Biology subjects

Hendricks, W. P.

Publications and source records attributed to Hendricks, W. P..

3 recordsLinked to original sources

bioRxiv2023

Landscape of super-enhancers in small cell carcinoma of the ovary, hypercalcemic type and efficacy of targeting with natural product triptolide

PurposeSmall cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare form of ovarian cancer affecting young women and girls. SCCOHT is driven by loss of both SWI/SNF ATPases SMARCA4 and SMARCA2, having major effects on enhancer landscapes. Super-enhancers are a distinct subset of enhancer clusters frequently associated with oncogenes in cancer. Experimental DesignSCCOHT cell lines and PDX models were interrogated for super-enhancer landscape with H3K27ac CUT&RUN integrated with RNAseq data for associated oncogene analysis. IHC staining and drug efficacy studies in PDX models demonstrate clinical translatability. ResultsHere we discovered key distinctions between SWI/SNF chromatin occupancy following SMARCA4 restoration at enhancer vs. super-enhancer sites and characterized putative oncogene expression driven by super-enhancer activity. SCCOHT super-enhancer target genes were particularly enriched in developmental processes, most notably nervous system development. We found high sensitivity of SCCOHT cell lines to triptolide, a small molecule that targets the XPB subunit of the transcription factor II H (TFIIH) complex, found at super-enhancers. Triptolide inhibits expression of many super-enhancer associated genes, including oncogenes. Notably, SALL4 expression is significantly decreased following short triptolide treatment, and its RNA expression was high in SCCOHT tumors relative to other ovarian cancers. In SCCOHT patient-derived xenograft models, triptolide and its prodrug derivative minnelide are particularly effective in inhibiting tumor growth. ConclusionsThese results demonstrate the key oncogenic role of super-enhancer activity following epigenetic dysfunction in SCCOHT, which can be effectively targeted through inhibition of its functional components, such as TFIIH inhibition with triptolide. Statement of Translational RelevanceThis work identifies a potential therapeutic strategy for small cell carcinoma of the ovary-hypercalcemic type (SCCOHT), a rare and aggressive ovarian cancer affecting young women and children. This study highlights the role of the loss of SWI/SNF ATPase SMARCA4 in altering super-enhancers to promote high oncogene expression. We discovered that SCCOHT cells exhibited high sensitivity to triptolide, a small molecule derived from Tripterygium wilfordii, which targets the XPB subunit of the transcription factor II H (TFIIH) complex found at super-enhancers. Triptolide inhibits the expression of super-enhancer-associated genes, including oncogenes like SALL4, which is highly expressed in SCCOHT. Moreover, in SCCOHT patient-derived xenograft models, triptolide and its derivative minnelide effectively inhibited tumor growth. These findings suggest that targeting super-enhancer activity could be a promising therapeutic approach for SCCOHT, offering potential clinical benefits to patients who currently face limited treatment options and poor outcomes.

cancer biology↗

bioRxiv2020

Feasibility and promise of circulating tumor DNA analysis in dogs with naturally-occurring sarcoma.

Comparative studies of naturally-occurring canine cancers have provided new insight into many areas of cancer research. The inclusion of pet dogs in the development and validation of circulating tumor DNA (ctDNA) diagnostics may be uniquely informative for human translation for many reasons, including: high incidence of certain spontaneous cancers, repeated access to blood and tumor from the same individuals during the course of disease progression, and molecular heterogeneity of naturally-occurring cancers in dogs. Here, we present a feasibility study of ctDNA analysis performed in 9 healthy dogs and 39 dogs with either benign or malignant splenic tumors (hemangiosarcoma) using shallow whole genome sequencing (sWGS) of cell-free DNA. To enable detection and quantification of ctDNA using sWGS, we adapted two informatic approaches and compared their performance for the canine genome. At presentation, mean ctDNA tumor fraction in dogs with malignant splenic tumors was 11.2%, significantly higher than dogs with benign lesions (3.2%; p 0.001), achieving an AUC of 0.84. ctDNA tumor fraction was 14.3% and 9.0% in dogs with metastatic and localized disease, respectively although this difference was not statistically significant (p 0.227). In paired analysis, ctDNA fraction decreased from 11.0% to 7.9% after resection of malignant tumors (p 0.047). Our results demonstrate that ctDNA analysis is feasible in dogs with hemangiosarcoma using a cost-effective approach such as sWGS. Future studies are underway to validate these findings, and further evaluate the role of ctDNA to assess burden of disease and treatment response during drug development.

genomics↗

bioRxiv2019

Novel functional insights revealed by distinct protein-protein interactions of the residual SWI/SNF complex in SMARCA4-deficient small cell carcinoma of the ovary, hypercalcemic type

Chromatin remodeling plays a critical role in tumor suppression as demonstrated by 20% of human cancers bearing inactivating mutations in SWI/SNF chromatin remodeling complex members. Mutations in different SWI/SNF subunits drive a variety of adult and pediatric tumor types, including non-small cell lung cancers, rhabdoid tumors, medulloblastomas, and ovarian cancers. Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is an aggressive subtype of ovarian cancer occurring in young women. Nearly all (>98%) SCCOHTs have inactivating mutations in SMARCA4, which encodes 1 of 2 mutually exclusive catalytic subunits of the SWI/SNF complex. Less than half of SCCOHT patients survive 5 years despite aggressive surgery and multimodal chemotherapy. Empirical support for effective SCCOHT treatments is scarce, in part because of the poor understanding of SCCOHT tumorigenesis. To gain insight into the functional consequences of SWI/SNF subunit loss, we defined SWI/SNF composition and its protein-protein interactions (PPIs) by immunoprecipitation and mass spectrometry (IP-MS) of SWI/SNF subunits in 3 SCCOHT cell lines. Comparing these results to a cell line containing a wild-type SWI/SNF complex, the interaction of most canonical core SWI/SNF subunits was observed in all SCCOHT cell lines at a lower abundance. The SCCOHT SWI/SNF also lacked ATPase module subunits and showed a drastic reduction in PBAF-specific subunit interactions. The wild-type and SCCOHT SWI/SNF subunits immunoprecipitated a shared set of 26 proteins, including core SWI/SNF subunits and RNA processing proteins. We observed 131 proteins exclusively interacting with the wild-type SWI/SNF complex including isoform-specific SWI/SNF subunits, members of the NuRD complex, and members of the MLL3/4 complex. We observed 60 PPIs exclusive to the SCCOHT residual SWI/SNF shared in at least 2 of the 3 SCCOHT cell lines, including many proteins involved in RNA processing. Differential interactions with the residual SWI/SNF complex in SCCOHT may further elucidate altered functional consequences of SMARCA4 mutations in these tumors as well as identify synthetic lethal targets that translate to other SWI/SNF-deficient tumors.

cancer biology↗