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CURATOR
A pinboard by
Matt Paul

PhD Candidate, University of Pennsylvania

PINBOARD SUMMARY

Identification of mutations in metastatic tumors to discover new breast cancer therapies/strategies.

Breast cancer is the most common cancer affecting women world-wide. Though the first stage of the disease - primary cancer of the breast - is treatable and can be effectively cured in the majority of women, the disease can come back years later in 20-30% of women. Because this recurrence is often resistant to modern drug therapies and surgery, this form of the disease is usually fatal. Knowing this, it is a surprising that >90% of genomic studies have focused solely on primary breast cancer and have effectively ignored the more fatal recurrent form of the disease. I am currently leading one of the largest analyses of metastatic recurrent breast cancer to date, where we have sequenced primary and metastatic recurrent tumors from ~70 patients. In this study, we have identified genes and cellular pathways that are specifically mutated in recurrent breast cancer, which may serve as new targets for therapy during breast cancer treatment. Furthermore, I sought to elucidate the evolutionary history of these metastatic recurrent tumors to identify mutations that may be responsible for their initial growth and spread.

3 ITEMS PINNED

Next generation sequencing of progressive colorectal liver metastases after portal vein embolization.

Abstract: Portal vein embolization (PVE) can be required to stimulate liver regeneration before hepatectomy for colorectal liver metastasis (CRCLM), however PVE may also trigger CRCLM progression in patients initially exhibiting chemotherapy response. Using RNA-seq, we aimed to determine the molecular networks involved in metastatic progression in this context. A prospective study including all CRCLM patients undergoing PVE prior to hepatectomy was conducted. Paired biopsies of metastatic lesions were obtained prior to and after PVE and total RNA was isolated and used to prepare Illumina rRNA-depleted TruSeq stranded cDNA libraries for HiSeq 100 bp paired-end sequencing. Patients were classified with progression of disease (PDPVE) or stable disease (SDPVE) post-PVE using 3D-CT tumor volumetric analysis.Twenty patients were included, 13 (65.0%) in the PDPVE group (median 58.0% (18.6-234.3) increase in tumor volume) and 7 (35.0%) in the SDPVE group exhibiting continuous chemotherapy response (median -14.3% (-40.8 to -2.8) decrease in tumor volume) (p < 0.0001). Our results showed that progressive CRCLM after PVE undergo gene expression changes that indicate activation of core cancer pathways (IL-17 (p = 5.94 × 10(-03)), PI3K (p = 8.71 × 10(-03)), IL6 and IGF-1 signaling pathways), consistent with changes driven by cytokines and growth factors. Differential expression analysis in a paired model of progression (EdgeR, DeSeq) identified significantly dysregulated genes in the PDPVE group (FOS, FOSB, RAB20, IRS2).Differentially expressed genes and pathways with known links to cancer and metastasis were identified post-PVE in patients with disease progression. Highlighting these molecular changes is a crucial first step towards development of targeted therapeutic strategies that may mitigate the effects of PVE on tumor growth.

Pub.: 02 Aug '17, Pinned: 17 Aug '17

Metabolic reprogramming underlies metastatic potential in an obesity-responsive murine model of metastatic triple negative breast cancer.

Abstract: The vast majority of cancer-related deaths are due to metastatic disease, whereby primary tumor cells disseminate and colonize distal sites within the body. Triple negative breast cancer typically displays aberrant Wnt signaling, lacks effective targeted therapies, and compared with other breast cancer subtypes, is more likely to recur and metastasize. We developed a Wnt-driven lung metastasis model of triple negative breast cancer (metM-Wnt(lung)) through serial passaging of our previously described, nonmetastatic, claudin-low M-Wnt cell line. metM-Wnt(lung) cells displayed characteristics of epithelial-to-mesenchymal transition (e.g., increased invasiveness) with some re-epithealization (e.g., increased adhesion, tight colony formation, increased E-cadherin expression, and decreased Vimentin and Fibronectin expression). When orthotopically transplanted into syngeneic mice, metM-Wnt(lung) cells readily formed tumors and metastasized in vivo, and tumor growth and metastasis were enhanced in obese mice compared with non-obese mice. Gene expression analysis revealed several genes and pathways altered in metM-Wnt(lung) cells compared with M-Wnt cells, including multiple genes associated with epithelial-to-mesenchymal transition, energy metabolism and inflammation. Moreover, obesity caused significant transcriptomic changes, especially in metabolic pathways. Metabolic flux analyses showed greater metabolic plasticity, with heightened mitochondrial and glycolytic energetics in metM-Wnt(lung) cells relative to M-Wnt cells. Similar metabolic profiles were found in a second triple negative breast cancer progression series, M6 and M6C cells. These findings suggest that metabolic reprogramming is a feature of metastatic potential in triple negative breast cancer. Thus, targeting metastases-associated metabolic perturbations may represent a novel strategy for reducing the burden of metastatic triple negative breast cancer, particularly in obese women.

Pub.: 28 Jul '17, Pinned: 17 Aug '17