creating a
healthier future

Cancer Drug Resistance

ABOUT

Drug resistance remains a major obstacle to successful cancer treatment. Our research group studies drug resistance mechanisms, particularly the intercellular transfer of drug resistance traits mediated by Extracellular Vesicles. Our aim is to contribute to the identification of novel biomarkers of drug response and resistance, novel molecular targets, and novel molecules or repurposed drugs to overcome drug resistance mechanisms.

 

RESEARCH

The group’s main achievements include:

  1. Understanding molecular mechanisms of drug resistance involving the transfer of drug-resistant traits between cancer cells or between cells from the tumour microenvironment and cancer cells.
    We demonstrated that Extracellular Vesicles released by macrophages reduce pancreatic ductal adenocarcinoma cellular response to some chemotherapy drugs (Xavier C.P.R. et al., Cancer Letters 2021). We also identified metabolic alterations in multidrug-resistant cancer cells, which may be transferred by Extracellular Vesicles to drug-sensitive cells (Lopes-Rodrigues V. et al., Scientific Reports 2017).
  2. Identifying biomarkers of drug resistance and of minimal residual disease on tumour Extracellular Vesicles obtained from liquid biopsies of patients with cancer, to support clinical decisions and precision medicine.
    We addressed the monitoring of measurable residual disease in liquid biopsies from multiple myeloma patients (Bergantim R. et al., Int J Mol Sci 2022).
  3. Identifying molecular targets associated with drug resistance.
    By using next-generation sequencing, we found distinctive non-coding RNAs when comparing tumour multidrug-resistant cells and Extracellular Vesicles with their drug-sensitive counterparts (Sousa D. et al., Cancers 2020). We also identified two molecular targets, chitinase 3-like-1 and fibronectin, responsible for pancreatic ductal adenocarcinoma drug resistance in vitro (Xavier C.P.R. et al., Cancer Letters 2021).
  4. Identifying novel molecules or repurposed drugs to overcome drug resistance.
    We conducted preclinical studies on the antitumour and non-toxic effect of combining pirfenidone with vinorelbine and carboplatin in non-small cell lung cancer (Branco H. et al., Int J Cancer 2024). We also identified compounds as promising starting points to overcome cancer multidrug resistance (Kruschel R.D., Barbosa M.A.G. et al., J Med Chem 2024).

Our group has multiple national and international interdisciplinary collaborations with both scientists and clinicians, which are crucial to our translational research work.

Intercellular transfer of P-glycoprotein (Pgp) mediated by Extracellular Vesicles (EVs). This confocal microscopy image shows Pgp detection in (non-Pgp expressing) drug-sensitive tumour cells following co-culture with EVs from drug-resistant (Pgp-overexpressing) tumour cells.

Team

Selected Publications

Lopes-Rodrigues V., Di Luca A., Mleczko J., Meleady P., Henry M., Pesic M., Cabrera D., Van Liempd S., Lima R.T., O'Connor R., Falcon-Perez J.M., Vasconcelos M.H.
Identification of the metabolic alterations associated with the multidrug resistant phenotype in cancer and their intercellular transfer mediated by extracellular vesicles. Scientific Reports7:, 2017. [Journal: Article] [CI: 62] [IF: 4,1]
DOI: 10.1038/srep44541 SCOPUS: 85015308172

Fais S., O'Driscoll L., Borras F.E., Buzas E., Camussi G., Cappello F., Carvalho J., Cordeiro Da Silva A., Del Portillo H., El Andaloussi S., Ficko Trček T., Furlan R., Hendrix A., Gursel I., Kralj-Iglic V., Kaeffer B., Kosanovic M., Lekka M.E., Lipps G., Logozzi M., Marcilla A., Sammar M., Llorente A., Nazarenko I., Oliveira C., Pocsfalvi G., Rajendran L., Raposo G., Rohde E., Siljander P., Van Niel G., Vasconcelos M.H., Yáñez-Mó M., Yliperttula M.L., Zarovni N., Zavec A.B., Giebel B.
Evidence-Based Clinical Use of Nanoscale Extracellular Vesicles in Nanomedicine. ACS Nano10(4):3886-3899, 2016. [Journal: Review] [CI: 400] [IF: 13,9]
DOI: 10.1021/acsnano.5b08015 SCOPUS: 84968866526

