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Lymphoma

HD-MT With/Without IT-MT and WBRT for Primary CNS Lymphoma

KEY TAKEAWAYS The study aimed to evaluate the efficacy and safety of HD-MT with or without IT-MT and WBRT for PCNSL. The results showed no significant difference in efficacy between HD-MT alone or with IT-MT plus radiotherapy, with manageable side effects. Primary...

Sep 19, 2024

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3d illustration of Lymphoma Cancer
Lymphoma

HD-MT With/Without IT-MT and WBRT for Primary CNS Lymphoma

KEY TAKEAWAYS The study aimed to evaluate the efficacy and safety of HD-MT with or without IT-MT and WBRT for PCNSL. The results showed no significant difference in efficacy between HD-MT alone or with IT-MT plus radiotherapy, with manageable side effects. Primary...

Sep 19, 2024

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Genetic Basis of Elevated Hemoglobin in Andean Aymaras

KEY TAKEAWAYS

  • The study aimed to identify genetic signatures of elevated hemoglobin levels in Aymara using transcriptome analysis.
  • Aymara-enriched NFKB1 SNPs and AS-NFKB1 link elevated hemoglobin levels to increased inflammation.

Tibetans, Ethiopians, and Andeans have been extensively studied for their evolutionary genetic adaptations to high-altitude hypoxia. Quechua and Aymara are the principal Andean ethnicities. At high altitudes, Tibetans and Ethiopians maintain hemoglobin levels similar to those at sea level, while Andeans exhibit higher hemoglobin levels than Europeans living at the same altitude.

Previous research determined that Tibetan selection of 2 genetic variants in the hypoxia-inducible factor pathway, EPAS1 (HIF-2a) and EGLN1 (prolyl hydroxylase 2) genes, correlates with their lower hemoglobin levels (Science 2010, Nat Gen 2014). The whole-genome sequencing study of Aymara (Am J Hum Genet. 2017) identified strong selection signals in BRINP3, NOS2, and TBX5 genes, linked to cardiovascular function and development, but failed to explain elevated hemoglobin levels.

Jihyun Song and the team aimed to identify genetic signatures associated with high hemoglobin levels in Aymara using transcriptome analysis.

Aymara and European samples were collected in La Paz, Bolivia (~4,000 m). Granulocytes were used for RNA sequencing (RNA-seq). Data were generated using a HiSeq system with 125 Cycle Paired-End Sequencing v4. Differential gene expression levels were determined using DESeq2, and differentially spliced exons were identified using rMATS.

The results revealed 2,601 differentially expressed genes and 1,922 spliced genes in Aymaras, associated with immune, inflammatory, and hypoxia-related pathways. Cis-genetic regulators were assessed as expression quantitative trait loci (eQTLs) and splicing quantitative trait loci (sQTLs).

Novel transcripts with exon 4 or 5, or both, skipped in NFKB1 (AS-NFKB1) were found. AS-NFKB1, a key part of the NF-κB pathway, contributes to the suppression of the inflammatory pathway and activation of HIFs. AS-NFKB1 without exon 4 or exons 4 and 5 is not translated into protein, while exon 5 skipped AS-NFKB1 is translated but improperly processed into p50, unable to correctly translocate into the nucleus.

Thus, AS-NFKB1 transcripts cause a partial loss of canonical NFKB1 function as the suppressor of NF-κB. These AS-NFKB1 transcript levels were associated with five sQTLs and enriched in Aymara compared to other populations. Among these five sQTLs, rs230511 was the most selected SNP in Aymara. AS-NFKB1 transcript levels and the T allele (Aymara-enriched allele) of rs230511 positively correlated with elevated hemoglobin in Aymara.

They also correlated with transcript and protein levels of NF-κB-regulated inflammatory genes, including interferon gamma and interleukin 6. Increased inflammation suppresses erythropoiesis through the upregulation of hepcidin, which also correlated with AS-NFKB1 transcript levels. AS-NFKB1 also correlated with marked upregulation of many HIF-regulated genes, the principal regulators of augmented erythropoiesis, explaining Aymara’s erythrocytosis.

