Browsing by Author "Friedersdorf, Matthew B"

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Open Access
Ras Post-transcriptionally Enhances a Pre-malignantly Primed EMT to Promote Invasion.
(iScience, 2018-06) Bisogno, Laura S; Friedersdorf, Matthew B; Keene, Jack D
Epithelial-to-mesenchymal transition (EMT) is integral to cancer progression, with considerable evidence that EMT has multiple intermediary stages. Understanding the mechanisms of this stepwise activation is of great interest. We recreated a genetically defined model in which primary cells were immortalized, resulting in migratory capacity, and subsequently H-Ras-transformed, causing malignancy and invasion. To determine the mechanisms coordinating stepwise malignancy, we quantified the changes in messenger RNA (mRNA) and protein abundance. During immortalization, we found dramatic changes in mRNA, consistent with EMT, which correlated with protein abundance. Many of these same proteins also changed following Ras transformation, suggesting that pre-malignant cells were primed for malignant conversion. Unexpectedly, changes in protein abundance did not correlate with changes in mRNA following transformation. Importantly, proteins involved in cellular adhesion and cytoskeletal structure decreased during immortalization and decreased further following Ras transformation, whereas their encoding mRNAs only changed during the immortalization step. Thus, Ras induced EMT-associated invasion via post-transcriptional mechanisms in primed pre-malignant cells.
Open Access
The RNA-binding protein DND1 acts Sequentially as a negative regulator of pluripotency and a positive regulator of epigenetic modifiers required for germ cell reprogramming.
(Development (Cambridge, England), 2019-06-28) Ruthig, Victor A; Friedersdorf, Matthew B; Garness, Jason A; Munger, Steve C; Bunce, Corey; Keene, Jack D; Capel, Blanche
The adult spermatogonial stem cell population arises from pluripotent primordial germ cells (PGCs) that enter the fetal testis around embryonic day (E)10.5. PGCs undergo rapid mitotic proliferation, then enter prolonged cell cycle arrest (G1/G0) during which they transition to pro-spermatogonia. In mice homozygous for the Ter mutation in the RNA-binding protein Dnd1 (Dnd1 Ter/Ter ), many male germ cells (MGCs) fail to enter G1/G0, and form teratomas, tumors containing many embryonic cell types. To investigate the origin of these tumors, we sequenced the MGC transcriptome in Dnd1 Ter/Ter mutants at E12.5, E13.5, and E14.5, just prior to teratoma formation, and correlated this information with DO-RIP-Seq identified DND1 direct targets. Consistent with previous results, we found DND1 controls down-regulation of many genes associated with pluripotency and active cell cycle, including mTor, Hippo and Bmp/Nodal signaling pathway elements. However, DND1 targets also include genes associated with male differentiation including a large group of chromatin regulators activated in wild type but not mutant MGCs during the E13.5 and E14.5 transition. Results suggest multiple DND1 functions, and link DND1 to initiation of epigenetic modifications in MGCs.