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Tumor-Tissue Expression of the Hyaluronic Acid Receptor RHAMM Predicts Histological Transformation in Follicular Lymphoma Patients.

ABSTRACT: Histological transformation (HT) remains the leading cause of mortality in follicular lymphoma (FL), underlining the need to identify reliable transformation predictors. The hyaluronic acid receptors CD44 and the receptor for hyaluronan mediated motility (RHAMM, also known as HMMR and CD168), have been shown to be involved in the pathogeneses of both solid tumors and hematological malignancies. In an attempt to improve risk stratification, expression of RHAMM and CD44 were evaluated by immunohistochemistry and digital image analysis in pre-therapeutic tumor-tissue biopsies from FL patients, either without (nt-FL, n = 34), or with (st-FL, n = 31) subsequent transformation, and in paired biopsies from the transformed lymphomas (tFL, n = 31). At the time of initial diagnosis, samples from st-FL patients had a higher expression of RHAMM compared with samples from nt-FL patients (p < 0.001). RHAMM expression further increased in tFL samples following transformation (p < 0.001). Evaluation of CD44 expression showed no differences in expression comparing nt-FL, st-FL, and tFL samples. Shorter transformation-free survival was associated with high tumoral and intrafollicular RHAMM expression, as well as with low intrafollicular CD44 expression (p = 0.002, p < 0.001, and p = 0.034, respectively). Our data suggest that high tumor-tissue RHAMM expression predicts the risk of shorter transformation-free survival in FL patients already at initial diagnosis.

SUBMITTER: Enemark MB

PROVIDER: S-EPMC8909114 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Tumor-Tissue Expression of the Hyaluronic Acid Receptor RHAMM Predicts Histological Transformation in Follicular Lymphoma Patients.

Enemark Marie Beck MB Hybel Trine Engelbrecht TE Madsen Charlotte C Lauridsen Kristina Lystlund KL Honoré Bent B Plesner Trine Lindhardt TL Hamilton-Dutoit Stephen S d'Amore Francesco F Ludvigsen Maja M

Cancers 20220304 5

Histological transformation (HT) remains the leading cause of mortality in follicular lymphoma (FL), underlining the need to identify reliable transformation predictors. The hyaluronic acid receptors CD44 and the receptor for hyaluronan mediated motility (RHAMM, also known as HMMR and CD168), have been shown to be involved in the pathogeneses of both solid tumors and hematological malignancies. In an attempt to improve risk stratification, expression of RHAMM and CD44 were evaluated by immunohis ...[more]

PMID: 35267625

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Project description:BackgroundFollicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories.Methods and findingsUsing a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1.ConclusionsOur results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.

Project description:Hyaluronic acid (HA) is an extracellular matrix (ECM) component that has been shown to play a significant role in regulating muscle cell behavior during repair and regeneration. For instance, ECM remodeling after muscle injury involves an upregulation in HA expression that is coupled with skeletal muscle precursor cell recruitment. However, little is known about the role of HA during skeletal muscle development. To gain insight into the way in which HA mediates embryonic myogenesis, we first determined the spatial distribution and gene expression of CD44, RHAMM and other HA related proteins in embryonic day (E)10.5 to E12.5 murine forelimbs. While HA and CD44 expression remained high, RHAMM decreased at both the protein (via immunohistochemistry) and RNA (via qPCR) levels. Next, we determined that 4-methylumbelliferone-mediated knockdown of HA synthesis inhibited the migration and proliferation of E11.5/E12.5 forelimb-derived cells. Then, the influence of CD44 and RHAMM on myoblast and connective tissue cell behavior was investigated using antibodies against these receptors. Anti-RHAMM, but not anti-CD44, significantly decreased the total distance myogenic progenitors migrated over 24?h, whereas both inhibited connective tissue cell migration. In contrast, anti-CD44 inhibited the proliferation of connective tissue cells and muscle progenitors, but anti-RHAMM had no effect. However, when myoblasts and connective tissue cells were depleted of CD44 and RHAMM by shRNA, motility and proliferation were significantly inhibited in both cells indicating that blocking cell surface-localized CD44 and RHAMM does not have as pronounced effect as global shRNA-mediated depletion of these receptors. These results show, for the first time, the distribution and activity of RHAMM in the context of skeletal muscle. Furthermore, our data indicate that HA, through interactions with CD44 and RHAMM, promotes myogenic progenitor migration and proliferation. Confirmation of the role of HA and its receptors in directing myogenesis will be useful for the design of regenerative therapies that aim to promote the restoration of damaged or diseased muscle.

Project description:Background: Follicular lymphoma (FL) presents significant clinical heterogeneity, with some patients experiencing transformation into an aggressive disease, a key contributor to FL-related mortality. Based on gene expression profiles, this study aimed to provide insights into immunological differences associated with transformation. Methods: Gene expression analysis using the NanoString nCounter Tumor Signaling 360 Panel was performed on diagnostic lymphoma samples from 70 FL patients diagnosed in the rituximab era, either non-transforming FL (nt-FL, n = 34) or subsequently transforming FL (st-FL, n = 36), with paired high-grade transformed FL (tFL, n = 36) samples available. In silico immunophenotyping was performed to infer immune cell infiltration using the CIBERSORTx algorithm. Results: The gene expression analysis revealed 164 significantly differentially expressed genes, distinguishing st-FL from nt-FL and generally presenting an upregulation of B cell-related genes (CD40, IRF4, RELB), immunosuppressive molecules (IL10, SOCS3), and immune checkpoint molecules (CD276, TIM3). Analysis of immune cell proportions indicated significant differences in infiltrates of M1-like macrophages (p = 0.007) and neutrophils (p = 0.012) in nt-FL versus st-FL samples. Transformation-free survival (TFS) was associated with high numbers of both these cellular subsets (p = 0.006 and 0 = 0.002, respectively). This was even more evident when combined with inferior TFS in lymphomas with high infiltrates of both cell types (p < 0.001). After transformation, tFL samples showed a reduction in T follicular helper cells (p = 0.008) and an increase in immunosuppressive M2-like macrophages and neutrophils (p < 0.001 and p = 0.028, respectively). Conclusion: By elucidating the distinct molecular and immune landscapes of FL at the time of diagnosis and transformation, this study underscores the importance of immune microenvironment in FL transformation and patient outcome.

Dataset Information

Tumor-Tissue Expression of the Hyaluronic Acid Receptor RHAMM Predicts Histological Transformation in Follicular Lymphoma Patients.

Publications

Tumor-Tissue Expression of the Hyaluronic Acid Receptor RHAMM Predicts Histological Transformation in Follicular Lymphoma Patients.

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