These results indicated the increased HIF transcriptional activity, resulting in Aymara erythrocytosis, overcomes the suppression of erythropoiesis caused by inflammation modulated by AS-NFKB1.

The study concluded by identifying, for the first time, the elusive genetic signature of elevated hemoglobin in Andean Aymaras and its molecular basis. It demonstrated the association between Aymara-enriched NFKB1 SNPs and AS-NFKB1 with both elevated hemoglobin levels and heightened inflammation, elucidating a mechanism involving the loss of NFKB1 function due to AS-NFKB1. The evolutionary benefit of increased inflammation in Aymara remains to be identified.

No funding information was available.

Source: https://library.ehaweb.org/eha/2024/eha2024-congress/4136518/josef.prchal.elevated.hemoglobin.of.andean.aymaras.is.caused.by.alternatively.html?f=menu%3D6%2Abrowseby%3D8%2Asortby%3D2%2Ace_id%3D2552%2Amarker%3D5097%2Afeatured%3D18498

Song J, Han S, Amaru R, et al. (2024). “ELEVATED HEMOGLOBIN OF ANDEAN AYMARAS IS CAUSED BY ALTERNATIVELY SPLICED NFKB1” Presented at EHA 2024. (LB3441)

D-VRd+D-R Regimen as Emerging Standard Treatment in NDMM

KEY TAKEAWAYS

  • The PERSEUS phase 3 trial aimed to showcase the further deepening responses & MRD negativity during maintenance of TE subgroup in pts with NDMM.
  • D-R maintenance improved MRD negativity; D-VRd showed higher deep and sustained MRD clearance, enhancing PFS.

In this trial transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM) patients (pts) were randomized to receive either subcutaneous daratumumab (DARA SC) in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) or VRd followed by lenalidomide (R) maintenance. During both induction and maintenance phases, D-VRd treatment showed superior progression-free survival (PFS) and increased rates of complete response and minimal residual disease (MRD) negativity.

Deeper responses were observed in pts treated with D-VRd, over time with higher rates of MRD negativity compared to those receiving VRd followed by R maintenance. These findings support the use of D-VRd followed by D-R maintenance as a new standard of care for TE pts with multiple myeloma (MM), highlighting the clinical benefit of incorporating subcutaneous daratumumab in maintenance therapy.

Pieter Sonneveld and the team determined to report here, the further deepening response and MRD negativity in TE pts with NDMM.

TE pts with NDMM were randomized 1:1 to receive D-VRd or VRd. Each underwent up to 6 28-day cycles (4 pre-ASCT induction, 2 post-ASCT consolidation) of VRd (V 1.3 mg/m² SC on Days 1, 4, 8, 11; R 25 mg PO on days 1-21; d 40 mg PO/IV on Days 1-4, 9-12), followed by R maintenance (10 mg PO on Days 1-28 until PD). D-VRd pts also received DARA SC (DARA 1,800 mg + rHuPH20 [2,000 U/mL; Halozyme]) QW in Cycles 1-2, Q2W in Cycles 3-6, Q4W during maintenance until PD. MRD-negativity rate (clonoSEQ®) was the proportion achieving ≥CR and MRD negativity in pts with ITT.

About 709 randomized pts (D-VRd, n = 355; VRd, n = 354), D-VRd demonstrated superior responses compared to VRd. Rates of ≥CR were significantly higher with D-VRd at the end of consolidation (44.5% vs 34.7%) and overall (87.9% vs 70.1%).

MRD-negativity rates were consistently higher with D-VRd at 12, 24, and 36 months after Cycle 1 Day 1, showing significant improvements compared to VRd (all P < 0.0001). Sustained MRD negativity rates for ≥12 months were also markedly higher with D-VRd across thresholds (10–5: 64.8% vs 29.7%; 10–6: 47.3% vs 18.6%; both P < 0.0001), consistently seen in various patient subgroups.

