Eventos

Speaker: Marta Cascante
Institution: Dept of Biochemistry and Molecular Biomedicine-Institute of Biomedicine (IBUB) University of Barcelona , Spain
Place: Jerónimo Forteza CIPF conference room

Abstract:

Metabolic phenotyping from cells to tumor biopsies: towards the design of personalized therapies

Colorectal cancer (CRC) is the second leading cancer in mortality, with the vast majority of its deaths attributable to distant metastasis. Even though genetic alterations drive cancer initiation, few genetic changes are identified during the metastatic process and epigenetic or metabolic changes have emerged as hallmarks of metastasis. Current standard-of-care for metastatic colorectal cancer (mCRC) patients includes chemotherapy such as FOLFOX and anti-angiogenic or anti-EGFR in microsatellite stable (MSS). Immunotherapy only has been successful for microsatellite instable (MSI) tumors. The efficacy of chemotherapy in CRC is limited by the emergence of chemoresistance, which remarks the need of new tools for patient selection for specific therapies and for the design of new combined therapies to overcome chemoresistance.  Since metabolic reprogramming is known to be an important hallmark of cancer, tumor metabolic metabolism is considered a sensitive target in the design of combined therapies.

Here I will present our recent results characterizing metabolic adaptations of mCRC and on tools towards a metabolic classification of tumours that contribute to the identification of patient subsets more suitable for optimally tailored combined therapies.

First, I will show the workflow that we developed to integrate multiple layers of -omics data and characterize putative drug targets to impair metabolic adaptations that sustain CRC metastatic potential. Using this workflow, we built genome-scale metabolic flux models (GSMMs)Marta that allowed us to predicted and validated cystine uptake and folate metabolism as potential targets against mCRC.

Second, I will present our work in progress towards the identification of  immunometabolic distinctive phenotypes conserved across diverse tumour types and the potential that offers the metabolic stratification of tumours in the design of patient-tailored combined therapies.

Finally, I will discuss the possibilities that offer GSMMs to complement integrated physiology towards the identification of metabolic key players in metabolic diseases and to inform the design of new combined therapies.

12:00 – 12:30 Camilla Pegoraro

Novel polypeptide-based drug delivery systems for precise mitochondria targeting

In today’s pharmaceutical era, many emerging therapies rely on releasing therapeutics at a subcellular level. Given the role of mitochondrial dysfunctions in diseases such as cancer, there is a particular focus on developing systems targeting mitochondria specifically. However, it is challenging to deliver therapies to this organelle due to its compartmentalized and difficult-to-penetrate membranes, as well as the need to bypass the cell membrane and ensure cytosolic delivery. Polypeptide-based systems offer a promising solution for delivering therapeutics in a controlled and targeted manner.

In this context, within my Ph.D. thesis being performed as part of the Marie Curie International Training Network (ITN) Biomolmacs, we have designed, synthesized and characterized two different polyornithine (PLO)-based systems with a high propensity for mitochondria. In the first platform, a complex system based on PLO and TPP was designed to ensure cytosolic release after endocytosis and mitochondria targeting. In the second design, PLO-based diblock copolymers were developed to target the mitochondria after direct cell membrane permeation. Internalization studies by confocal fluorescence microscopy and extensive studies with model membrane systems (GUVs and SUVs) were applied to confirm the mitochondria affinity. To test the effectiveness of the diblock copolymer carrier, we covalently linked two drugs that target mitochondria, lonidamine and α-tocopherol succinate (TOS), and evaluated their activity by analyzing the mitochondria membrane potential with the JC-1 assay and measuring the mitochondria respiration using Seahorse Analytics. Moreover, the mitochondria targeting vector was covalently coupled to a molecular motor to test the hybrid system’s effectiveness in enhancing membrane permeation. In conclusion, we designed, characterized and extensively tested in vitro novel mitochondria-targeted platforms and their derivatives with promising features as a subcellular cancer therapy.

12:30 – 13:00 Francesca de Angelis

HAPLN1 is a driver for peritoneal carcinomatosis in PDAC

Pancreatic ductal adenocarcinoma (PDAC) frequently metastasizes into the peritoneum, which contributes to poor prognosis. Despite the cancer cell intrinsic features, a key regulator of metastasis is the microenvironment that tumor cells are facing during their metastatic journey. Here, we show that a protein of the extracellular matrix, HAPLN1, which crosslinks Hyaluronan (HA) and proteoglycan, is associated with worse overall patient survival. Its presence in the extracellular matrix enhances tumor cell plasticity and PDAC metastasis in the peritoneal cavity. Mechanistically, we observed that HAPLN1 promotes upregulation of Hyaluronan (HA) production, facilitating EMT, stemness, invasion and immunomodulation. As such, we identified HAPLN1 as a prognostic marker and as a driver for peritoneal metastasis in PDAC.