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JNCI Cancer Spectrum: Neighborhood-level Social Determinants of Health Burden among AYA Cancer Patients and Impact on Overall Survival (Aune)

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Abstract

Purpose

Neighborhood socioeconomic deprivation has been linked to adverse health outcomes. Yet, it is unclear if neighborhood-level social determinants of health (SDOH) measures impact overall survival in adolescent and young adult (AYA) cancer patients.

Methods

This study utilized a diverse cohort of AYA cancer patients (N = 10,261) seen at MD Anderson Cancer Center. Zip codes were linked to Area Deprivation Index (ADI) values, a validated neighborhood-level SDOH measure, with higher ADI representing worse SDOH.

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Cell Reports: Ceramide-induced cleavage of GPR64 intracellular domain drives Ewing sarcoma (Chen, Houghton, & Shiio Labs)

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  • Kruthi Suvarna
  • Panneerselvam Jayabal
  • Xiuye Ma
  • Hu Wang
  • Yidong Chen
  • Susan T. Weintraub
  • Xianlin Han
  • Peter J. Houghton
  • Yuzuru Shiio 8

Highlights

Ewing sarcoma depends on secreted SMPD1, a ceramide-generating enzyme, and ceramide GPR64 responds to ceramide and mediates critical growth signaling in Ewing sarcoma Ceramide induces the cleavage of the C-terminal intracellular domain (ICD) of GPR64 GPR64 ICD restrains the protein levels of RIF1 via a SPOP-dependent mechanism

Summary

Ewing sarcoma is a cancer of bone and soft tissue in children and young adults primarily driven by the EWS-FLI1 fusion oncoprotein, which has been undruggable. Here, we report that Ewing sarcoma depends on secreted sphingomyelin phosphodiesterase 1 (SMPD1), a ceramide-generating enzyme, and ceramide. We find that G-protein-coupled receptor 64 (GPR64)/adhesion G-protein-coupled receptor G2 (ADGRG2) responds to ceramide and mediates critical growth signaling in Ewing sarcoma. We show that ceramide induces the cleavage of the C-terminal intracellular domain of GPR64, which translocates to the nucleus and restrains the protein levels of RIF1 in a manner dependent on SPOP, a substrate adaptor of the Cullin3-RING E3 ubiquitin ligase. We demonstrate that both SMPD1 and GPR64 are transcriptional targets of EWS-FLI1, indicating that SMPD1 and GPR64 are EWS-FLI1-induced cytokine-receptor dependencies. These results reveal the SMPD1-ceramide-GPR64 pathway, which drives Ewing sarcoma growth and is amenable to therapeutic intervention.

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Science Advances: IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHCII complexes (Gupta Lab)

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Abstract

The mechanism by which interferon regulatory factor 8 (IRF8) mutation contributes to lymphomagenesis is unknown. We modeled IRF8 variants in B cell lymphomas and found that they affected the expression of regulators of antigen presentation. Expression of IRF8 mutants in murine B cell lymphomas suppressed CD4, but not CD8, activation elicited by antigen presentation and downmodulated CD74 and human leukocyte antigen (HLA) DM, intracellular regulators of antigen peptide processing/loading in the major histocompatibility complex (MHC) II. Concordantly, mutant IRF8 bound less efficiently to the promoters of these genes. Mice harboring IRF8 mutant lymphomas displayed higher tumor burden and remodeling of the tumor microenvironment, typified by depletion of CD4, CD8, and natural killer cells and an increase in regulatory T cells and T follicular helper cells. Deconvolution of bulk RNA sequencing data from IRF8-mutant human diffuse large B cell lymphoma (DLBCL) recapitulated part of the immune remodeling detected in mice. We concluded that IRF8 mutations contribute to DLBCL biology by facilitating immune escape.

