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Unraveling Cancer's Secrets: The Truth About Stem Cells, Microenvironments, and Immune Strategies

December 10, 2023
Abdul Rafae, MD, (@a_rafaemd), Samer Al Hadidi, MD, MS, (@HadidiSamer)
Myeloma Ctr, Winthrop P. Rockefeller Cancer Inst., U. of Arkansas for Medical Sciences, Little Rock

As hematologists, discussing disease relapse with our patients is among the most difficult conversations we can have. Cancer stem cells are believed to be the elusive instigators behind disease relapse, and understanding their resistance to cancer therapies has been a longstanding area of study. While remarkable strides have been made in comprehending stem cell biology, leading to the development of more sophisticated and precise treatments, targeting these cancer stem cells continues to pose a challenge. The influence of the stem cell microenvironment on the regulation of stem cell proliferation and differentiation remains inadequately understood, representing a vast realm of ongoing scientific exploration and breakthroughs.  

Today’s ASH-EHA Joint Symposium, (12:30 p.m. – 1:30 p.m., Convention Center, Hall A) will showcase presentations by Alexander Medvinsky, PhD, and Linheng Li, PhD. In this session by the ASH and the European Hematology Association, Drs. Medvinsky and Li will delve into the realm of stem cell transcriptomics within their respective niches and its significance in both normal and leukemic stem cell differentiation. The session will shed light on the pivotal role of the Wnt/β-catenin and PI3K-Akt pathways in tumorigenesis, particularly in the immune evasion mechanisms of leukemia stem cells (LSCs). Attendees will gain insight into the heightened expression of various immune checkpoint genes such as programmed death-ligand 1, T-cell immunoglobulin and mucin domain-containing protein 3, and CD23, regulated by these pathways. Additionally, the discussion will explore the application of this knowledge in targeting LSCs, focusing on how anthracyclines disrupt the Akt/β-catenin interaction within LSCs. This disruption renders the cells susceptible to immune attacks, exemplified by a small clinical trial demonstrating a 50% reduction in LSCs through the use of daunorubicin.1 

Beyond these cellular pathways, the stem cell microenvironment, known as the niche, significantly influences cell proliferation, survival, and differentiation. Prepare for an immersive exploration into the tumor microenvironment in which Dr. Li and colleagues, leveraging state-of-the-art, high-resolution transcriptomic techniques, have meticulously constructed a comprehensive spatial cell atlas of the mouse fetal liver. This groundbreaking work, “Spatial Transcriptomics Reveals Distinct Hematopoietic Stem Cell Niches in Mouse Fetal Liver,” will be presented today in Bone Marrow Microenvironment: Poster II. (6:00 p.m. – 8:00 p.m., Convention Center, Halls G-H). It provides an intricate transcriptomic profile and spatial insights at the single-cell level. Their findings revealed distinct niches within the fetal liver that support various subsets of hematopoietic stem cells (HSCs). The investigators also discerned correlations in the expression patterns of different markers such as Cdh2 and Cxcl12 within these HSC niches, ultimately enhancing our understanding of the regulation of HSCs and introducing new potential therapeutic strategies. 

The question of whether similar diversified niches supporting stem cells exist in normal bone marrow remained open until research by Xunlei Kang, MD, PhD, shed light on this topic. Dr. Kang independently discovered the existence of two niches in the adult leukemic bone marrow.2 His study highlighted the influence of the tumor microenvironment on the survival of LSCs. Through the deletion of Cxcl12 induced by N-cad-CreER in the stem cell niche, LSCs initially confined in the trabecular bone area — where they were shielded from apoptosis — relocated to the central marrow (CM) covered by compact bone. In this new location, they exhibited heightened proliferation but were more susceptible to apoptosis. Remarkably, this LSC relocation translated into improved survival rates in mice harboring LSCs in the CM when compared with those that had LSCs in the trabecular bone area, truly exemplifying the adage of “location, location, location.’ 

These discoveries not only enrich our comprehension of stem cell biology but also serve as a stimulating catalyst for deeper exploration. The imminent application of this knowledge holds promise for our patients by aiding in the development of therapeutic techniques that can overcome resistance mechanisms, targeting the core vulnerabilities of hematologic cancers. 

The influence of the tumor microenvironment extends beyond leukemia; It has also been a subject of exploration in lymphomas, as elucidated in yesterday’s session, Lymphomas: Translational – Non-Genetic: Illuminating the Tumor Microenvironment and Immune Landscape in Lymphoma. 

For those eager to delve further, we recommend reviewing Single Cell Omics and High-Resolution Imaging to Unravel the Role of the Niche in Stress and Ageing Hematopoiesis, part of yesterday’s Scientific Program. This program spotlighted the utilization of single-cell omics and various newly developed imaging technologies, fundamentally shedding light on the role of the bone marrow niche during inflammation and aging. 

In conclusion, the above-mentioned sessions collectively help crack the cancer code through a closer examination of the evidence at the “scene of the crime” (i.e., the bone marrow niche), as well as the suspects and accomplices (code-named stem cells), bringing us one step closer to unlocking the mystery of cancer stem cells and associated hematologic neoplasms.  

References 

1 Lin, TL, Perry, JM, He, X., et al, L., 2017. Treatment with low-dose daunorubicin reduces the number of leukemia stem cells in patients with relapsed/refractory acute myeloid leukemia. Blood. 2017:130, p.1336. 

2 Wang, C., Nistala, R., Cao, M., et al. Dipeptidylpeptidase 4 promotes survival and stemness of acute myeloid leukemia stem cells. Cell Reports. 2023:42(2). 

Drs. Rafae and Al Hadidi indicated no relevant conflicts of interest. 

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