Among MRD-positive pts post-consolidation, a greater proportion achieved MRD negativity during maintenance with D-VRd compared to VRd, particularly at deeper MRD thresholds (10–5: 68.8% vs 52.7%; 10–6: 62.3% vs 31.0%; both P < 0.0001). Sustained MRD negativity for ≥12 months at both 10–5 and 10–6 thresholds was significantly higher with D-VRd (10–5: PFS).

Further analyses will provide additional insights into response rates across study phases and sustained MRD negativity, highlighting the robustness of D-VRd followed by D-R maintenance as a new standard of care in TE pts with NDMM.

The study concluded that maintenance therapy with D-R assisted in achieving more MRD-positive pts and enhancing the MRD negativity vs R alone. Whereas D-VRd induction followed by D-R maintenance showed superior deep and sustained MRD negativity, correlating with improved PFS, advocating the D-VRd followed by D-R maintenance as an emerging standard for TE pts with NDMM.

The trial was sponsored by Stichting European Myeloma Network.

Source: https://library.ehaweb.org/eha/2024/eha2024-congress/422305

Clinical Trials: https://clinicaltrials.gov/study/NCT03710603

Sonneveld P, Moreau P, Dimopoulos P M, et al. (2024). “Daratumumab + bortezomib/lenalidomide/dexamethasone in transplant-eligible patients with newly diagnosed multiple myeloma: analysis of minimal residual disease in the PERSEUS trial.” Presented at EHA 2024. (abstr 422305; S201), https://library.ehaweb.org/eha/2024/eha2024-congress/422305

Prognostic and Immunological Role of EphA2: Pan-Cancer Analysis

KEY TAKEAWAYS

  • The study aimed to conduct a pan-cancer analysis for oncogenic mechanisms and of EphA2 across 33 different types of tumors.
  • EphA2 emerged as a potential biomarker for poor prognosis and immune infiltration in cancer.

Although a significant relationship has been established between Ephrin receptor A2 (EphA2) and malignant progression in numerous cancers yet, there is a lack of pan-cancer analysis for the prognostic value, mutation status, methylation landscape, and potential immunological function of EphA2.

Yuchun Li and the team aimed to analyze EphA2 expression dynamics between normal and tumor tissues and assess EphA2’s impact on tumor prognosis across various cancer types.

Researchers investigated the differences in EphA2 expression between normal and tumor tissues as well as its impact on the cancer prognosis by using the Cancer Genome Atlas, Genotype Tissue Expression Database and GEO data. They conducted a comprehensive analysis of EphA2’s potential oncogenic mechanisms across 33 different tumor types by employing GSCALite, cBioPortal, TISDB, ULCLAN, and TIMER 2.0 databases.

The analysis included tumor mutation status, DNA methylation status, immune cell infiltration, and correlations with immune checkpoints, tumor mutational burden, DNA microsatellite instability, and DNA repair genes. Moreover, they validated the effects of EphA2 inhibitors on human glioma and lung cancer cell proliferation through cellular experiments.

EphA2 shows differential expression across tumors, correlating with poorer overall survival in patients with overexpressed EphA2. It exhibits mutations, copy number variations, and DNA/RNA methylation changes in various cancers. EphA2 is also linked to increased immune infiltration by macrophages and CD8+ T cells, and its mRNA expression correlates significantly with immune checkpoints, notably programmed death-ligand 1. Additionally, the EphA2 inhibitor ALW-II-41-27 demonstrates strong anti-tumor efficacy.

The pan-cancer analysis highlights the prognostic and immunological roles of EphA2 across different types of cancers, indicating it to be a potential biomarker for poor prognosis and immune infiltration in cancer.

No funding information was provided.

Source: https://pubmed.ncbi.nlm.nih.gov/38886133/

Li Y., Fei H., Xiao Z., et al. (2024). “Comprehensive analysis of EphA2 in pan-cancer: A prognostic biomarker associated with cancer immunity.” Clin Exp Pharmacol Physiol. 2024 Aug;51(8):e13902. doi: 10.1111/1440-1681.13902. PMID: 38886133.