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MDPI Cells: Comprehensive Review of Uterine Leiomyosarcoma: Pathogenesis, Diagnosis, Prognosis, and Targeted Therapy (Bishop Lab)

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Abstract

Uterine leiomyosarcoma (uLMS) is the most common subtype of uterine sarcomas. They have a poor prognosis with high rates of recurrence and metastasis. The five-year survival for uLMS patients is between 25 and 76%, with survival rates approaching 10–15% for patients with metastatic disease at the initial diagnosis. Accumulating evidence suggests that several biological pathways are involved in uLMS pathogenesis. Notably, drugs that block abnormal functions of these pathways remarkably improve survival in uLMS patients. However, due to chemotherapy resistance, there remains a need for novel drugs that can target these pathways effectively. In this review article, we provide an overview of the recent progress in ascertaining the biological functions and regulatory mechanisms in uLMS from the perspective of aberrant biological pathways, including DNA repair, immune checkpoint blockade, protein kinase and intracellular signaling pathways, and the hedgehog pathway. We review the emerging role of epigenetics and epitranscriptome in the pathogenesis of uLMS. In addition, we discuss serum markers, artificial intelligence (AI) combined with machine learning, shear wave elastography, current management and medical treatment options, and ongoing clinical trials for patients with uLMS. Comprehensive, integrated, and deeper insights into the pathobiology and underlying molecular mechanisms of uLMS will help develop novel strategies to treat patients with this aggressive tumor.

JCO Precision Oncology: Disparate Rates of Germline Variants in Cancer Predisposition Genes in African American/Black Compared With Non-Hispanic White Individuals Between 2015 and 2022 (Tomlinson)

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Rachel B. Wyatt Castillo, MS, CGC, Sarah M. Nielsen, MS, CGC, Elaine Chen, PhD, Brandie Heald, MS, CGC,, Rachel E. Ellsworth, PhD  Edward D. Esplin, MD, PhD, FACMG, and Gail E. Tomlinson, MD, PhD 

Abstract

Purpose

African American/Black (AA/B) individuals are under-represented in genomic databases and thus less likely to receive definitive information from germline genetic testing (GGT) than non-Hispanic White (NHW) individuals. With nearly 500,000 AA/B and NHW individuals having undergone multigene panel testing (MGPT) for hereditary cancer risk at a single commercial laboratory, to our knowledge, we present the largest study to date investigating cancer GGT results in AA/B and NHW individuals.

Methods

MGPT results from a retrospective cohort of AA/B (n = 48,684) and NHW (n = 444,831) patients were evaluated. Frequencies of pathogenic germline variants (PGVs) and variants of uncertain significance (VUS) were compared between AA/B and NHW individuals. Changes in frequency of VUS over time were determined. Pearson’s chi-squared test was used to compare categorical variables among groups. All significance tests were two-tailed, and P < .05 was considered statistically significant.

Results

Between 2015 and 2022, rates of VUS decreased 2.3-fold in AA/B and 1.8-fold in NHW individuals; however, frequencies of VUS and PGV remained significantly higher (46% v 32%; P < .0001) and lower (9% v 13%; P < .0001) in AA/B compared with NHW individuals. Rates of VUS in ATM, BRCA1, BRCA2, PALB2, and PMS2 were significantly higher in AA/B compared with NHW individuals, whereas rates of PGV in BRCA1, BRCA2 and PALB2 were higher in AA/B compared with NHW individuals (P < .001).

Conclusion

Despite reductions in VUS frequencies over time, disparities in definitive GGT results persist. Increasing the inclusion of AA/B populations in both testing and research will further increase knowledge of genetic variants across these racial groups.

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eLife: SERBP1 interacts with PARP1 and is Present in PARylation-Dependent Protein Complexes Regulating Splicing, Cell Division, and Ribosome Biogenesis (Penalva, Libich, et al)

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Kira Breunig
Xiufen Lei
Mauro Montalbano
Gabriela D. A. Guardia
Shiva Ostadrahimi
Victoria Alers
Adam Kosti
Jennifer Chiou
Nicole Klein
Corina Vinarov
Lily Wang
Mujia Li
Weidan Song
W. Lee Kraus
David S. Libich
Stefano Tiziani
Susan T. Weintraub
Pedro A. F. Galante
Luiz O. F. Penalva

Abstract

RNA binding proteins (RBPs) containing intrinsically disordered regions (IDRs) are present in diverse molecular complexes where they function as dynamic regulators. Their characteristics promote liquid-liquid phase separation (LLPS) and the formation of membrane-less organelles such as stress granules and nucleoli. IDR-RBPs are particularly relevant in the nervous system, and their dysfunction is associated with neurodegenerative diseases and brain tumor development. SERBP1 is a unique member of this group, being mostly disordered and lacking canonical RNA-binding domains. Using a proteomics approach followed by functional analysis, we defined SERBP1’s interactome. We uncovered novel SERBP1 roles in splicing, cell division, and ribosomal biogenesis and showed its participation in pathological stress granules and Tau aggregates in Alzheimer’s disease brains. SERBP1 preferentially interacts with other G-quadruplex (G4) binders, implicated in different stages of gene expression, suggesting that G4 binding is a critical component of SERBP1 function in different settings. Similarly, we identified important associations between SERBP1 and PARP1/polyADP-ribosylation (PARylation). SERBP1 interacts with PARP1 and its associated factors and influences PARylation. Moreover, protein complexes in which SERBP1 participates contain mostly PARylated proteins and PAR binders. Based on these results, we propose a feedback regulatory model in which SERBP1 influences PARP1 function and PARylation, while PARylation modulates SERBP1 functions and participation in regulatory complexes.