Gonçalves A.C., Richiardone E., Jorge J., Polónia B., Xavier C.P.R., Salaroglio I.C., Riganti C., Vasconcelos M.H., Corbet C., Sarmento-Ribeiro A.B.
Impact of cancer metabolism on therapy resistance – Clinical implications. Drug Resistance Updates59:, 2021. [Journal: Review] [CI: 64] [IF: 22,8]
DOI: 10.1016/j.drup.2021.100797 SCOPUS: 85121838523

Peixoto da Silva S., Caires H.R., Bergantim R., Guimarães J.E., Vasconcelos M.H.
miRNAs mediated drug resistance in hematological malignancies. Seminars in Cancer Biology83:283-302, 2022. [Journal: Review] [CI: 19] [IF: 14,5]
DOI: 10.1016/j.semcancer.2021.03.014 SCOPUS: 85104141539

Xavier C.P.R., Castro I., Caires H.R., Ferreira D., Cavadas B., Pereira L., Santos L.L., Oliveira M.J., Vasconcelos M.H.
Chitinase 3-like-1 and fibronectin in the cargo of extracellular vesicles shed by human macrophages influence pancreatic cancer cellular response to gemcitabine. Cancer Letters501:210-223, 2021. [Journal: Article] [CI: 59] [IF: 9,8]
DOI: 10.1016/j.canlet.2020.11.013 SCOPUS: 85096944364

Sousa D., Matthiesen R., Lima R.T., Helena Vasconcelos M.
Deep sequencing analysis reveals distinctive non-coding RNAs when comparing tumor multidrug-resistant cells and extracellular vesicles with drug-sensitive counterparts. Cancers12(1):, 2020. [Journal: Article] [CI: 14] [IF: 6,6]
DOI: 10.3390/cancers12010200 SCOPUS: 85079196794

Sousa D., Lima R.T., Lopes-Rodrigues V., Gonzalez E., Royo F., Xavier C.P.R., Falcón-Pérez J.M., Vasconcelos M.H.
Different ability of multidrug-resistant and-sensitive counterpart cells to release and capture extracellular vesicles. Cells10(11):, 2021. [Journal: Article] [CI: 7] [IF: 7,7]
DOI: 10.3390/cells10112886 SCOPUS: 85117907370

