Breakthrough in pancreatic cancer treatment: Inhibiting specific enzymes slows tumor progression

In a recent study published in Nature Communications, researchers reported on stromal class I histone deacetylase (HDAC) inhibition to curb pancreatic cancer progression.

Female doctor with a stethoscope is holding pancreas in the hands
Study: Inhibiting stromal Class I HDACs curbs pancreatic cancer progression. Image Credit: Tattoboo/Shutterstock.com

Pancreatic ductal adenocarcinoma (PDAC) is a disease that causes a desmoplastic and treatment-resistant tumor microenvironment (TME), with a predicted rise in lethality by 2030. The active stroma, a desmoplastic response caused by altered pancreatic epithelium, contributes to the disease's poor prognosis and resistance.

Fibroblast-like cells, such as pancreatic stellate cells (PSCs), promote myofibroblast trans-differentiation and proliferation. Targeting PDAC stromal fibroblasts may enhance therapy results.

About the study

In the present study, researchers identified class I HDACs as epigenetic drivers of pro-tumorigenic and pro-desmoplastic transcriptional activities in stromal fibroblasts of the pancreas.

The researchers investigated the potential of hydroxy-dimethylsulfoxide (HDACi) as a stromal targeting strategy in pancreatic cancer. Researchers discovered that entinostat (Ent), a class I HDAC inhibitor, can alter PSC activation in vitro. They examined the alterations in genome-wide expression caused by PSC activation in vitro in Ent presence and absence.

The team hypothesized that Ent influences the activation of transcription factors (TFs) or coregulators that drive these processes. They searched databases for TFs or cofactors that may selectively bind to the subset of genes activated by in vitro activation and inhibited by Ent.

They also investigated the effects of forkhead box protein M1 (FOXM10) and serum response factor (SRF) knockdowns on pro-desmoplastic transcriptional pathways in activated PSCs. They also investigated HDAC involvement in the tumor growth factor-beta (TGF-β) pathway and whether HDACi could lower the tumor-promoting activities of cancer-associated fibroblasts (CAFs) by influencing paracrine signaling.

The researchers investigated whether HDACi affected CAF secretome pro-tumorgenicity. They examined the potential of conditioned media from Veh- and Ent-treated CAFs to activate the tumorigenic signal transducer and activator of the transcription 3 (STAT3) pathway and facilitate anchor-independent spheroid formation in PDAC cells.

They examined HDAC expression in patient cohorts using publicly accessible databases to investigate the applicability of these findings to human disease. The researchers extracted primary mouse PSCs from wild-type C57BL/6J male mice and used primary CAFs to generate mouse CAF lines imCAF1 and imCAF2.

HDACi effectiveness was assessed in vivo using in vitro tests. The researchers created lentiviral shRNAs and cloned them into the vector-producing pTY-U6-Pgk-Puro. They selected the top potential sequences for further testing. Puromycin selection, assay for transposase-accessible chromatin with high-throughput (ATAC) sequencing, and TGF and tumor necrosis factor (TNF) activation were performed on transduced cells.

The team also performed conditioned media (CM) preparation, STAT3 activation, Western blotting, spheroid formation tests, mass spectrometry analysis for Ent in CM, and orthotopic co-transplantation of fibroblasts and tumor cells and created the PDX model using tumor samples from patients with pathologically proven PDAC.

Results

The researchers identified class I histone deacetylases as critical epigenetic regulators that promote pro-tumorigenic and pro-desmoplastic transcriptional activation in stromal fibroblasts of the pancreas. HDACs promoted PSC stimulation by promoting pro-desmoplastic transcription associated with quiescence.

HDACs also coordinate fibroblast pro-inflammatory programs that induce LIF expression, thereby boosting paracrine pro-tumorigenic crosstalk. HDAC inhibition in CAFs and Ent therapy in murine PDAC models decreased stromal stimulation and slowed tumor development.

HDACi could disrupt chromatin modifications essential for activating pro-desmoplastic transcriptional pathways, lending credence to the involvement of HDACs in coordinating chromatin establishment in PSC activation. In vivo, HDACi therapy modifies stromal fibroblast heterogeneity by inhibiting the lipogenic-to-myofibroblastic program flip and reversing fibroblast composition change in stromal activation and tumor growth. The bicompartmental effects of HDACi in PDAC mice lower disease severity, indicating the therapeutic effectiveness of the HDACi-based bicompartmental targeting method.

Class I HDAC knockdown, especially of HDAC1 and HDAC2, and ent administration from the first day onward inhibited proliferation gene activity [including Ki67 and alpha-smooth muscle actin (α-SMA) and myofibroblast production.

The findings indicated that HDACs are crucial to pro-desmoplastic process induction. Transplants of HDAC-deficient CAFs resulted in decreased tumor volume and weight and a lower abundance of intratumoral leukemia inhibitory factor (LIF).

Ent therapy reduced the number of tumor cells in cultures of human and mouse PDAC cell lines and organoids, with the effects primarily due to cell cycle arrest rather than apoptosis. Ent therapy increases the expression of various epithelial markers and genes in pathways important for epithelial processes, including angiogenesis, wound healing, epithelial development, and differentiation.

Overall, the study findings showed that HDACi, a chromatin modification, can be used in PDAC treatments as a stromal targeting method. HDACs promote the advancement of PDAC by activating pro-tumorigenic and pro-desmoplastic transcriptional pathways.

They also help stromal fibroblasts transition from normal to pro-desmoplastic programs, which aids tumor growth. HDACi affects fibroblast transcriptional programs, reducing stromal stimulation and pro-tumorgenicity, lowering disease severity in animal models.

Journal reference:
Pooja Toshniwal Paharia

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Pooja Toshniwal Paharia

Dr. based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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