bims-almceb 2022-10-16 papers

Front Oncol. 2022 ;12 972323

A distinct subpopulation of leukemia initiating cells in acute precursor B lymphoblastic leukemia: quiescent phenotype and unique transcriptomic profile.

Alex Q Lee, Hiroaki Konishi, Connie Duong, Sakiko Yoshida, Ryan R Davis, Jonathan E Van Dyke, Masami Ijiri, Bridget McLaughlin, Kyoungmi Kim, Yueju Li, Laurel Beckett, Nitin Nitin, John D McPherson, Clifford G Tepper, Noriko Satake.

In leukemia, a distinct subpopulation of cancer-initiating cells called leukemia stem cells (LSCs) is believed to drive population expansion and tumor growth. Failing to eliminate LSCs may result in disease relapse regardless of the amount of non-LSCs destroyed. The first step in targeting and eliminating LSCs is to identify and characterize them. Acute precursor B lymphoblastic leukemia (B-ALL) cells derived from patients were incubated with fluorescent glucose analog 2-(N-(7-Nitrobenz-2-oxa-1, 3-diazol-4-yl) Amino)-2-Deoxyglucose (NBDG) and sorted based on NBDG uptake. Cell subpopulations defined by glucose uptake were then serially transplanted into mice and evaluated for leukemia initiating capacity. Gene expression profiles of these cells were characterized using RNA-Sequencing (RNA-Seq). A distinct population of NBDG-low cells was identified in patient B-ALL samples. These cells are a small population (1.92% of the entire leukemia population), have lower HLA expression, and are smaller in size (4.0 to 7.0 μm) than the rest of the leukemia population. All mice transplanted with NBDG-low cells developed leukemia between 5 and 14 weeks, while those transplanted with NBDG-high cells did not develop leukemia (p ≤ 0.0001-0.002). Serial transplantation of the NBDG-low mouse model resulted in successful leukemia development. NBDG-medium (NBDG-med) populations also developed leukemia. Interestingly, comprehensive molecular characterization of NBDG-low and NBDG-med cells from patient-derived xenograft (PDX) models using RNA-Seq revealed a distinct profile of 2,162 differentially-expressed transcripts (DETs) (p<0.05) with 70.6% down-regulated in NBDG-low cells. Hierarchical clustering of DETs showed distinct segregation of NBDG-low from NBDG-med and NBDG-high groups with marked transcription expression alterations in the NBDG-low group consistent with cancer survival. In conclusion, A unique subpopulation of cells with low glucose uptake (NBDG-low) in B-ALL was discovered. These cells, despite their quiescence characteristics, once transplanted in mice, showed potent leukemia initiating capacity. Although NBDG-med cells also initiated leukemia, gene expression profiling revealed a distinct signature that clearly distinguishes NBDG-low cells from NBDG-med and the rest of the leukemia populations. These results suggest that NBDG-low cells may represent quiescent LSCs. These cells can be activated in the appropriate environment in vivo, showing leukemia initiating capacity. Our study provides insight into the biologic mechanisms of B-ALL initiation and survival.

Keywords: B-ALL; glucose; leukemia initiating capacity; leukemia initiating cells; metabolic activity; transcriptome profiling

DOI: https://doi.org/10.3389/fonc.2022.972323

Curr Mol Med. 2022 Oct 07.

Cell adhesion molecule CD99 in cancer immunotherapy.

Feng Yu, Guodong Liu, Hailing Zhang, Xiaoyan Wang, Zhi Wu, Qinggang Xu, Yan Wu, Dongfeng Chen.

The CD99 antigen is a transmembrane protein expressed in a broad variety of tissues, particularly in hematopoietic cells, thymus, endothelial cells, etc. It participates in several crucial biological processes including cell adhesion, migration, death, differentiation and inflammation. CD99 has been shown oncogenic or tumor suppressor roles in different types of cancer. Therefore, it has been used as a biomarker and therapeutic target for several types of cancer. Moreover, it has also been reported to be involved in several critical immune processes, such as T cell activation and differentiation, dendritic cell differentiation, and so on. Hence, CD99 may have potential values in cancer immunotherapy. Anti-CD99 antibodies have been shown therapeutic effects on certain types of cancer, especially on Ewing sarcoma and T cell acute lymphoblastic leukemia (ALL). This review summarizes the recent progresses of CD99 in cancer research and targeting therapies, especially in cancer immunotherapy, which may help researchers understand the crucial roles of CD99 in cancer development and design new therapeutic strategies.

Keywords: CD99; Cell adhesion.; biomarker; cancer; immunotherapy; targeting therapy

DOI: https://doi.org/10.2174/1566524023666221007143513

Front Cell Dev Biol. 2022 ;10 909424

Resetting the epigenome: Methylation dynamics in cancer stem cells.

Aiendrila Roy, Swati Shree Padhi, Ibakordor Khyriem, Saket Nikose, Harsha Sankar S H, Ruthrotha Selvi Bharathavikru.