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Scientific Reports: STEAP2 promotes hepatocellular carcinoma progression via increased copper levels and stress-activated MAP kinase activity (Chen)

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  • Carla Zeballos Torrez,
  • Acarizia Easley,
  • Hakim Bouamar,
  • Guixi Zheng,
  • Xiang Gu,
  • Junhua Yang,
  • Yu-Chiao Chiu,
  • Yidong Chen,
  • Glenn A. Halff,
  • Francisco G. Cigarroa
  • Lu-Zhe Sun

Abstract

Six Transmembrane Epithelial Antigen of Prostate 2 (STEAP2) belong to a family of metalloreductases, which indirectly aid in the uptake of iron and copper ions. Its role in hepatocellular carcinoma (HCC) remains to be characterized. Here, we report that STEAP2 expression was upregulated in HCC tumors compared with paired adjacent non-tumor tissues by RNA sequencing, RT-qPCR, Western blotting, and immunostaining. Public HCC datasets demonstrated upregulated STEAP2 expression in HCC and a positive association with tumor grade. Transient and stable knockdown (KD) of STEAP2 in HCC cell lines abrogated their malignant phenotypes in vitro and in vivo, while STEAP2 overexpression showed opposite effects. STEAP2 KD in HCC cells led to significant alteration of genes associated with extracellular matrix organization, cell adhesion/chemotaxis, negative enrichment of an invasiveness signature gene set, and cell migration/invasion inhibition. STEAP2 KD reduced intracellular copper levels and activation of stress-activated MAP kinases, including p38 and JNK. Treatment with copper rescued the reduced HCC cell migration due to STEAP2 KD and activated p38 and JNK. Furthermore, treatment with p38 or JNK inhibitors significantly inhibited copper-mediated cell migration. Thus, STEAP2 plays a malignant-promoting role in HCC cells by driving migration/invasion via increased copper levels and MAP kinase activities. Our study uncovered a novel molecular mechanism contributing to HCC malignancy and a potential therapeutic target for HCC treatment.

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MDPI Cancers: Synergistic Antitumor Activity of Talazoparib and Temozolomide in Malignant Rhabdoid Tumors (Kurmasheva, Lai, & Chen)

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Elena Mironova, Sebastian Molinas, Vanessa Del Pozo, Abhik M. Bandyopadhyay, Zhao Lai, Dias Kurmashev, Eric L. Schneider, Daniel V. Santi, Yidong Chen, Raushan T. Kurmasheva

Simple Summary

Mutation of the SMARCB1 gene can cause one of the most aggressive and lethal cancers of early childhood and infancy, malignant rhabdoid tumor (MRT). Despite the standard multimodal therapy (resection, conventional chemotherapy, and radiotherapy), the outlook for young children with MRT is poor. For infants, the disease can also preclude the use of radiotherapy. Numerous experimental treatments explore epigenetic mechanisms, but the DNA damage response has not yet been extensively evaluated as a therapeutic approach for MRT. We report a new therapeutic strategy for SMARCB1-deficient MRTs, combining PARP1 inhibition and DNA damage induction. The observed synergy between the PEGylated PARP1 inhibitor talazoparib (PEG~TLZ) and the DNA alkylating agent temozolomide (TMZ) may lead to improved therapeutic strategies for patients with this challenging cancer. We identified a new potential biomarker of response to PEG~TLZ+TMZ, O6-methylguanine methyltransferase (MGMT), and uncovered dysregulated signaling pathways involved in the response. Additionally, we elucidated the pro-survival role of SMARCB1 loss in MRT cells.