Novel Haplotype and miRNA Insights for Cancer Genetic Testing

Novel Haplotype and miRNA Insights for Cancer Genetic Testing

KEY TAKEAWAYS

  • The study aimed to explore genetic associations between cancer types using GWAS data and bioinformatics.
  • The findings highlighted key haplotype structures and miRNA interactions, potentially useful for genetic panels.

Genome-wide association studies (GWAS) have revealed numerous genetic variants linked to cancer risk. These data are crucial for cancer prevention and understanding cancer mechanisms.

Morteza Gholami and the team aimed to explore genetic links between various cancers using GWAS data and bioinformatics methods.

The study identified significant GWAS variants linked to multiple cancer types. Common linkage disequilibrium (LD) variants between different cancers were found using 1000 Genomes phase 3 LD data. Haplotype blocks were determined through analysis of 1000 Genomes phase 3 genotyping data in GWAS populations.

Subsequent analyses included functional SNP analyses and TCGA gene expression data. Significant GWAS variants (P<5E-8) revealed the following haplotype associations in the European population: GT rs4808075-rs8170 haplotype on BABAM1 with breast and ovarian cancers, GC rs16857609-rs11693806 haplotype on DIRC3 with breast and thyroid cancers, GCG rs380286-rs401681-rs31487 haplotype on CLPTM1L with skin and lung cancers, GGG rs4430796-rs11651052-rs11263763 haplotype on HNF1B with prostate and endometrial cancers, and GT rs10505477-rs6983267 haplotype on CASC8 with colorectal and prostate cancers.

All these genes showed significantly different expressions in tumor tissues (P<1E-3). Additionally, the rs11693806 variant is located in the hsa-miR-873-5p binding site and enhances the hsa-miR-873-5p interaction.

The study’s novel haplotype structures and miRNA interactions are crucial for understanding common genetic links between cancers. These findings could be applied to genetic panels.

No funding information was available.

Source: https://pubmed.ncbi.nlm.nih.gov/39031745/

Gholami M. (2024) “Common and novel haplotype structures between different types of cancer.” Cancer Rep (Hoboken). 2024 Jun;7(6):e2107. doi: 10.1002/cnr2.2107. PMID: 39031745; PMCID: PMC11190585.

EHA 2024 Hybrid Conference: Overview

The European Hematology Association (EHA) is gearing up for its annual EHA 2024 Hybrid conference, which will occur from June 13 to 16, 2024, in Madrid, Spain. This is one of the most highly regarded scholarly gatherings in the international hematology science, practice, research, and hematology event calendar.

The event will foster an environment that enables the opportunity to share knowledge and ideas, encourage teamwork, and help to remain up to date on the most important discoveries in the continuously developing field of hematology.

The conference offers the option for both live and remote attendance. This makes the meeting accessible for attendees from different geographical locations and ensures that people from across the world can work together to find a solution to the challenges facing the subject in such a short span of time.

Focus on Emerging Fields

The EHA 2024 Hybrid conference will highlight two key areas within its Topics-in-Focus program:

  • Precision Hematology: It explores novel diagnostic tools and clinical trial designs to personalize patient care and accelerate the implementation of precision medicine in hematology.

  • Hemoglobinopathies: This program aims to raise awareness and education about genetic blood disorders, specifically Sickle Cell Disease, among healthcare professionals, patients, and the general public.

Unveiling the Cutting Edge of Hematology Science

The EHA2024 Hybrid conference has curated selected scientific programs that cover the sections and topics of hematological subspecialties. Attendees can expect in-depth explorations of:

  • Hemostasis and Thrombosis: The program will cover recent research on Coagulation, hypertension, and thrombosis. It is intended to develop fresh approaches to prevent blood clot formation and improve the management of hemophilia and other bleeding disorders.

Presentations will provide the latest insight into antiphospholipid syndrome, and novel oral anticoagulants for venous thromboembolism prophylaxis might lead the charge in this area.

  • Hematologic Malignancies: It will cover various blood malignancies, including leukemia, lymphoma, and myeloma, and is expected to demonstrate recent developments in targeted therapies, CAR-T cell therapy, and other emerging strategies for managing these cancers.

Attendees can look forward to hearing presentations on CAR-T cell therapy from various other presentations, including the effectiveness of FLT3 inhibitors in the treatment of AML.

