bims-ectoca 2024-11-24 papers

bims-ectoca

Biomed News

on Epigenetic control of tolerance in cancer

Issue of 2024–11–24
eight papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Targeting ErbB and tankyrase1/2 prevent the emergence of drug-tolerant persister cells in ALK-positive lung cancer.
PTEN depletion reduces H3K27me3 levels to promote epithelial-to-mesenchymal transition in epithelial colorectal cancer cells.
Immunohistochemical study of histone protein 3 modification in pediatric osteosarcoma identifies reduced H3K27me3 as a marker of poor treatment response.
Acute myeloid leukemia drug tolerant persister cells survive chemotherapy by transiently increasing plasma membrane rigidity, that also increases their sensitivity to immune cell killing.
Deep Diving Into the Fusion Across Cancer Types in the Indian Population From Formalin-Fixed Paraffin-Embedded RNA-Exome Data: A Road to Discovering Novel Rearrangements With Clinical Relevance.
Spatiotemporal evolutionary process of osteosarcoma immune microenvironment remodeling and C1QBP-driven drug resistance deciphered through single-cell multi-dimensional analysis.
Unleashing the therapeutic power of verteporfin-eluting stents: modulating YAP signaling to combat carotid artery restenosis and cerebral watershed infarction.
Polyploid cancer cells reveal signatures of chemotherapy resistance.

NPJ Precis Oncol. 2024 Nov 17. 8(1): 264

Targeting ErbB and tankyrase1/2 prevent the emergence of drug-tolerant persister cells in ALK-positive lung cancer.

Takaaki Fujimura, Koh Furugaki, Hayato Mizuta, Satoshi Muraoka, Makoto Nishio, Jun Adachi, Ken Uchibori, Eisaku Miyauchi, Hidetoshi Hayashi, Ryohei Katayama, Shigeki Yoshiura.

Targeting the drug tolerant persister (DTP) state in cancer cells should prevent further development of resistance mechanisms. This study explored combination therapies to inhibit alectinib-induced DTP cell formation from anaplastic lymphoma kinase-positive non-small cell lung cancer (ALK + NSCLC) patient-derived cells. After drug-screening 3114 compounds, pan-HER inhibitors (ErbB pathway) and tankyrase1/2 inhibitors (Wnt/β-catenin signaling) emerged as top candidates to inhibit alectinib-induced DTP cells growth. We confirmed knockdown of both TNKS1/2 in DTP cells recovered the sensitivity to alectinib. Further, our study suggested knockdown of TNKS1/2 increased stability of Axin1/2, which induced β-catenin degradation and decreased its nuclear translocation, thereby suppressing transcription of antiapoptotic and proliferation-related genes (survivin, c-MYC). Targeting both pathways with alectinib+pan-HER inhibitor and alectinib+TNKS1/2 inhibitor suppressed alectinib-induced DTP cells, and the triple combination almost completely prevented the appearance of DTP cells. In conclusion, combination with ALK-TKI, pan-HER and TNKS1/2 inhibitors has the potential to prevent the emergence of DTP in ALK + NSCLC.

DOI: https://doi.org/10.1038/s41698-024-00757-w
PLoS One. 2024 ;19(11): e0313769

PTEN depletion reduces H3K27me3 levels to promote epithelial-to-mesenchymal transition in epithelial colorectal cancer cells.

Ahmed H Ghobashi, Jane W Kimani, Christopher A Ladaika, Heather M O'Hagan.

