Research Areas

Investigation of New Mechanisms of Sarcomagenesis and Progression

Soft-tissue sarcomas comprise a heterogeneous group of aggressive tumors that originate from cells belonging to the mesenchymal lineages, and that affect almost 200,000 individuals worldwide each year. Compared to epithelial carcinomas, sarcomas have been less studied and lack effective therapeutic alternatives to radiation and chemotherapy. With the aim of identifying new and more effective therapies for these tumors, the Guarnerio Laboratory is employing syngeneic mouse models (Guarnerio et al. Cancer Discov. 2015) to study immune and non-immune cells of the tumor microenvironment through single-cell transcriptomics and functional genomics. 

Additionally, the Guarnerio Lab is developing new mouse models of different sub-types of soft-tissue sarcoma and metastasis.

Figure 1. Schematic representation of the sarcoma genetic platform used to identify new drivers of sarcomagenesis. Adapted from Guarnerio et al. Cancer Discov. 2015. These sarcoma mouse models will be used to dissect the composition of the sarcoma microenvironment.

Investigation of the Leukemia Microenvironment

The persistence of resistant leukemic cells after treatment with chemotherapy represents the fundamental problem impeding successful treatment of leukemia. Therefore, elucidating the mechanisms of resistance is critical to uncover curative modalities. 

Previous work in the Guarnerio Lab showed that mesenchymal stem cells (MSCs) are essential to maintain both normal hematopoietic stem cells and leukemic cells within the endosteal bone marrow niche (Guarnerio et al. Stem Cell Reports. 2014; Guarnerio et al. Nat Commun. 2018). Future work will elucidate the cancer-sustaining interactions between leukemic cells and MSCs and will employ spatial single-cell transcriptomic approaches as well as functional genomic screenings to define the molecules at the crosstalk between MSCs and leukemic cells.

Figure 2. Schematic representation of the interactions between MSCs and leukemic cells, and the recent discovery of the role of progressive multifocal leukoencephalopathy (PML) in sustaining leukemic cells from the bone marrow niche. Adapted from Guarnerio, et al. Nat. Comm. 2018.

Investigation of Circular RNAs in the Tumor Microenvironment

In the last years, next-generation sequencing analyses have produced a sizable data set on tumor-associated gene expression profiles paving the way to characterize the functions of specific candidates in preclinical models. However, while research to date has comprehensively studied the tumorigenic impact of several tumor suppressors and oncogenes encoded by linear mRNA transcripts, the realm of non-coding RNAs, which are transcripts that are not translated into proteins, has been only poorly explored for some tumor types. Different types of noncoding RNAs exist based on length and structure of the transcript, and among them are circular RNAs (circRNAs), which have been recently discovered in many tumor types. circRNAs result from an intriguing and specialized form of alternative splicing in which the 3’-tail of an exon back-splices and joins the 5’-head of the exon localized upstream. Although some transcripts exist mainly in circular form, the majority of circRNAs co-originate with their linear transcript counterpart from mRNA precursors. In this respect, although circRNAs have been suggested as biomarkers or therapeutic targets, their contribution to cancer progression is still largely undefined and, more importantly, their targeting in therapeutic settings are unexplored.

The Guarnerio Laboratory has previously discovered tumor-associated circRNAs that act as oncogenes in the process of tumorigenesis (Guarnerio et al. Cell. 2016). More recently, the Guarnerio Lab has observed that the circRNA derived from the Zbtb7a gene (labelled circPOK) can impact the tumor cells’ secretome and ultimately the composition of the tumor microenvironment (Guarnerio et al. Cell Res. 2019). Using novel biochemistry techniques refined in our lab, we are studying the unique mechanisms by which tumor-associated circRNAs define the immune and non-immune composition of the tumor mass.

Figure 3. Role of circPOK in regulating tumor angiogenesis in sarcoma. (A) circPOK derives from the Exon2 of the Zbtb7a gene. In Zbtb7a_Ex2F/F cells both linear and circular transcripts were knocked-out by CRE-recombinase. (B) Construct used to express circPOK and Pokemon proteins (cDNA-POK) into p53-/-Zbtb7a_Ex2F/F MSCs used for in vivo experiments and schematics. Right chart: tumor sizes generated by cells expressing either circPOK, circGFP or Pokemon protein. (C) Identification of CD31+ endothelial cells in UPS expressing circPOK or circGFP (controls). (D) Expression of Vegf by UPS cells expressing circPOK. Adapted from Guarnerio et al. Cell Res. 2019.

Contact the Guarnerio Lab

8700 Beverly Blvd.
Davis Building, Room 3027
Los Angeles, CA 90048