Biology subjects

Warda, S.

Publications and source records attributed to Warda, S..

3 recordsLinked to original sources

bioRxiv2025

PRC2 Restricts Malignant Peripheral Nerve Sheath Tumorigenesis in a Genetically Engineered Mouse Model of MPNST

Polycomb Repressive Complex 2 (PRC2), which normally regulates transcriptional silencing, chromatin compaction, and stem cell biology, has both oncogenic and tumor suppressor roles in cancer development depending on tumor type. Malignant peripheral nerve sheath tumor (MPNST), characterized by NF1, CDKN2A and PRC2 loss, is an aggressive subtype of sarcoma with poor prognosis and no effective therapy. In high-grade human MPNSTs, inactivating mutations in PRC2 core components SUZ12 or EED are prevalent and contributes to oncogenic transformation and progression of MPNST. How PRC2 inactivation contributes to MPNST pathogenesis, however, remains incompletely understood. Here we show that genetic inactivation of Eed in addition to Nf1 and Cdkn2a in the Schwann-progenitor lineage leads to widespread tumorigenesis within the sciatic nerve compartment of mice. In contrast, loss of Nf1 and Cdkn2a is insufficient to drive tumorigenesis in the sciatic nerve but leads to MPNST development in other anatomic locations with a longer latency. Single-nucleus multiome sequencing of the sciatic nerves revealed that PRC2-loss reprograms Nf1/Cdkn2a-deficient Schwann-lineage cells toward a dedifferentiated, neural crest stem cell-like state that resembles the transcriptomic signatures of human PRC2-loss MPNST. Together, these findings suggest a context-dependent tumor suppressive role for PRC2 within the sciatic nerve and establish a novel mouse model that recapitulates human PRC2-loss MPNST. SIGNIFICANCEWe present a novel genetically engineered mouse model that faithfully recapitulates human PRC2-loss MPNST, enabling mechanistic and preclinical studies of malignant transformation in the context of PRC2 loss.

cancer biology↗

bioRxiv2022

PRC2 Inactivating Mutations in Cancer are Synthetic Lethal with DNMT1 Targeted Therapy via Enhanced Viral Mimicry

Polycomb Repressive Complex 2 (PRC2) establishes and maintains di- and tri-methylation at histone 3 at lysine 27 (H3K27me2/3) in the genome and plays oncogenic and tumor suppressor roles in context-dependent cancer pathogenesis. While there is clinical success of therapeutically targeting PRC2 core component, EZH2, in PRC2-dependent cancers (e.g., follicular lymphoma, epithelioid sarcoma), it remains an unmet therapeutic bottleneck in PRC2-inactivated cancer. Biallelic inactivating mutations in PRC2 core components are a hallmark feature of high-grade malignant peripheral nerve sheath tumor (MPNST), an aggressive subtype of sarcoma with poor prognosis and no effective targeted therapeutics. Using a custom RNAi-based drop out screen, we observed that PRC2-inactivation is synthetic lethal with DNA methyltransferase 1 (DNMT1) downregulation; we further observed that small molecule DNMT inhibitors (DNMTis) resulted in enhanced cytotoxicity and antitumor response in PRC2-loss cancer context in vitro and in vivo. Mechanistically, DNMTi-mediated de-repression of retrotransposons (e.g., endogenous retroviral elements (ERVs)/LTR, LINE, SINE) and gene targets is partly restricted by PRC2, which potentially contributes to limited therapeutic activity in PRC2-wild-type (wt) cancer context. In contrast, DNMTi treatment synergizes with PRC2 inactivation and cooperatively amplifies the expression of retrotransposons (e.g., ERV/LTR, LINE, SINE), and subsequent viral mimicry response that promotes robust cell death in part through PKR-dependent double stranded-RNA (dsRNA) sensing. Collectively, our observations posit DNA methylation as a safeguard against anti-tumorigenic cell fate decisions in the context of PRC2-inactivation to promote cancer pathogenesis. Further, they identified a novel targeted therapeutic strategy in PRC2-inactivated MPNST and delineated the PRC2-inactivated cancer context for future preclinical exploration and clinical investigation of DNMT1-targeted therapies in cancer. SIGNIFICANCEPRC2-inactivation drives oncogenesis in various cancers but therapeutically targeting PRC2-loss has remained challenging. Here we show that PRC2 inactivating mutations sets up a tumor context-specific liability for synthetic lethal interaction with genetic and therapeutic inhibition of DNMT1. DNMT1 inhibitor-induced cytotoxicity in PRC2-loss cancer context is accompanied by innate immune signaling signature through PKR-mediated sensing of endogenous retrotransposons. These observations posit a therapeutic window via direct anti-tumor effect by DNMT1 inhibitors in PRC2-loss cancers, and point to potentials to be combined with innovative immunotherapeutic strategies to capitalize on innate immune signaling activation.

cancer biology↗

bioRxiv2022

Tumor-intrinsic PRC2 inactivation drives a context-dependent immune-desert tumor microenvironment and confers resistance to immunotherapy

Immune checkpoint blockade (ICB) has demonstrated clinical success in "inflamed" tumors with significant T-cell infiltrates, but tumors with an immune-desert tumor microenvironment (TME) fail to benefit. The tumor cell-intrinsic molecular mechanisms of the immune-desert phenotype remain poorly understood. Here, we demonstrate that inactivation of the Polycomb-repressive complex 2 (PRC2) core components, EED or SUZ12, a prevalent genetic event in malignant peripheral nerve sheath tumor (MPNST) and sporadically in other cancer types, drives a context-dependent immune-desert TME. PRC2 inactivation reprograms the chromatin landscape that leads to a cell-autonomous shift from primed baseline signaling-dependent cellular responses (e.g., interferon {gamma}) to PRC2-regulated development and cellular differentiation transcriptional programs. Further, PRC2 inactivation reprograms the TME, leads to diminished tumor immune infiltrates and immune evasion through reduced chemokine production and impaired antigen presentation and T-cell priming, and confers ICB primary resistance through blunted T-cell recruitment in vivo. We demonstrate that strategies that enhancing innate immunity via intratumoral delivery of inactivated modified vaccinia virus Ankara (MVA) leads to increased tumor immune infiltrates and sensitizes PRC2-loss tumors to ICB. Our results provide novel molecular mechanisms of context-dependent dysfunctional epigenetic reprogramming that underline the immune-desert phenotype in MPNST and other cancers with PRC2 inactivation. Importantly, our findings highlight genetic-inactivation of PRC2 as a novel context-dependent ICB therapeutic resistance biomarker in cancer, and caution that therapeutic strategies that non-selectively target PRC2 in the host may lead to undesirable context-dependent immune evasion and ICB resistance in tumors. Our studies also point to intratumoral delivery of immunogenic therapeutic viruses as an initial strategy to modulate the immune-desert TME and capitalize on the clinical benefit of ICB.

cancer biology↗