  • Transfusion Medicine: The program may also cover focus areas such as blood product production, patient— and disease-specific transfusion practice, and transfusion and handling related consequences.

The discussion would include the newest data about red blood cell storage or the individual approach to platelet transfusion.

  • Stem Cell Transplantation: Participants can expect the event to cover topics like stem cell mobilization techniques, the history of stem cell conditioning, and the prevention of graft-versus-host disease (GVHD).

This section will present talks such as ‘The new ways for preventing GVHD’ by Dr. John Gribben, London, UK. Another topic will be ‘The utility of haplo-identical stem cell transplantation.’

Learning Opportunities

The EHA 2024 Hybrid conference caters to diverse learning preferences and needs by offering a variety of formats, including:

  • Plenary Lectures: Leading professionals in the field will deliver keynote plenary lectures focusing on recent findings and promising research questions on hematologic disease.

  • Oral Presentations: Attendees will be able to get acquainted with the results of current studies on countless topics related to the hematological subject and expect lively discussions.

  • Poster Sessions: This format enables the participant to discuss presenting their study in poster form with researchers.

  • Interactive Workshops: These sessions provide hands-on experience with the latest techniques and technologies in hematology, empowering participants with practical skills.

Fostering Connections and Collaboration

The EHA 2024 Hybrid conference transcends being a mere scientific forum. It is a unique platform for fostering connections and collaborations among hematology professionals. Attendees have the opportunity to:

  • Network with Industry Representatives: Gain insights into the latest diagnostic tools, therapeutic agents, and cutting-edge technologies showcased by leading hematology companies. Professionals from leading firms like AbbVie, Amgen, or Roche may attend and exhibit new scientific achievements.

  • Engage with Patient Groups: Connect with patient advocacy organizations like the Leukemia & Lymphoma Society or the European Hematology Patients’ Association to better understand patient needs and priorities. This will ultimately lead to more patient-centric treatment approaches.

  • Build International Collaborations:  The event will provide network opportunities for participants worldwide to develop joint research initiatives and share best practices, accelerating advancements in hematology globally.

Presidential Sessions Speakers

The EHA 2024 Hybrid conference will have distinguished Presidential Sessions where leading hematologists present their results. Here are some of the confirmed presentations for 2024:

Saturday, June 15, 2024 – Presidential Session I

  • Conducting multinational RCTs in pregnancy to improve maternal health in thrombosis: Prof. Saskia Middeldorp (The Netherlands). This presentation is expected to discuss the retention and feasibility issues and possible advantages of using major clinical trials to assess new anticoagulant treatments for pregnant women with a history of blood clots.

  • Targeting the epigenome in lymphoma by Prof. Ari Melnick (United States). This talk will be about the spectacular biochemistry of epigenetics, where the gene-expressing pattern can be altered without any change in the DNA sequence in the context of lymphomas.

Sunday, June 16, 2024 – Presidential Session II

  • Innovative tools for disease monitoring in Multiple Myeloma by Prof. Bruno Paiva from Spain. This presentation is expected to involve the description of novel biomarkers or imaging methods to improve the measurement of multiple myeloma, a cancer stemming from the plasma cells in bone marrow.

  • Therapeutic inhibition of the complement system by Prof. Antonio Risitano from Italy. Complement systems have been implicated in playing a major role in the immune response of the body. This discussion will look at whether this system can be the target for novel drugs that can be used to treat different hematological diseases.

  • Myeloproliferative neoplasms: Are we ready to disease modify? by Prof. Claire Harrison, United Kingdom. A myeloproliferative syndrome is a type of blood cancer that causes abnormal production of blood cells. This presentation is expected to describe advancements in the therapeutic treatments of these cancers, which could focus on treating them, potentially moving beyond symptom management.

Future of Hematology

The EHA 2024 Hybrid conference has paved the way for future discussions of hematology.

  • Personalized Medicine: The conference is expected to discuss some of the novel trends in personalized medicine, which adapts the care given to individual differences in genetics and molecular composition. Such a move towards personalized and consumer-driven care plans has the potential to herald better outcomes and fewer adverse effects on the patient.

