Session: 621. Lymphoma—Genetic/Epigenetic Biology: Poster II
Hematology Disease Topics & Pathways:
Diseases, Animal models, Mantle Cell Lymphoma, Non-Hodgkin Lymphoma, cellular interactions, B-Cell Lymphoma, Biological Processes, Technology and Procedures, immune cells, Cell Lineage, Xenograft models, Lymphoid Malignancies, Study Population, genomics, genetic profiling, Clinically relevant, integrative -omics, NGS, microenvironment, RNA sequencing, multi-systemic interactions, pathogenesis, pathways
Due to the distinct microenvironment, orthotopic PDX models have been shown to be much better platforms for preclinical and mechanistic studies than heterotopic or subcutaneous PDX (PDX_sc) models. Therefore, we established multiple MCL PDX models via intravenous (PDX_iv) or intraosseous routes and characterized them for the first time on how they recapitulate the disease in MCL patients in comparison to subcutaneous models when available. These PDX_iv models were successfully passed onto serious generations (up to 10) through IV or SC via PDX cells from spleen of PDX_iv or PDX_sc tumor, respectively (Figure 1). To understand the recapitulation of ITH in PDX models and their contribution to disease progression and clonal evolution, we collected specimens from both disseminated PDX_iv and PDX_sc cells from serious generations and subject them to a multi-dimensional investigation, including pathological, transcriptomic, and genetic profiling (Figure 1).
Consistent in MCL patients, we observed a high degree of histopathological heterogeneity across PDX models originating from different patients, including splenomegaly, hepatomegaly, lymphadenopathy, and involvement of BM, GI tract and/or PB in our PDX_iv models. These models displayed similar dissemination patterns across generations when checked at 2 months after intravenous cell implantation, while additional dissemination sites may be reached at late disease stages, such as the stomach, colon, kidney and uterus. To understand the disease progression and clonal evolution, we performed whole exome sequencing (WES) on 62 PDX samples collected across tissues and generations, primary patient samples used to establish the models (n=6), and their matched germline samples (n=6). Our data revealed a high degree of recapitulation of PDX_iv to patients and genetic inter-patient heterogeneity. Clonal evolution events were investigated for both PDX_iv and PDX_sc models. We demonstrated that PDX_iv models passed by PDX cells from the spleen are genetically more stable than PDX_sc models, in which more frequent chromosomal gain/loss and/or gene mutations occurred toward later generations. Mutations in certain genes such as SVEP1 and STAB1, which play important roles in lymphocyte homing, were found to associate with tissue tropism. To further address this, we performed single-cell RNA sequencing on 41 PDX samples collected across tissues and generations together with primary patient samples (n=8) and PBMC samples from healthy donors (n=2). Transcriptomic profiling showed that G1 PDX_iv models recapitulated primary patient samples very well, and along generations, further upregulation of cancer hallmarks was observed, indicating disease progression into more aggressive stages along generations and late disease stages. Again, PDX_sc models were more transcriptionally dysregulated across generations. Moreover, in vivo efficacy studies showed that PDX cells responded differently to drug treatments such as venetoclax and rituximab based on their homing sites.
In conclusion, we addressed the tissue tropism, therapeutic response, clonal evolution in MCL PDX models at multi-dimensional platforms, for the first time, and comparing the mutagenesis and disease progression of orthotopic and heterotopic PDX models at an unprecedented resolution.
Disclosures: Wang: Lu Daopei Medical Group: Honoraria; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Molecular Templates: Research Funding; Verastem: Research Funding; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Nobel Insights: Consultancy; Oncternal: Consultancy, Research Funding; InnoCare: Consultancy; Acerta Pharma: Research Funding; VelosBio: Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Targeted Oncology: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding.
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