The molecular mechanisms that regulate stem cell pluripotency and differentiation has shown the crucial role that methylation plays in this process. DNA methylation has been shown to be important in the context of developmental pathways, and the role of histone methylation in establishment of the bivalent state of genes is equally important. Recent studies have shed light on the role of RNA methylation changes in stem cell biology. The dynamicity of these methylation changes not only regulates the effective maintenance of pluripotency or differentiation, but also provides an amenable platform for perturbation by cellular stress pathways that are inherent in immune responses such as inflammation or oncogenic programs involving cancer stem cells. We summarize the recent research on the role of methylation dynamics and how it is reset during differentiation and de-differentiation.

Keywords: RNA methylation; cancer stem cells; chromatin; epigenetics; epitranscriptomic modification; readers

DOI: https://doi.org/10.3389/fcell.2022.909424

MedComm (2020). 2022 Dec;3(4): e176

Signaling pathways in the regulation of cancer stem cells and associated targeted therapy.

Wang Manni, Wu Min.

Cancer stem cells (CSCs) are defined as a subpopulation of malignant tumor cells with selective capacities for tumor initiation, self-renewal, metastasis, and unlimited growth into bulks, which are believed as a major cause of progressive tumor phenotypes, including recurrence, metastasis, and treatment failure. A number of signaling pathways are involved in the maintenance of stem cell properties and survival of CSCs, including well-established intrinsic pathways, such as the Notch, Wnt, and Hedgehog signaling, and extrinsic pathways, such as the vascular microenvironment and tumor-associated immune cells. There is also intricate crosstalk between these signal cascades and other oncogenic pathways. Thus, targeting pathway molecules that regulate CSCs provides a new option for the treatment of therapy-resistant or -refractory tumors. These treatments include small molecule inhibitors, monoclonal antibodies that target key signaling in CSCs, as well as CSC-directed immunotherapies that harness the immune systems to target CSCs. This review aims to provide an overview of the regulating networks and their immune interactions involved in CSC development. We also address the update on the development of CSC-directed therapeutics, with a special focus on those with application approval or under clinical evaluation.

Keywords: CAR‐T therapies; cancer stem cells; inhibitors; signal pathway

DOI: https://doi.org/10.1002/mco2.176

Mol Oncol. 2022 Oct 10.

MYC and therapy resistance in cancer: risks and opportunities.

Giulio Donati, Bruno Amati.

The MYC transcription factor, encoded by the c-MYC proto-oncogene, is activated by growth-promoting signals, and is a key regulator of biosynthetic and metabolic pathways driving cell growth and proliferation. These same processes are deregulated in MYC-driven tumors, where they become critical for cancer cell proliferation and survival. As other oncogenic insults, overexpressed MYC induces a series of cellular stresses (metabolic, oxidative, replicative, etc.) collectively known as oncogenic stress, which impact not only on tumor progression, but also on the response to therapy, with profound, multifaceted consequences on clinical outcome. On one hand, recent evidence uncovered a widespread role for MYC in therapy resistance in multiple cancer types, with either standard chemotherapeutic or targeted regimens. Reciprocally, oncogenic MYC imparts a series of molecular and metabolic dependencies to cells, thus giving rise to cancer-specific vulnerabilities that may be exploited to obtain synthetic-lethal interactions with novel anticancer drugs. Here we will review the current knowledge on the links between MYC and therapeutic responses, and will discuss possible strategies to overcome resistance through new, targeted interventions.

Keywords: Myc; synthetic lethality; targeted therapy; therapy resistance

DOI: https://doi.org/10.1002/1878-0261.13319

Front Oncol. 2022 ;12 988626

Metabolite-derived protein modifications modulating oncogenic signaling.

Yawen Liu, Anke Vandekeere, Min Xu, Sarah-Maria Fendt, Patricia Altea-Manzano.

Malignant growth is defined by multiple aberrant cellular features, including metabolic rewiring, inactivation of tumor suppressors and the activation of oncogenes. Even though these features have been described as separate hallmarks, many studies have shown an extensive mutual regulatory relationship amongst them. On one hand, the change in expression or activity of tumor suppressors and oncogenes has extensive direct and indirect effects on cellular metabolism, activating metabolic pathways required for malignant growth. On the other hand, the tumor microenvironment and tumor intrinsic metabolic alterations result in changes in intracellular metabolite levels, which directly modulate the protein modification of oncogenes and tumor suppressors at both epigenetic and post-translational levels. In this mini-review, we summarize the crosstalk between tumor suppressors/oncogenes and metabolism-induced protein modifications at both levels and explore the impact of metabolic (micro)environments in shaping these.

Keywords: metabolites; oncogenic signaling; post-translational modification; tumor microenvironment; tumor suppressor gene

DOI: https://doi.org/10.3389/fonc.2022.988626