Cell Plasticity & Epigenetics - Maximiliano Portal

Maximiliano Portal is a biotechnology-trained molecular biologist who obtained his degree from the University of Quilmes, Buenos Aires, Argentina in 2001. Following his initial studies, he pursued his PhD at National University of Cordoba, Argentina where he worked unraveling the molecular basis underlying non-canonical signaling/metabolic pathways governed by the transcription factor c-Fos during tumorigenesis. Immediately after his PhD, he joined the Institute of Genetics, Molecular and Cellular Biology (IGBMC) in Strasbourg, France where he focused his research into the biology of non-coding RNAs. During this period Maximiliano unveiled the crosstalk between miRNAs and the basal transcriptional machinery during cell division and further discovered a novel family of non-coding RNAs termed as natural double-stranded RNAs (ndsRNAs). The widespread ramifications of the later led to two international patents and dedicated funding to develop a platform that enables the use of ndsRNAs as molecular diagnostic tools.

In 2017, Maximiliano joined the CRUK Manchester Institute as an Institute Fellow to establish the Cell Plasticity & Epigenetics group focusing on unravelling the role that non-coding RNA molecules play in the genesis and propagation of non-genetic information through the acquisition of drug-tolerance in cancer relevant settings.


It is generally accepted that tumours are subjected to a myriad of evolutionary constraints at their niche of origin and further within the ecosystems encountered while invading novel tissues. Thus, evolutionary forces shape cancer development on many levels, as progression of the disease is often correlated with the appearance of somatic mutations and the selection of genetic traits that eventually become beneficial to neoplastic growth and often prejudicial to the host. Indeed, often-acquired mutations alter growth control systems and obliterate cell death programs, ultimately granting mutated cells with replicative immortality at the expense of genetic instability. However, due to the variable nature of the selective pressure in a particular niche, stable somatic mutations arise only after recurrent encounters with a challenging force. This suggests that, though under heavy evolutionary constraints, genetic changes driving adaptation do not occur immediately and highlights the biological relevance of cancer cell plasticity during neoplastic evolution.

Figure 1: Conceptual flow underlying our research lines. As RNA molecules encode genetic and epigenetic information we propose that they serve as information reservoirs and also functions as genome interpreters. We hypothesise that the RNA content of a cell plays a fundamental role in the genesis, maintenance and propagation of molecular memory thus bridging cell plasticity with mechanisms ensuring the proper inheritance of epigenetically encoded traits. Ultimately, we propose that the improper acquisition of molecular memories has a profound impact in cellular homeostasis that results in the emergence of pathological states.

A striking example that brings forward the plasticity of cancer cells is their resilience when confronted with therapeutic paradigms. Indeed it is acknowledged that, in response to sustained treatment, cancer cells may acquire genetic mutations that permanently block the tumouricidal action of the administered drug. However, in other settings, the emergence of fully drug-resistant clones cannot be explained by genetic mechanisms and results from cells that escape the initial death challenge by “adapting” to the pernicious agent. In the latter scenario, the traits granting adaptation to treatment are reversible in nature and are readily inherited through several cell divisions. This particularity strongly suggests the existence of a non-genetically encoded “temporal memory” underlying the acquisition of “drug-tolerant” phenotypes and represents an exquisite example of the transfer of non-genetic information through cell division.

Along those lines, the ultimate goal of our lab is to unravel the network of molecular systems supporting cell plasticity and to shed light onto the core mechanisms underlying the inheritance of epigenetically encoded traits. We are currently setting up a multidisciplinary team that takes advantage of high-throughput sequencing and imaging technologies as well as more traditional molecular and cellular biology techniques to analyse the role of non-coding RNA molecules in the generation and propagation of epigenetic memories through subsequent cell divisions with particular interest in the acquisition of drug-tolerance in cancer relevant settings.


Selected Publications

Portal MM*, Pavet V, Erb C and Gronemeyer H*. (2015)
TARDIS, a Targeted RNA Directional Sequencing method for rare RNA discovery.
Nature Protocols 10(12):1915-38. *Corresponding authors. PubMed abstract

Portal MM*, Pavet V, Erb C and Gronemeyer H*. (2015)
Human cells contain natural double stranded RNAs with potential regulatory functions”.
Nature Structural & Molecular Biology 22(1):89-97. *Corresponding authors. PubMed abstract

Portal MM. (2011)
miR-27a regulates basal transcription by targeting the p44 subunit of TFIIH.
Proc Natl Acad Sci U S A 108(21):8686-91. PubMed abstract

Portal MM. (2011)
Clash of the Titans: microRNAs masters basal transcription.
Cell Cycle 10(19):3219-20. PubMed abstract

Pavet V, Portal MM, Moulin JC, Herbrecht R and Gronemeyer H. (2011)
Towards novel paradigms for cancer therapy.
Oncogene 30(1):1-20. PubMed abstract

Portal MM, Ferrero GO and Caputto BL. (2007)
N-terminal c-Fos tyrosine phosphorylation regulates c-Fos/ER association and c-Fos dependent phospholipid synthesis activation.
Oncogene 26(24):3551-8. PubMed abstract

Gil GA, Bussolino DF, Portal MM, Pecchio AA, Renner ML, Borioli GA, Guido ME, Caputto BL. (2004)
c-Fos activated phospholipid synthesis is required for neurite elongation in differentiating PC12 cells.
Molecular Biology of the Cell 15(4):1881-94. PubMed abstract

Postdoctoral Fellow
Yelizaveta Shlyakthina

Graduate Student
Katherine L. Moran

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