Research in the Okimoto lab broadly aims to understand how transcriptional dependence leads to cancer progression and metastasis. Current efforts in the lab include:
Identifying the molecular determinants of cancer metastasis.
Metastasis is the greatest contributor to cancer-related death, yet there are few effective therapies to prevent or limit the spread of cancer. The challenge to therapeutically inhibit metastasis is due to the lack of tractable in vivo systems that rapidly recapitulate the entire metastatic cascade, from primary tumor formation to distant organ colonization in a single host organism. We aim to develop and employ in vivo model systems to identify and functionally dissect the molecular events that promote cancer metastasis.
Selected References:
Inactivation of Capicua drives cancer metastasis. Nat Genet. 2017
Nuclear TARBP2 Drives Oncogenic Dysregulation of RNA Splicing and Decay. Mol Cell. 2019
Functional screening identifies aryl hydrocarbon receptor as suppressor of lung cancer metastasis. Oncogenesis. 2020
Single-cell lineages reveal the rates, routes, and drivers of metastasis in cancer xenografts. Science. 2021
Primary and metastatic tumors exhibit systems-level differences in dependence on mitochondrial respiratory function. PLoS Biol. 2022
Understanding Capicua (CIC) biology across human cancer.
Aberrant transcription factor (TF) control arises through diverse mechanisms, including altered gene expression, genetic changes, and post-translational modification. A key unanswered question remains whether the mode of TF dysregulation uniquely contributes to defined phenotypes across human cancer subtypes. As a model system, we focus on Capicua (CIC), a transcriptional factor with critical roles in normal development, cancer progression, and metastasis. CIC is differentially regulated through ERK mediated post-translational modification in certain adenocarcinoma subsets. Beyond post-translational modification, CIC can be genetically altered through mutation, deletion, or gene rearrangement. Remarkably, the mode of CIC disruption is unique in distinct cancer histologies. For example, in undifferentiated small round cell sarcoma, alterations in CIC occur in the context of an oncogenic fusion. In contrast to the repressor activity of wild-type CIC, the CIC-DUX4 fusion results in activation of conserved CIC target genes, which is sufficient to induce undifferentiated small round cell sarcoma formation and lethal metastatic disease. Thus, a fundamental question that our research will address is how differential dysregulation of CIC can lead to cancer relevant phenotypes, including metastasis, across distinct histological subtypes of human cancer and to develop novel therapies that target this molecular program.
Selected References:
Inactivation of Capicua drives cancer metastasis. Nat Genet. 2017.
CIC-DUX4 oncoprotein drives sarcoma metastasis and tumorigenesis via distinct regulatory programs. J Clin Invest. 2019
Negative MAPK-ERK regulation sustains CIC-DUX4 oncoprotein expression in undifferentiated sarcoma. Proc. Natl. Acad. Sci. 2020
Capicua in Human Cancer. Trends Cancer, 2020
WEE1 kinase is a therapeutic vulnerability in CIC-DUX4 undifferentiated sarcoma. JCI Insight. 2022
Capicua suppresses YAP1 to limit tumorigenesis and maintain drug sensitivity in human cancer. Cell Rep. 2022
The CIC-ERF co-deletion underlies fusion-independent activation of ETS family member, ETV1, to drive prostate cancer progression. Elife. 2022
Exploiting transcription factor dependence in human sarcoma.
Genomic transcription factor (TF) translocations are observed in ~20-30% of soft-tissue tumors and represent a major driver of sarcoma biology. Despite their identification, our ability to therapeutically target TF fusions remains limited. Leveraging sarcoma as a clinica model, our research program has developed a collaborative bio-specimen resource aimed at establishing, profiling, and developing ex vivo and in vivo model systems to study TF dependence in cancer. Collectively, we aim to construct a clinically annotated sarcoma fusion repository to deeply understand how TF fusion oncoproteins lead to transcriptional dysregulation across sarcoma subtypes. Harnessing molecular and mechanism-based therapeutics, we aim to reveal TF-fusion specific vulnerabilities to overcome transcriptional dependence in human cancer.
