Thread by @HoeppnerLab

Thrilled to share our work showing ASCL1 transcriptionally activates DARPP-32 to promote small cell #lungcancer growth published in @BrJCancer. #OpenAccess A thread! 1/
nature.com/articles/s4141…

This project was admirably led by a talented postdoc, @kayumalam, and resulted from outstanding @UMNresearch, @UMNCancer, and @MayoClinic
collaborations with @cauyrd, Dr. Farhad Kosari, and Dr. Anja Roden. Thanks to all co-authors for their important contributions! 2/

DARPP-32 and its N-terminally truncated splice variant, named t-DARPP, promote oncogenesis in a variety of adenocarcinomas, but the role of DARPP-32 in neuroendocrine tumors hadn't been explored yet. 3/

In 2018, we showed DARPP-32 & t-DARPP stimulate lung tumor cell survival & IKKa-mediated migration to stimulate NSCLC growth. Elevated t-DARPP protein levels in NSCLC patients were associated with increased tumor staging and worsened patient survival. 4/ nature.com/articles/s4200…

DARPP-32 and t-DARPP modulate PP-1 activity to control dopaminergic neurotransmission as well as regulate oncogenic signaling when DARPP-32 isoforms are aberrantly overexpressed in tumor cells. Essentially, DARPP-32 can act as a kinase or a protein phosphatase inhibitor. 5/

We hypothesized that DARPP-32 and t-DARPP contribute to neuroendocrine tumor growth in small cell lung cancers, given the primary function of DARPP-32 proteins in neurons and their multifaceted oncogenic role in many non-brain cancers. 6/

We demonstrate that DARPP-32 and t-DARPP promote SCLC growth through increased Akt/Erk-mediated
proliferation and anti-apoptotic signalling in human SCLC cells and show in orthotopic xenograft models that DARPP-32 isoforms drive tumor growth. 7/

Thanks to support from Dr. Farhad Kosari & pulmonary pathologist, Dr. Anja Roden, at @MayoClinic, we found DARPP-32 isoforms are overexpressed in patient-derived SCLC tumors, but virtually undetectable in normal lung tissue. Future studies w/ more specimens warranted & needed. 8/

We relied on @cauyrd's bioinformatics expertise to show transcripts associated w/ Notch signaling are upregulated in a subset of SCLC patient-derived tumors expressing high levels of DARPP-32 (RNA-Seq dataset: 29 SCLC patients, 23 w/ paired normal lung tissue- Rudin CM, 2012) 9/

Achaete-scute homologue 1 (ASCL1) transcript, a neuroendocrine lineage-specific oncogene whose expression is inhibited by active Notch signalling, was highly upregulated in SCLCs overexpressing t-DARPP. 10/

We identified 3 ASCL1 binding sites (CAGCTG motif) within the PPP1R1B promoter (from which DARPP-32 and t-DARPP proteins are transcribed) and showed ASCL1 transcriptionally regulates DARPP-32 expression. 11/

In summary, we show DARPP-32 & t-DARPP promote SCLC proliferation, evasion apoptosis, activation of AKT & ERK, & increased tumor growth in vivo. DARPP-32 proteins are overexpressed in patient-derived SCLCs and are transcriptionally regulated by ASCL1. 12/

Based on the clinical significance of DARPP-32 in cancer & its role in AKT activation & resistance, DARPP-32 and/or associated signaling molecules may represent potential therapeutic target(s). Future direction: Determining exact mechanism of DARPP-32-mediated AKT activation. 13/

Happy to discuss our work, explore potential collaborations, share #openscience resources, and/or answer any questions. Thanks so much for reading this thread and your interest in our studies! #AcademicChatter #LCSM 14/ (end)

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