Online Competition Winners 2020

FIRST PRIZE 

Lisa Situ | G2
Biological and Biomedical Sciences
Cichowski lab

Targeting mitochondrial dynamics in melanoma

Although 15-30% of melanomas harbor activating mutations in NRAS, there are currently no approved targeted therapies for this subtype of melanoma. We are interested in developing a novel combination therapy that can improve the clinical efficacy of MEK inhibitors in these tumors. We previously performed a genome-scale CRISPR negative selection screen to identify genes which when suppressed confer sensitization to MEK inhibition. MARCH5 was one of the most significant hits, and our goal is to understand the mechanism by which dual inhibition of MARCH5 and MEK specifically kills NRAS-mutant melanoma cells. MARCH5 is a mitochondrial E3 ubiquitin ligase that has been implicated in the regulation of mitochondrial morphology. We hypothesize that MARCH5 and MEK cooperate to regulate mitochondrial dynamics and that disruption of this axis sensitizes NRAS-mutant melanomas to cell death. While the goal of this research is to advance a potential combination therapy into the clinic for patient benefit, our work will also elucidate novel information about an important but understudied mitochondrial E3 ligase and its interactions with the Ras signaling pathway.

Lisa Situ - 1st Prize

SECOND PRIZE

Bing Shui | G4
Biological and Biomedical Sciences
Kevin Haigis lab

KRas activation induces global down regulation of miRNA function in colorectal cancer

KRas is frequently mutated in three of the four deadliest human cancers (PDAC, CRC, NSCLC) and regulates miRNAs. miRNAs are immediately actionable therapeutic targets given the large repertoire of miRNA mimics and inhibitors. Investigations of miRNA targets have been dependent on computational algorithms. My thesis project has used newly developed HEAP-CLIP to map physiologic targets of miRNA in vivo in murine colorectal cancer +/- oncogenic KRas. Our data suggest that the activation of KRas in tumors greatly expands the miRNA target repertoire and increases miRNA targeting intensity across all major miRNA families. However, this global up-regulation of miRNA targeting paradoxically de-suppresses target expressions. The concordant global increase of miRNA targeting and miRNA targets could be attributed to the down-regulation of Ago2 phosphorylation at S829-S835, regulated by CK1. We hypothesize that KRas activation in colon cancer suppresses CK1 family kinases, subsequently decreases phospho-Ago2 (S829-S835). A recent study reported that the loss of these phosphorylations inhibited the dynamic cycling of Ago2, causing increased miRNA binding to mRNA targets with decreased gene suppression. My work will elucidate a novel interaction between KRas signaling and miRNA machinery and potentially reveal therapeutic vulnerabilities of colorectal cancer, which remains elusive to modern therapies.

 

THIRD PRIZE

Kristin Qian | G2
Biological and Biomedical Sciences
Kadoch lab

Elucidating the differential roles of human ATP-dependent chromatin remodeling complexes

ATP-dependent chromatin remodeling complexes (CRCs) play critical roles in the maintenance of tissue- and state-specific chromatin structure and the regulation of gene expression by dynamically positioning nucleosomes along the genome. Importantly, these CRCs are involved in development and differentiation, and mutations in genes encoding CRC protein subunits result in diverse pathologies of cancer and neurodevelopmental disorders. SWI/SNF remodeling complexes, which are mutated in ~20% of cancers, have been extensively studied in our lab. In addition to SWI/SNF, there are three other families of related ATP-dependent CRCs: ISWI, CHD, and INO80. Across these families, there are approximately two dozen CRCs conserved from yeast to human. However, the field lacks an integrative analysis dissecting the roles of these CRCs, and it is unknown how perturbations in each complex family affect the global chromatin landscape. I propose to assess the chromatin localization and remodeling activities of each family of CRCs and their role in regulating accessibility and gene expression at various stages of differentiation and in disease settings driven by CRC mutations. To that end, this study aims to advance our understanding of CRC-directed chromatin changes and to define differential CRC functions in establishing and maintaining chromatin architecture.