VHIO-led research unveils a novel microprotein as a critical regulator of epithelial cell identity with tumor suppressor activity

Laboratorio de VHIO
  • Results of a study led by María Abad, Principal Investigator of VHIO’s Cellular Plasticity and Cancer Group, identify a new microprotein – named pTINCRas a driver of epithelial differentiation with tumor suppressor activity.
  • Published in Nature Communications*, the investigators report that various epithelial tumors lose pTINCR expression to dedifferentiate and acquire malignant properties, and that forcing pTINCR expression in patient-derived xenografts reduces tumor growth and could represent a novel therapeutic target for these tumor types.
  • This research adds to mounting evidence exposing the microproteome as a valuable source of new regulators of cell identity relevant for cancer.

Published as an open access Article in Nature Communications* VHIO-led research has functionally characterized a novel microprotein – named by the investigators as pTINCR- and shown that it plays an important role in the development of epithelial cancers. “Hundreds of microproteins are hard at work in our cells but the functions of the vast majority of them remain unknown. We have now shown that pTINCR is a key regulator of epithelial identity, promotes cellular differentiation and suppresses tumor growth,” says María Abad, Principal Investigator of the Vall d’Hebron Institute of Oncology’s (VHIO) Cellular Plasticity and Cancer Group, and corresponding author of this present study.

Over the past decade advances in genomic computational analysis, peptidomics and ribosome profiling have revealed that the human genome contains thousands of small open reading frames (sORFs) located in previously assumed non-coding regions, whose translation produces many small bioactive proteins. The modes of action of many of these microproteins have not yet been elucidated and to date only a subset of them have been functionally characterized.

“Mounting evidence including our present findings show how microproteins play key roles in many important biological processes including DNA repair, RNA splicing, calcium signaling, cell metabolism, tumor initiation and tumor suppression. These important insights are revealing the extent of their biological relevance in the regulation of physiological and pathological processes such as cancer,” observes Olga Boix, a Post-Doctoral Fellow of María Abad’s Group and first author of this present study.

Cell differentiation and tumor growth

Cell differentiation is a biological process by which cells gain specialized functions in the body and change from one cell type to another. When a differentiated cell loses its special form or function, often after exposure to damage or injury, this is referred to as dedifferentiation. This process of loss of identity is a fundamental initial step in tumor development that triggers cancer cells to divide uncontrollably, spread, evade anti-cancer therapies, and metastasize. In general, the less differentiated a tumor is, the more malignant the tumor tends to be.

Epithelial cells, such as those of the skin, are constantly challenged by exposure to different causes of cell damage including ultraviolet light. Maintaining mechanisms that safeguard cell identity is crucial in preventing the development of tumors. “We have discovered that pTINCR plays an essential role as a guardian of cell identity, promoting cell differentiation and protecting against cancer, and could therefore show promise as a novel therapeutic target,” adds Abad.

pTINCR as a novel tumor-suppressor microprotein

Dedicated to identifying new microproteins, deciphering their biological functions and studying their possible application as therapeutic targets in cancer, María Abad’s team has now functionally characterized the biological relevance of pTINCR, revealing that it is in fact is a conserved ubiquitin-like protein expressed in many epithelia and upregulated upon differentiation and under cellular stress.  Using several cellular models and patient-derived tissue samples, the researchers have shown that pTINCR is a key inducer of epithelial differentiation and enables tumor cells that have undergone loss of cellular identity through the malignant stages to reacquire characteristics of normal epithelial tissue.

To continue to wreak their havoc, tumors typically shed what disadvantages them. In human squamous cell carcinoma, the authors report partial or complete loss of pTINCR expression. This correlates with loss of epithelial cell identity and increased malignancy in tumor cells and therefore points to pTINCR as a novel tumor-suppressor microprotein.

Upon overexpressing pTINCR in patient-derived tumor xenografts the researchers observed decreased tumor aggressiveness. “Considering that cell dedifferentiation occurs in almost all tumor types, pTINCR could be an interesting therapeutic target. Moreover, our data show that the expression level of pTINCR correlates with survival in patients with different tumor types including pancreatic and lung cancer. This new microprotein could therefore serve as a novel prognostic biomarker,” concludes María Abad.

 This research was supported by grants received from the Fundación FERO (FERO Foundation), ”la Caixa” Foundation, and the Ministerio de Ciencia e Innovación (Spanish Ministry of Science and Innovation).

Reference:

Boix O, Martinez M, Vidal S, Giménez-Alejandre M, Palenzuela L, Lorenzo-Sanz L, Quevedo L, Moscoso O, Ruiz-Orera J, Ximénez-Embún P, Ciriaco N, Nuciforo P, Stephan-Otto Attolini C, Albà MM, Muñoz J, Tian TV, Varela I, Vivancos A, Ramón Y Cajal S, Muñoz P, Rivas C, Abad M. pTINCR microprotein promotes epithelial differentiation and suppresses tumor growth through CDC42 SUMOylation and activation. Nat Commun. 2022 Nov 11;13(1):6840.

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