Epithelial-to-mesenchymal (EMT) transition is one of the best-known examples of tumor cell plasticity. EMT enhances cancer cell metastasis, which is the main cause of colorectal cancer (CRC)-related mortality. Therefore, understanding underlying molecular mechanisms contributing to the EMT process is crucial to finding druggable targets and more effective therapeutic approaches in CRC. In this study, we demonstrated that phosphatase and tensin homolog (PTEN) knockdown (KD) induces EMT in epithelial CRC, likely through the activation of AKT. PTEN KD modulated chromatin accessibility and reprogrammed gene transcription to mediate EMT in epithelial CRC cells. Active AKT can phosphorylate enhancer of zeste homolog 2 (EZH2) on serine 21, which switches EZH2 from a transcriptional repressor to an activator. Interestingly, PTEN KD reduced the global levels of trimethylation of histone 3 at lysine 27(H3K27me3) in an EZH2-phosphorylation-dependent manner. Additionally, EZH2 phosphorylation at serine 21 reduced the interaction of EZH2 with another polycomb repressive complex 2 (PRC2) component, suppressor of zeste 12 (SUZ12), suggesting that the reduced H3K27me3 levels in PTEN KD cells were due to a disruption of the PRC2 complex. Overall, we demonstrated that PTEN KD modulates changes in gene expression to induce the EMT process in epithelial CRC cells by phosphorylating EZH2 and activates transcription factors such as activator protein 1 (AP1).

DOI: https://doi.org/10.1371/journal.pone.0313769
PLoS One. 2024 ;19(11): e0309471

Immunohistochemical study of histone protein 3 modification in pediatric osteosarcoma identifies reduced H3K27me3 as a marker of poor treatment response.

Sebastian Kondratowski, Danielle Cohen, Rebecca J Deyell, Ash Sandhu, Jonathan W Bush.

The most common pediatric primary malignant bone tumor, osteosarcoma, is often described as genetically non-recurrent and heterogeneous. Neoadjuvant chemotherapy is typically followed by resection and assessment of treatment response, which helps inform prognosis. Identifying biomarkers that may impact chemotherapy response and survival could aid in upfront risk stratification and identify patients in highest need of innovative therapies for future clinical trials. Relative to conventional genetics, little is known about osteosarcoma epigenetics. We aimed to characterize the methylation and phosphorylation status in osteosarcoma using histone markers found in primary diagnostic biopsies and their paired metastases. We constructed two tissue microarray sets from 58 primary diagnostic samples and 54 temporally-separated but related metastatic or recurrent samples, with tissue blocks available from 2002-2022. Clinical charts were reviewed for post-therapy necrosis response, presence of metastatic disease or recurrence, and overall survival. We evaluated 6 histone H3 residues using immunohistochemistry, including H3K4me3, H3K9me3, H3K27me2, H3K27me3, H3S10T11phos, and H3S28phos. Tumors were scored with low (<25%) or high (≥25%) nuclear staining of tumor cells. Diagnostic biopsies with low H3K27me3 nuclear staining were associated with poor treatment response (≤90% necrosis) at the time of definitive excision (P<0.05). We observed loss of H3S10T11phos expression in metastatic and recurrent resections specimens compared to the primary tumor (P<0.05). Expression patterns for the remaining histone markers did not show significant associations with disease parameters or survival. Although larger cohort studies are needed, these results support the expanded evaluation of histone markers, particularly H3K27me3 and H3S10T11phos, in osteosarcoma biology and risk stratification.

DOI: https://doi.org/10.1371/journal.pone.0309471
Haematologica. 2024 Nov 21.

Acute myeloid leukemia drug tolerant persister cells survive chemotherapy by transiently increasing plasma membrane rigidity, that also increases their sensitivity to immune cell killing.

Yael Morgenstern, JongBok Lee, Yoosu Na, Brandon Y Lieng, Nicholas S Ly, William D Gwynne, Rose Hurren, Li Ma, Dakai Ling, Marcela Gronda, Andrea Arruda, Avraham Frisch, Tsila Zuckerman, Yishai Ofran, Mark D Minden, Li Zhang, Catherine O'Brien, Andrew T Quaile, J Rafael Montenegro-Burke, Aaron D Schimmer.