Abstract

Malignant rhabdoid tumors (MRTs) are among the most aggressive and treatment-resistant malignancies affecting infants, originating in the kidney, brain, liver, and soft tissues. The 5-year event-free survival rate for these cancers is a mere 20%. In nearly all cases of MRT, the SMARCB1 gene (occasionally SMARCA4)—a pivotal component of the SWI/SNF chromatin remodeling complex—is homozygously deleted, although the precise etiology of these tumors remains unknown. While young patients with localized MRT generally show improved outcomes, especially those who are older and have early-stage disease, the overall prognosis remains poor despite optimal standard treatments. This highlights the urgent need for more effective treatment strategies. We investigated the antitumor activity of a PARP1 inhibitor (talazoparib, TLZ) combined with a DNA alkylating agent (temozolomide, TMZ) in MRT xenograft models. PARP1 is a widely targeted molecule in cancer treatment, and beyond its role in DNA repair, it participates in transcriptional regulation by recruiting chromatin remodeling complexes to modulate DNA accessibility for RNA polymerases. To widen the therapeutic window of the drug combination, we employed PEGylated TLZ (PEG~TLZ), which has been reported to reduce systemic toxicity through slow drug release. Remarkably, our findings indicate that five out of six MRT xenografts exhibited an objective response to PEG~TLZ+TMZ therapy. Significantly, the loss of SMARCB1 was found to confer a protective effect, correlating with higher expression levels of DNA damage and repair proteins in SMARCB1-deficient MRT cells. Additionally, we identified MGMT as a potential biomarker indicative of in vivo MRT response to PEG~TLZ+TMZ therapy. Moreover, our analysis revealed alterations in signaling pathways associated with the observed antitumor efficacy. This study presents a novel and efficacious therapeutic approach for MRT, along with a promising candidate biomarker for predicting tumor response.

Keywords: 

malignant rhabdoid tumor; SMARCB1; PARP1; DNA damage and repair; pediatric cancer therapy

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Neoplasia: Aurkin-A, a TPX2-aurora a small molecule inhibitor, disrupts Alisertib-induced polyploidy in aggressive diffuse large B cell lymphoma. (Sung Lab)

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Chemotherapy-induced polyploidy is a mechanism of inherited drug resistance resulting in an aggressive disease course in cancer patients. Alisertib, an Aurora Kinase A (AK-A) ATP site inhibitor, induces cell cycle disruption resulting in polyaneuploidy in Diffuse Large B Cell Lymphoma (DLBCL). Propidium iodide flow cytometry was utilized to quantify alisertib-induced polyploidy in U2932 and VAL cell lines. In U2932 cells, 1µM alisertib generated 8n+ polyploidy in 48% of the total cell population after 5 days of treatment. A combination of Aurkin A, an AK-A/TPX2 site inhibitor, plus alisertib disrupted alisertib-induced polyploidy in a dose-dependent manner with associated increased apoptosis. We generated a stable FUCCI U2932 cell line expressing Geminin-clover (S/G2/M) and cdt1-mKO (G1), to monitor cell cycle progression. Using this system, we identified alisertib induces polyploidy through endomitosis, which was eliminated with Aurkin A treatment. In a VAL mouse xenograft model, we show polyploidy generation in alisertib-treated mice versus vehicle control or Aurkin A. Aurkin A plus alisertib significantly reduced polyploidy to vehicle control levels. Our in vitro and in vivo studies show that Aurkin A synergizes with alisertib and significantly decreases the alisertib dose needed to disrupt polyploidy while increasing apoptosis in DLBCL cells.

Keywords: Alisertib; Aneuploidy; Cell cycle; Chromosomal instability; Polyploidy.

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Yogesh Gupta, PhD, to Receive Grant from William and Ella Owens Medical Research Foundation to Study “Deciphering BAF Assembly for Pediatric Cancer Therapy”

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Deciphering BAF Assembly for Pediatric Cancer Therapy

Synopsis: The adenosine triphosphate (ATP) dependent multi-subunit assemblies such as (BRG1/BRM-associated factors) complexes utilize ATP hydrolysis energy to reorganize chromatin architecture and facilitate genomic accessibility to transcription factors.

However, in pediatric cancers, both assembly and recruitment of the BAF complexes are disrupted by mutations, deletions, and overexpression of individual subunits, causing aberrant rewiring of BAF-mediated signaling. Moreover, aggressive childhood cancers often display molecular partnerships between defective BAFs and chimeric transcription factors. If successful, this proposal will inform novel approaches to abolish the tumor-promoting functions of aberrant BAFs.