Pagano L., Salmanton-Garcia J., Marchesi F., Busca A., Corradini P., Hoenigl M., Klimko N., Koehler P., Pagliuca A., Passamonti F., Verga L., Visek B., Ilhan O., Nadali G., Weinbergerova B., Cordoba-Mascunano R., Marchetti M., Collins G.P., Farina F., Cattaneo C., Cabirta A., Gomes-Silva M., Itri F., van Doesum J., Ledoux M.-P., Cernan M., Jaksic O., Duarte R.F., Magliano G., Omrani A.S., Fracchiolla N.S., Kulasekararaj A., Valkovic T., Poulsen C.B., Machado M., Glenthoj A., Stoma I., Racil Z., Piukovics K., Navratil M., Emarah Z., Sili U., Maertens J., Blennow O., Bergantim R., Garcia-Vidal C., Prezioso L., Guidetti A., del Principe M.I., Popova M., de Jonge N., Ormazabal-Velez I., Fernandez N., Falces-Romero I., Cuccaro A., Meers S., Buquicchio C., Antic D., Al-Khabori M., Garcia-Sanz R., Biernat M.M., Tisi M.C., Sal E., Rahimli L., Colovic N., Schonlein M., Calbacho M., Tascini C., Miranda-Castillo C., Khanna N., Mendez G.-A., Petzer V., Novak J., Besson C., Dulery R., Lamure S., Nucci M., Zambrotta G., Zak P., Seval G.C., Bonuomo V., Mayer J., Lopez-Garcia A., Sacchi M.V., Booth S., Ciceri F., Oberti M., Salvini M., Izuzquiza M., Nunes-Rodrigues R., Ammatuna E., Obr A., Herbrecht R., Nunez-Martin-Buitrago L., Mancini V., Shwaylia H., Sciume M., Essame J., Nygaard M., Batinic J., Gonzaga Y., Regalado-Artamendi I., Karlsson L.K., Shapetska M., Hanakova M., El-Ashwah S., Borbenyi Z., Colak G.M., Nordlander A., Dragonetti G., Maraglino A.M.E., Rinaldi A., De Ramon-Sanchez C., Cornely O.A., Finizio O., Fazzi R., Sapienza G., Chauchet A., Van Praet J., Prattes J., Dargenio M., Rossi C., Rossi C., Shirinova A., Malak S., Tafuri A., Ommen H.-B., Bologna S., Khedr R.A., Choquet S., Joly B., Ceesay M.M., Philippe L., Kho C.S., Desole M., Tsirigotis P., Otasevic V., Borducchi D.M.M., Antoniadou A., Gaziev J., Almaslamani M.A., Garcia-Pouton N., Paterno G., Torres-Lopez A., Tarantini G., Mellinghoff S., Grafe S., Borschel N., Passweg J., Merelli M., Barac A., Wolf D., Shaikh M.U., Thieblemont C., Bernard S., Funke V.A.M., Daguindau E., Khostelidi S., Nucci F.M., Martin-Gonzalez J.-A., Landau M., Soussain C., Laureana C., Lacombe K., Kohn M., Aliyeva G., Piedimonte M., Fouquet G., Rego M., Hoell-Neugebauer B., Cartron G., Pinto F., Alburquerque A.M., Passos J., Yilmaz A.F., Redondo-Izal A.-M., Altuntas F., Heath C., Kolditz M., Schalk E., Guolo F., Karthaus M., Della Pepa R., Vinh D., Noel N., Deau Fischer B., Drenou B., Mitra M.E., Meletiadis J., Bilgin Y.M., Jindra P., Espigado I., Drgona L., Serris A., Di Blasi R., Ali N.
COVID-19 infection in adult patients with hematological malignancies: a European Hematology Association Survey (EPICOVIDEHA). Journal of Hematology and Oncology14(1):, 2021. [Journal: Article] [CI: 236] [IF: 23,2]
DOI: 10.1186/s13045-021-01177-0 SCOPUS: 85117512005

Assaraf Y.G., Brozovic A., Gonçalves A.C., Jurkovicova D., Linē A., Machuqueiro M., Saponara S., Sarmento-Ribeiro A.B., Xavier C.P.R., Vasconcelos M.H.
The multi-factorial nature of clinical multidrug resistance in cancer. Drug Resistance Updates46:, 2019. [Journal: Article] [CI: 381] [IF: 11]
DOI: 10.1016/j.drup.2019.100645 SCOPUS: 85072866477

Vasconcelos M.H., Caires H.R., Ābols A., Xavier C.P.R., Linē A.
Extracellular vesicles as a novel source of biomarkers in liquid biopsies for monitoring cancer progression and drug resistance. Drug Resistance Updates47:, 2019. [Journal: Article] [CI: 114] [IF: 11]
DOI: 10.1016/j.drup.2019.100647 SCOPUS: 85074466138

Xavier C.P.R., Belisario D.C., Rebelo R., Assaraf Y.G., Giovannetti E., Kopecka J., Vasconcelos M.H.
The role of extracellular vesicles in the transfer of drug resistance competences to cancer cells. Drug Resistance Updates62:, 2022. [Journal: Review] [CI: 42] [IF: 24,3]
DOI: 10.1016/j.drup.2022.100833 SCOPUS: 85128197831

Barbosa M.A.G., Xavier C.P.R., Pereira R.F., Petrikaitė V., Vasconcelos M.H.
3D Cell Culture Models as Recapitulators of the Tumor Microenvironment for the Screening of Anti-Cancer Drugs. Cancers14(1):, 2022. [Journal: Review] [CI: 113] [IF: 5,2]
DOI: 10.3390/cancers14010190 SCOPUS: 85122071208

