mutant cells and, over a 9-year period, progressed into an accelerated phase (AP) and then terminal blast phase (BP). WGS revealed that the diagnostic cells also contained mutations in ASXL1, SEC23B, MAD1L1, and RREB1 as well as 12,000 additional uncommon DNA variants. WGS of endothelial cells generated from circulating precursors revealed many of these were shared with the CML clone. Surprisingly, WGS of induced pluripotent stem cells (iPSCs) derived from the AP cells revealed only six additional coding somatic mutations, despite retention by the hematopoietic progeny of the parental AP cell levels of BCR-ABL1 expression and sensitivity to imatinib and pimozide. Limited analysis of BP cells revealed independent subclonal progression to homozygosity of the MAD1L1 and RREB1 variants. MAD1L1 and SEC23B mutations were also identified in 2 of 101 cases of myeloproliferative neoplasms, but not in 42 healthy subjects. These findings challenge historic concepts of clonal evolution in CML.

Mesenchymal Stem Cells: Key Actors in Tumor Niche.

Tumors grow in privileged microenvironment referred to as the cancer niche. This niche is composed of cancer cells and various components including mesenchymal stem cells (MSC), fibroblasts, network of microvasculature added to innate and primed immune cells. Additionally, it encloses other elements such as the extracellular matrix (ECM), cytokines, chemokines and growth factors. Crosstalk between cancer cells and different niche constituents is crucial for tumor growth and metastasis. Herein, we focus attention on the bidirectional relationship between MSC and cancer cells and its impact on tumor progression. Better comprehension of these events within the tumor niche might be valuable for developing effective anti-tumor therapeutic strategies.

Dendritic cells in the skin--potential use for melanoma treatment.

Melanoma is an aggressive malignancy with poor prognosis. Eradication of tumor cells requires an effective interaction between melanoma cells and different players of the immune system. As the most potent professional antigen-presenting cells, dendritic cells (DCs) play a pivotal role in mounting a specific immune response where their intratumoral and peritumoral density as well as their functional status are correlated with clinical staging of the disease and with patients' survival. Under steady-state conditions, internalization of apoptotic cells by immature DCs designates a state of tolerance to self-antigens. Nevertheless, pathogens and necrotic cells interacting with pattern recognition receptors trigger downstream signaling pathways that evoke maturation of DCs, leading to the production of pro-inflammatory cytokines. These mature DCs are essential for T-cell priming and subsequent development of a specific immune response. Altered functions of DCs have an impact on the development of various disorders including autoimmune diseases and cancers. Herein, we focus on the checkpoints created throughout DCs antigen capturing and presentation to T cells, with subsequent development of either tolerance or immune response, with an emphasis on the role played by DCs in melanoma tumorigenesis and their therapeutic potential.