Resistance to chemotherapy remains a major hurdle to the cure of Acute Myeloid Leukemia (AML) patients. Recent studies indicate a minority of malignant cells, termed drug-tolerant persisters (DTPs), stochastically upregulate stress pathways to evade cell death upon acute exposure to chemotherapy without acquiring new genetic mutations. This chemoresistant state is transient and the cells return to baseline after removal of chemotherapy. Yet, the mechanisms employed by DTPs to resist chemotherapy are not well understood and it is largely unknown whether these mechanisms are also seen in patients receiving chemotherapy. Here, we used leukemia cell lines, primary AML patient samples and samples from patients with AML receiving systemic chemotherapy to study the DTP state. We demonstrated that a subset of AML cells transiently increases membrane rigidity to resist killing due to acute exposure to Daunorubicin and Ara-C. Upon removal of the chemotherapy, membrane rigidity returned to baseline and the cells regained chemosensitivity. Although resistant to chemotherapy, the increased membrane rigidity, rendered AML cells more susceptible to T-cell mediated killing. Thus, we identified a novel mechanism by which DTP leukemic cells evade chemotherapy and a strategy to eradicate these persistent cells.

DOI: https://doi.org/10.3324/haematol.2024.286018
JCO Glob Oncol. 2024 Nov;10 e2400289

Deep Diving Into the Fusion Across Cancer Types in the Indian Population From Formalin-Fixed Paraffin-Embedded RNA-Exome Data: A Road to Discovering Novel Rearrangements With Clinical Relevance.

Satya Prakash Khuntia, Nilesh Mukherjee, Vyomesh Javle, Nishtha AjitSingh Tanwar, Peddagangannagari Sreekanthreddy, Linu Varghese, Pooja Gowda, Anju Kottlahouse, Pratik Chandrani, Anuradha Choughule, Priyanka Pange, Vinod Gupta, Vanita Noronha, Vijay Maruti Patil, Raja Pramanik, Sunil Kumar, Sandeep Peraje Nayak, Suresh Babu, Rohan Shetty, Madan Kantharaju, Pramod Shekarappa Chinder, Aruna Korlimarla, B S Srinath, Kumar Prabhash, Giridharan Periyasamy, Kshitij Datta Rishi, Hitesh Madan Goswami, Vidya Harini Veldore.

PURPOSE: Gene fusions are critical oncogenic mutations that drive cancer development and serve as diagnostic and prognostic biomarkers. Despite the increasing cancer burden in India, large-scale analyses of molecular landscapes, particularly gene fusions, have been relatively scarce.
MATERIALS AND METHODS: This retrospective study used RNA-exome data from 1,392 Indian patients with cancer across 15 major cancer types to explore gene fusions. The study used a comprehensive framework that integrated open-source and proprietary tools to detect gene fusions from formalin-fixed paraffin-embedded tumor samples. The process involved RNA extraction, RNA-exome library preparation, and analysis using tools such as FastQC, DRAGEN RNA Pipeline, STAR-Fusion, and FusionInspector. We validated and filtered potential false-positive fusion calls using AGFusion and FusionAnnotator to annotate fusion breakpoints and their functional impact through various in silico tools.
RESULTS: The study found a notable prevalence of FGFR fusions across cancer types, especially FGFR3, with FGFR3::TACC3 as the most recurrent. Kinase fusions were prevalent in the cohort accounting for 37% of incidence in the patients. We also identified 91 novel potential driver fusions, including those involving FGFR2, MET, ESR1, and PDGFRA.
CONCLUSION: This study underscores the critical role of gene fusions as biomarkers in cancer, extending beyond fusion-driven malignancies to encompass all cancer types. Gene fusions serve as both diagnostic markers and tumor-agnostic therapeutic targets within the current cancer treatment paradigm. Our insights into the prevalence of oncogenic drivers and novel targets expand the understanding of gene fusions, shedding new light on their mechanisms and clinical implications.

DOI: https://doi.org/10.1200/GO-24-00289
Bioeng Transl Med. 2024 Sep;9(5): e10654

Spatiotemporal evolutionary process of osteosarcoma immune microenvironment remodeling and C1QBP-driven drug resistance deciphered through single-cell multi-dimensional analysis.

Xin Wu, Ning Tang, Qiangqiang Zhao, Jianbin Xiong.