Xavier C.P.R., Caires H.R., Barbosa M.A.G., Bergantim R., Guimarães J.E., Vasconcelos M.H.
The role of extracellular vesicles in the hallmarks of cancer and drug resistance. Cells9(5):, 2020. [Journal: Review] [CI: 105] [IF: 6,6]
DOI: 10.3390/cells9051141 SCOPUS: 85084721560

Branco H., Xavier C.P.R., Riganti C., Vasconcelos M.H.
Hypoxia as a critical player in extracellular vesicles-mediated intercellular communication between tumor cells and their surrounding microenvironment. Biochimica et Biophysica Acta - Reviews on Cancer1880(1):, 2025. [Journal: Review] [IF: 9.7 (*)]
DOI: 10.1016/j.bbcan.2024.189244 SCOPUS: 85211747063

Teixeira-Marques A., Monteiro-Reis S., Montezuma D., Lourenço C., Oliveira M.C., Constâncio V., Sequeira J.P., Carvalho-Maia C., Freitas R., Martens-Uzunova E.S., Vasconcelos M.H., Henrique R., Jerónimo C.
Improved recovery of urinary small extracellular vesicles by differential ultracentrifugation. Scientific Reports14(1):, 2024. [Journal: Article] [CI: 1] [IF: 3.8 (*)]
DOI: 10.1038/s41598-024-62783-9 SCOPUS: 85194899067

Kruschel R.D., Barbosa M.A.G., Almeida M.J., Xavier C.P.R., Vasconcelos M.H., McCarthy F.O.
Discovery of Potent Isoquinolinequinone N-Oxides to Overcome Cancer Multidrug Resistance. Journal of Medicinal Chemistry67(16):13909-13924, 2024. [Journal: Article] [IF: 6.8 (*)]
DOI: 10.1021/acs.jmedchem.4c00705 SCOPUS: 85200372874

Lencioni G., Gregori A., Toledo B., Rebelo R., Immordino B., Amrutkar M., Xavier C.P.R., Kocijančič A., Pandey D.P., Perán M., Castaño J.P., Walsh N., Giovannetti E.
Unravelling the complexities of resistance mechanism in pancreatic cancer: Insights from in vitro and ex-vivo model systems. Seminars in Cancer Biology106-107:217-233, 2024. [Journal: Review] [IF: 12.1 (*)]
DOI: 10.1016/j.semcancer.2024.09.002 SCOPUS: 85207901348

Branco H., Rodrigues C.A., Oliveira J., Mendes N., Antunes C., Amorim I., Santos L.L., Vasconcelos M.H., Xavier C.P.R.
Preclinical studies on the antitumor and non-toxic effect of combining pirfenidone with vinorelbine and carboplatin in non-small cell lung cancer. International Journal of Cancer:, 2024. [Journal: Article] [IF: 5.7 (*)]
DOI: 10.1002/ijc.35276 SCOPUS: 85211141615

Rebelo R., Xavier C.P.R., Giovannetti E., Vasconcelos M.H.
Fibroblasts in pancreatic cancer: molecular and clinical perspectives. Trends in Molecular Medicine29(6):439-453, 2023. [Journal: Review] [CI: 30] [IF: 12.8]
DOI: 10.1016/j.molmed.2023.03.002 SCOPUS: 85153404146

Polónia B., Xavier C.P.R., Kopecka J., Riganti C., Vasconcelos M.H.
The role of Extracellular Vesicles in glycolytic and lipid metabolic reprogramming of cancer cells: Consequences for drug resistance. Cytokine and Growth Factor Reviews73:150-162, 2023. [Journal: Review] [CI: 10] [IF: 9.3]
DOI: 10.1016/j.cytogfr.2023.05.001 SCOPUS: 85159915506

Ongoing Projects

Detection of Measurable Residual Disease Biomarkers in Extracellular Vesicles from Liquid Biopsies of Multiple Myeloma Patients—A Proof of Concept
Reference: Premio Nacional de Hematologia SPH 2024
Proponent: Instituto de Investigação e Inovação em Saúde - Universidade do Porto
Sponsor: Sociedade Portuguesa de Hematologia (SPH)
From 01-JAN-25 to 31-DEC-25