Dataset Information

Characterization of CD44s glycoproteoforms in bladder tumours and bladder cancer cell culture models

ABSTRACT: Bladder cancer (BC) is a major health concern retaining high mortality rates when diagnosed at advanced stages. In this context, the clinical management of BC requires the introduction of new biomarkers and molecular targets capable to elicit precision medicine therapeutical approaches. A promising candidate is cluster of differentiation 44 (CD44), a multifunctional and heavily glycosylated transmembrane protein, involved in cell-cell and cell-matrix adhesion, and a transducer of several oncogenic signalling cascades. CD44 has been widely explored as a marker of BC aggressiveness and cancer stem cells (CSC), but this is a highly heterogenic protein and the lack of molecular tools for precise molecular characterization has led to conflicting results, delaying clinical application. CD44 molecular variability results from the number of proteoforms arising from alternative splicing. The human CD44 gene consists of 17 exons, and while the exons 1-5 are constitutively expressed, exons 6-14 are subjected to alternative splicing, generating a myriad of different variants whose functional implications are yet to be fully understood. Furthermore, this number of proteoforms is greatly amplified by O-GalNAc glycosylation, which is predicted to mostly occur in the protein variable regions. This microheterogeneity and its relevance for BC can only be addressed by obtaining a comprehensive characterization at the protein level. Herein, we devised a strategy, combining transcriptomics, glycomics and mass spectrometry based proteomics data, to interrogate CD44 proteoform expression in a series of BC cell culture models showing different aggressiveness (5637 and T24) and a sample pool from formalin fixed paraffin embedded (FFPE) tumours. Glycoengeneered T24 cells expressing the Tn antigen (T24 C1GALT1 knockout (KO)) were also analysed.

INSTRUMENT(S): LTQ Orbitrap, Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Urinary Bladder Urothelium

DISEASE(S): Urinary Bladder Cancer

SUBMITTER: André Silva

LAB HEAD: José Alexandre Ferreira

PROVIDER: PXD028307 | Pride | 2022-05-19

REPOSITORIES: pride

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Publications

Glycoproteogenomics characterizes the CD44 splicing code associated with bladder cancer invasion.

Gaiteiro Cristiana C Soares Janine J Relvas-Santos Marta M Peixoto Andreia A Ferreira Dylan D Paulo Paula P Brandão Andreia A Fernandes Elisabete E Azevedo Rita R Palmeira Carlos C Freitas Rui R Miranda Andreia A Osório Hugo H Prieto Jesús J Lima Luís L Silva André M N AMN Santos Lúcio Lara LL Ferreira José Alexandre JA

Theranostics 20220328 7

<b>Rationale:</b> Bladder cancer (BC) management demands the introduction of novel molecular targets for precision medicine. Cell surface glycoprotein CD44 has been widely studied as a potential biomarker of BC aggressiveness and cancer stem cells. However, significant alternative splicing and multiple glycosylation generate a myriad of glycoproteoforms with potentially distinct functional roles. The lack of tools for precise molecular characterization has led to conflicting results, delaying cl ...[more]

PMID: 35547758

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Project description:Breast cancers contain a minority population of cancer cells characterized by CD44 expression but low or undetectable levels of CD24 (CD44+CD24-/low) that have higher tumorigenic capacity than other subtypes of cancer cells. METHODS: We compared the gene-expression profile of CD44+CD24-/low tumorigenic breast-cancer cells with that of normal breast epithelium. Differentially expressed genes were used to generate a 186-gene invasiveness gene signature (IGS), which was evaluated for its association with overall survival and metastasis-free survival in patients with breast cancer or other types of cancer. RESULTS: There was a significant association between the IGS and both overall and metastasis-free survival (P<0.001, for both) in patients with breast cancer, which was independent of established clinical and pathological variables. When combined with the prognostic criteria of the National Institutes of Health, the IGS was used to stratify patients with high-risk early breast cancer into prognostic categories (good or poor); among patients with a good prognosis, the 10-year rate of metastasis-free survival was 81%, and among those with a poor prognosis, it was 57%. The IGS was also associated with the prognosis in medulloblastoma (P=0.004), lung cancer (P=0.03), and prostate cancer (P=0.01). The prognostic power of the IGS was increased when combined with the wound-response (WR) signature. CONCLUSIONS: The IGS is strongly associated with metastasis-free survival and overall survival for four different types of tumors. This genetic signature of tumorigenic breast-cancer cells was even more strongly associated with clinical outcomes when combined with the WR signature in breast cancer. Expression profling was performed on 6 tumorigenic, 3 non tumorigenic samples of breast tumors and 3 normal breast samples on two different platforms GPL96 and GPL97. A gene signature was derived by comparing the gene expressions of 6 tumorigenic samples with 3 normal breast samples.

			Action	DRS
	5637_CID_lane1_1.msf	Msf
	5637_CID_lane1_1.raw	Raw
	5637_CID_lane3.msf	Msf
	5637_CID_lane3.raw	Raw
	5637_CID_lane4.msf	Msf