  The tumor immune microenvironment has manifested a crucial correlation with tumor occurrence, development, recurrence, and metastasis. To explore the mechanisms intrinsic to osteosarcoma (OS) initiation and progression, this study synthesizes multiple single-cell RNA sequencing data sets, constructing a comprehensive landscape of the OS microenvironment. Integrating single-cell RNA sequencing with bulk RNA sequencing data has enabled the identification of a significant correlation between heightened expression of the fatty acid metabolism-associated gene (C1QBP) and patient survival in OS. C1QBP not only amplifies the proliferation, migration, invasion, and anti-apoptotic properties of OS but also instigates cisplatin resistance. Subsequent investigations suggest that C1QBP potentially promotes macrophage polarization from monocytes/macrophages toward M2 and M3 phenotypes. Consequently, C1QBP may emerge as a novel target for modulating OS progression and resistance therapy.

Keywords:  C1QBP; drug resistance; macrophage polarization; osteosarcoma; tumor immune microenvironment

DOI:  https://doi.org/10.1002/btm2.10654
Mol Cell Biochem. 2024 Nov 22.

Unleashing the therapeutic power of verteporfin-eluting stents: modulating YAP signaling to combat carotid artery restenosis and cerebral watershed infarction.

Peng Zhang, Chenyang Xu, Zhijun Liu, Yadong Geng, Honglin Liu.

  Carotid artery stenosis is the main cause of cerebral watershed infarction (CWI). In recent years, increasing attention has been given to treating this condition. The present study aimed to investigate how Verteporfin-eluting stent (VPES) modulates the YAP signaling pathway to inhibit restenosis of the carotid artery and alleviate CWI. Through transcriptome sequencing and functional experiments, it was found that VP could regulate the Yes-associated protein (YAP) signaling pathway and effectively suppress the proliferation and migration of smooth muscle cells (SMCs). Further investigation revealed that VPES could inhibit carotid artery restenosis through the YAP signaling pathway in a rabbit model, reducing the occurrence of CWI.

Keywords:  Carotid artery restenosis; Cerebral watershed infarction; Smooth muscle cells; Transcriptome sequencing; Verteporfin-eluting stent; YAP signaling pathway

DOI:  https://doi.org/10.1007/s11010-024-05160-4
Oncogene. 2024 Nov 22.

Polyploid cancer cells reveal signatures of chemotherapy resistance.

Michael J Schmidt, Amin Naghdloo, Rishvanth K Prabakar, Mohamed Kamal, Radu Cadaneanu, Isla P Garraway, Michael Lewis, Ana Aparicio, Amado Zurita-Saavedra, Paul Corn, Peter Kuhn, Kenneth J Pienta, Sarah R Amend, James Hicks.

Therapeutic resistance in cancer significantly contributes to mortality, with many patients eventually experiencing recurrence after initial treatment responses. Recent studies have identified therapy-resistant large polyploid cancer cells in patient tissues, particularly in late-stage prostate cancer, linking them to advanced disease and relapse. Here, we analyzed bone marrow aspirates from 44 advanced prostate cancer patients and found the presence of circulating tumor cells with increased genomic content (CTC-IGC) was significantly associated with poorer progression-free survival. Single cell copy number profiling of CTC-IGC displayed clonal origins with typical CTCs, suggesting complete polyploidization. Induced polyploid cancer cells from PC3 and MDA-MB-231 cell lines treated with docetaxel or cisplatin were examined through single cell DNA sequencing, RNA sequencing, and protein immunofluorescence. Novel RNA and protein markers, including HOMER1, TNFRSF9, and LRP1, were identified as linked to chemotherapy resistance. These markers were also present in a subset of patient CTCs and are associated with recurrence in public gene expression data. This study highlights the prognostic significance of large polyploid tumor cells, their role in chemotherapy resistance, and the expression of markers tied to cancer relapse, offering new potential avenues for therapeutic development.

DOI: https://doi.org/10.1038/s41388-024-03212-z