The discussion is expected to be on genomics within the framework of the individualized treatment of acute lymphoblastic leukemia (ALL) and on the personalized management of Myeloproliferative Neoplasms (MPNs).

  • Gene Editing: This invites the group to present discussions on various gene editing tools, such as CRISPR, which could be used for curative blood disorders at the genetic level. These revolutionary technologies are some of the only treatments that have the potential to bring permanent cures for various hematological malignancies.

Mr. Feng Zhang (Broad Institute, USA), a leading scientist in the CRISPR technology field, will be presenting its application in hematology.

  • Digital Hematology: The conference may showcase the use of digital technologies such as artificial intelligence and big data analysis in diagnosing, treating, and researching hematological diseases. These technologies can potentially transform essential areas such as diagnosis and treatment in hematology.

A Must-Attend Event for Hematology Professionals in 2024

The EHA 2024 Hybrid Conference is set to be a global symbol of achievement for hematology professionals. As a comprehensive scientifically diverse, engaging, and networking-rich conference with novel learning formats and a scientific program that is truly outstanding for the field of hematology, the conference remains an unrivaled opportunity to constantly update oneself and actively participate in shaping the field.

This conference brings together clinicians, researchers, industry representatives, and even patients. It offers a unique opportunity to unearth the latest developments across all haematologic subspecialties, including advanced therapies, digital aids, and personalized medicine.

Safety & Efficacy of Pexidartinib+Sirolimus in MPNST

KEY TAKEAWAYS

  • The PLX3397 phase 1 & 2 trials aimed to assess the combined safety & efficacy of pexidartinib+sirolimus in pts with unresectable MPNST.
  • The statistical determinants were PFS and TIME.
  • Pexidartinib+sirolimus showed limited efficacy in MPNST with specific subset benefit; further investigation is ongoing.

Cytotoxic chemotherapy in patients (pts) with unresectable malignant peripheral nerve sheath tumor (MPNST) affords minimal benefit with significant toxicity. Combination with an mTOR inhibitor resulted in sustained tumor control in our phase I study and administration of pexidartinib+sirolimus suggested the safety of the and tumoral static activity where 2 of 6 MPNST pts experienced a progression-free survival (PFS) of >18 weeks.

Gulam Abbas Manji and the team aimed to further evaluate the safety and efficacy of pexidartinib+sirolimus in pts with unresectable MPNST. The initial results from the phase I study were promising, indicating potential benefits in terms of disease stabilization and PFS, thus warranting further exploration in a larger cohort of pts.

Researchers utilized a multicenter, single-arm and initiated a phase 2 trial to enroll pts with unresectable MPNST who had 0-3 prior systemic therapies, excluding inhibitors of tyrosine kinases or mTOR. Selected pts were administered with pexidartinib+sirolimus (1000mg+2mg, respectively) and tumor response was assessed every 6 weeks by RECIST v1.1.

About 25 pts were enrolled in the study, with a statistical power 90% to detect a median PFS difference of 12 weeks, under the assumption of a 6-week median PFS in historical controls. Exploratory analysis of both pre-treatment and on-treatment tumor biopsies involved characterizing the tumor immune microenvironment (TIME) using multiplex immunofluorescence and transcriptional analysis methods.

They enrolled 15 pts between January 1, 2019, and January 19, 2023, for the study, with 14 initiating therapy and being evaluable of those 4 had Neurofibromatosis Type 1 (NF1) associated MPNST . Enrollment was stopped due to a lower enrollment rate during the COVID-19 pandemic on April 12, 2023, with a data cutoff on September 20, 2023.

The data indicated median age of participants was 39 years (range 19-72), with 28.6% being female. Ten pts had received prior systemic therapy, with a median of 1 regimen. Twelve pts discontinued therapy due to disease progression, 1 patient died from COVID-19 during treatment before radiologic evaluation, and 1 ceased therapy due to rash. The study was designed with a statistical power of 90% to detect clinically significant outcomes.

