Enrico Caserta

City of Hope

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Co-Authors

Flavia Pichiorri

City of Hope

John E. Shively

Beckman Research Institute

Vikram Adhikarla

City of Hope

Russell C. Rockne

City Of Hope National Medical Center

Xiuli Wang

City of Hope

Maxim Kuznetsov

P.N. Lebedev Physical Institute of the Russian Academy of Sciences

Amrita Krishnan

City Of Hope National Medical Center

James F. Sanchez

City of Hope

Flavia Pichiorri

Beckman Research Institute

Craig C. Hofmeister

Emory University

Cooperative Institutions

The Ohio State University

126

City of Hope

112

City Of Hope National Medical Center

Beckman Research Institute

The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute

The Ohio State University Wexner Medical Center

Ohio University

Cancer Genetics (United States)

Comprehensive Blood & Cancer Center

U-M Rogel Cancer Center

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Daratumumab induces CD38 internalization and impairs myeloma cell adhesion

OncoImmunology (2018)

Jayeeta Ghose Domenico Viola César Terrazas Enrico Caserta Estelle Troadec

Daratumumab (Dara), a human immunoglobulin G1 kappa (IgG1κ) monoclonal anti-CD38 antibody, has been approved by the U.S. Food and Drug Administration for the treatment of relapsed multiple myeloma (MM) as a single agent as well as in combination with immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI). Although the scientific rationale behind the use of Dara in combination with IMiDs has been extensively explored, the molecular mechanisms underlying Dara-PI regimens have not yet been investigated. Here, we demonstrate that CD38 on the surface of MM cells is rapidly internalized after Dara treatment; we also show that Dara treatment impairs MM cell adhesion, an effect that can be rescued by using the endocytosis inhibitor Dynasore. Finally, we show that Dara potentiates bortezomib (BTZ) killing of MM cells in vitro and in vivo, independent of its function as an immune activator. In conclusion, our data show that Dara impairs MM cell adhesion, which results in an increased sensitivity of MM to proteasome inhibition.

Daratumumab

Internalization

10.1080/2162402x.2018.1486948

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Citations (49)

MiR-16 regulates crosstalk in NF-κB tolerogenic inflammatory signaling between myeloma cells and bone marrow macrophages

JCI Insight (2019)

Jihane Khalife Jayeeta Ghose Marianna Martella Domenico Viola Alberto Rocci

High levels of circulating miR-16 in the serum of multiple myeloma (MM) patients are independently associated with longer survival. Although the tumor suppressor function of intracellular miR-16 in MM plasma cells (PCs) has been elucidated, its extracellular role in maintaining a nonsupportive cancer microenvironment has not been fully explored. Here, we show that miR-16 is abundantly released by MM cells through extracellular vesicles (EVs) and that differences in its intracellular expression as associated with chromosome 13 deletion (Del13) are correlated to extracellular miR-16 levels. We also demonstrate that EVs isolated from MM patients and from the conditioned media of MM-PCs carrying Del13 more strongly differentiate circulating monocytes to M2-tumor supportive macrophages (TAMs), compared with MM-PCs without this chromosomal aberration. Mechanistically, our data show that miR-16 directly targets the IKKα/β complex of the NF-κB canonical pathway, which is critical not only in supporting MM cell growth, but also in polarizing macrophages toward an M2 phenotype. By using a miR–15a-16-1–KO mouse model, we found that loss of the miR-16 cluster supports polarization to M2 macrophages. Finally, we demonstrate the therapeutic benefit of miR-16 overexpression in potentiating the anti-MM activity by a proteasome inhibitor in the presence of MM-resident bone marrow TAM.

Crosstalk

Extracellular vesicles

10.1172/jci.insight.129348

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Citations (36)

Analysis of spatial variation of nuclear morphology in tissue microenvironments

Shantanu Singh Sundaresan Raman Enrico Caserta Gustavo Leone Michael C. Ostrowski

We present a study of the spatial variation of nuclear morphology of stromal and cancer-associated fibroblasts in the mouse mammary gland. The work is part of a framework being developed for the analysis of the tumor microenvironment in breast cancer. Recent research has uncovered the role of stromal cells in promoting tumor growth and progression. In specific, studies have indicated that stromal fibroblasts - formerly considered to be passive entities in the extra-cellular matrix - play an active role in the progression of tumor in mammary tissue. We have focused on the analysis of the nuclear morphology of fibroblasts, which several studies have shown to be a critical phenotype in cancer. An essential component of our approach is that the nuclear morphology is studied within the 3D spatial context of the tissue, thus enabling us to pose questions about how the locus of a cell relates to its morphology, and possibly to its function. In order to make quantitative comparisons between nuclear populations, we build statistical shape models of cell populations and infer differences between the populations through these models. We present our observation on both normal and tumor tissues from the mouse mammary gland.

Mammary tumor

Morphology

10.1109/isbi.2010.5490233

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Citations (2)

Capturing variations in nuclear phenotypes

Journal of Computational Science (2019)

Sundaresan Raman Shantanu Singh Thierry Pécot Enrico Caserta Kun Huang

10.1016/j.jocs.2019.07.001

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Citations (0)

Sumoylation Inhibition Potentiates Daratumumab Activity Against Multiple Myeloma

Blood (2022)

Li Du Wei Liu Enrico Caserta Flavia Pichiorri Steven T. Rosen

Daratumumab

10.1182/blood-2022-158040

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Allele-specific tumor spectrum in Pten knockin mice

Proceedings of the National Academy of Sciences (2010)

Hui Wang Matt Karikomi Shan K. Naidu Ravi Rajmohan Enrico Caserta

Germline mutations in the tumor suppressor gene PTEN (phosphatase and tensin homology deleted on chromosome 10) cause Cowden and Bannayan–Riley–Ruvalcaba (BRR) syndromes, two dominantly inherited disorders characterized by mental retardation, multiple hamartomas, and variable cancer risk. Here, we modeled three sentinel mutant alleles of PTEN identified in patients with Cowden syndrome and show that the nonsense Pten ∆4–5 and missense Pten C124R and Pten G129E alleles lacking lipid phosphatase activity cause similar developmental abnormalities but distinct tumor spectra with varying severity and age of onset. Allele-specific differences may be accounted for by loss of function for Pten ∆4–5 , hypomorphic function for Pten C124R , and gain of function for Pten G129E . These data demonstrate that the variable tumor phenotypes observed in patients with Cowden and BRR syndromes can be attributed to specific mutations in PTEN that alter protein function through distinct mechanisms.

Tensin

Cowden syndrome

Loss function

10.1073/pnas.0912524107

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Citations (60)

Supplementary Figure S.14 from Mathematical Modeling Unveils Optimization Strategies for Targeted Radionuclide Therapy of Blood Cancers

Maxim Kuznetsov Vikram Adhikarla Enrico Caserta Xiuli Wang John E. Shively

Supplementary Figure S.14

Radionuclide therapy

10.1158/2767-9764.27723451

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