Dataset Information

SILAC & LC-MSMS in total cell extracts or in the secretome of POU5F1B- vs. GFP-overexpressing SW480 cells

ABSTRACT: The treatment of colorectal cancer (CRC) is an unmet medical need in absence of early diagnosis. Here, upon characterizing cancer-specific transposable element-driven transpochimeric gene transcripts (TcGTs) produced by this tumor, we found that expression of the hominid-restricted retrogene POU5F1B through aberrant activation of a primate-specific endogenous retroviral promoter is a strong negative prognostic CRC biomarker. Correlating this observation, we could demonstrate that POU5F1B fosters the proliferation and metastatic potential of CRC cells. We further determined that POU5F1B, in spite of its phylogenetic relationship with the POU5F1/OCT4 transcription factor, is a membrane-enriched protein that associates with protein kinases and known targets or interactors as well as with cytoskeleton-related molecules, and induces intracellular signaling events and the release of trans-acting factors involved in cell growth and cell adhesion. As POU5F1B is an apparently non-essential gene only lowly expressed in normal tissues, and as POU5F1B-containing TcGTs are detected in other tumors besides CRC, our data provide interesting leads for the development of cancer therapies.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Colon Cancer

SUBMITTER: Julien Duc

LAB HEAD: Didier Trono

PROVIDER: PXD028035 | Pride | 2022-10-14

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	LS_210602_Lumos_SA_F01.raw	Raw
	LS_210602_Lumos_SA_F02.raw	Raw
	LS_210602_Lumos_SA_F03.raw	Raw
	LS_210602_Lumos_SA_F04.raw	Raw
	LS_210602_Lumos_SA_F05.raw	Raw

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Publications

Transposon-activated POU5F1B promotes colorectal cancer growth and metastasis.

Simó-Riudalbas Laia L Offner Sandra S Planet Evarist E Duc Julien J Abrami Laurence L Dind Sagane S Coudray Alexandre A Coto-Llerena Mairene M Ercan Caner C Piscuoglio Salvatore S Andersen Claus Lindbjerg CL Bramsen Jesper Bertram JB Trono Didier D

Nature communications 20220820 1

The treatment of colorectal cancer (CRC) is an unmet medical need in absence of early diagnosis. Here, upon characterizing cancer-specific transposable element-driven transpochimeric gene transcripts (TcGTs) produced by this tumor in the SYSCOL cohort, we find that expression of the hominid-restricted retrogene POU5F1B through aberrant activation of a primate-specific endogenous retroviral promoter is a strong negative prognostic biomarker. Correlating this observation, we demonstrate that POU5F ...[more]

PMID: 35987910

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Project description:The epithelial growth factor receptor (EGFR) signalling network plays an essential role inproliferation and survival of colorectal cancer cells. For this reason, EGFR is targeted using therapeutic antibodies blocking EGFR signalling (e.g. cetuximab). However, anti-EGFR therapy is rarely curative as subpopulations of tumor cells survive the initial treatment and develop therapy-resistance. To analyse cellular signalling and assess the quantitative changes of the proteome and the phosphoproteome several proteomics approaches have been established. Here, we compared the widely used quantification strategies label-free (LF), SILAC and TMT and systematically evaluated their technical characteristics including coverage, technical variability, complementarity and the ability to assess statistical significant differences. We studied the dynamics of the EGFR signalling network upon treatment withcetuximab after 0 h, 3 h and 24 h, representing the first cellular adaption towards anti-EGFR therapy, with the aim to identify the most powerful approach for monitoring cellular signalling in this setup. We demonstrate that LF had a superior coverage regarding quantification of both, the proteome and phosphoproteome, while SILAC exhibited the highest precision resulting in superior assessment of differentially abundant proteins and class I phosphosites (p-sites). TMT was outperformed by the other two approaches, illustrating its critical dependency on the applied labelling-design. On the protein level, we observed only little regulation upon cetuximab treatment, whereas a great fraction of p-sites was significantly regulated after 3 h and 24 h. The dynamics of significantly regulated p-sites illustrated an initial downregulation of the EGFR and MAPK signalling pathways, which was partially rescued as soon as after 24h. We identified upregulation and signalling via ERBB3 as a possible mechanism bypassing the blockage of EGFR. Moreover, phosphorylation motifs associated to calcium signalling were continuously upregulated, thereby representing compensatory signalling presumably resulting in the observed reactivation of MAPK1/3 (Erk1/2).