The median PFS was 6 weeks (95% CI, 6-19.1), and the median overall survival (OS) was 21.8 weeks (95% CI, 14.6-NA). Three pts had PFS ≥12 weeks, and 5 survived more than 8 months, with 4 receiving subsequent therapy. Only 1 patient remained alive after 2.7 years of follow-up. Therapy was generally well tolerated, with grade 3 treatment-related adverse events observed in 4 pts (28.6%), primarily leukopenia and rash. Exploratory analyses, including multiplex immunofluorescence and bulk RNAseq on paired biopsies from 8 pts, will be presented.

The study concluded that pexidartinib+sirolimus co-treatment shows limited efficacy in unresectable MPNST pts but may benefit some. Further exploration of TIME modulation is still ongoing.

The trial was sponsored by Gulam Abbas Manji from Columbia University.

Source: https://meetings.asco.org/abstracts-presentations/233343

Clinical Tiral: https://www.clinicaltrials.gov/study/NCT02584647

Manji G A, Stanton L J, Ge L, et al. (2024). “A phase II study of the combination of pexidartinib and sirolimus to target tumor-associated macrophages in unresectable malignant peripheral nerve sheath tumors.” Presented at ASCO 2024. J Clin Oncol 42, 2024 (suppl 16; abstr 11565), 10.1200/JCO.2024.42.16_suppl.11565

CAFs and Fibrosis Link to Lymph Node Metastasis in PTC

KEY TAKEAWAYS

  • The study aimed to elucidate the role of CAFs in PTC and their impact on LNM risk.
  • The results revealed CAF subsets, especially CD36+ myoCAFs, significantly promote lymph node metastasis in PTC.

Papillary thyroid carcinoma (PTC) is a common global malignancy linked to a heightened risk of lymph node metastasis (LNM). The specific function of cancer-associated fibroblasts (CAFs) in PTC progression and metastasis remains poorly understood.

Yixian Wang and the team aimed to investigate the role of CAFs in PTC and their influence on the risk of LNM.

Researchers collected postoperative hematoxylin-eosin (HE) pathological slides from 984 patients with PTC to analyze CAF density at the tumor’s invasive front using QuPath software. They assessed the relationship between CAF density and LNM.

They integrated single-cell RNA sequencing (scRNA-seq) data from the GSE193581 and GSE184362 datasets to analyze CAF infiltration in PTC. A comprehensive suite of in vitro experiments, including EdU labeling, wound scratch assays, Transwell assays, and flow cytometry, was conducted to elucidate the regulatory role of CD36+ CAFs in 2 PTC cell lines, TPC1 and K1.

The results revealed a notable correlation between elevated fibrosis density at the tumor’s invasive front and LNM. Analysis of scRNA-seq data unveiled metastasis-associated myoCAFs characterized by robust intercellular interactions. Additionally, a diagnostic model based on genes associated with metastasis-associated myoCAFs was developed and refined using deep learning techniques.

Furthermore, it was found that the expression of CD36 in CAFs significantly enhances the proliferation, migration, and invasion capabilities of PTC cells, while also inhibiting PTC cell apoptosis.

The study concluded that there is a significant correlation between LNM risk in PTC and high fibrosis density at the tumor’s invasive front, as observed through analysis of postoperative HE pathological slides from a large patient cohort.

Furthermore, integration of scRNA-seq data enabled comprehensive analysis of CAF infiltration in PTC, identifying metastasis-associated myoCAFs characterized by strong intercellular interactions. In vitro experimental findings suggested that CD36+ expression in CAFs contributes to the progression of PTC. These collective results offer crucial insights into the role of CAF subsets in PTC metastasis.

Funding was provided by the National Natural Science Foundation of China.

Source: https://pubmed.ncbi.nlm.nih.gov/38858612/

Wang Y, Li X, Gang Q, et al. (2024). “Pathomics and single-cell analysis of papillary thyroid carcinoma reveal the pro-metastatic influence of cancer-associated fibroblasts.” BMC Cancer. 2024 Jun 10;24(1):710. doi: 10.1186/s12885-024-12459-4. PMID: 38858612.

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