Luís Costa Lab

Translational Oncobiology

Metastases are the hallmark of cancer lethality. They represent a unique and complex phenomenon, associated not only with genomic alterations in cancer cells, but also with a heterotypic signaling between cancer cells and host tissues. Our main goals are to better understand the molecular mechanisms driving tumor progression at the metastatic site (using bone metastases as a paradigm); to unravel molecular signatures of organotropism through identification of “leader gene signatures” common to the primary tumor and corresponding metastasis (using colorectal cancer (CRC) as a model); and to understand how systemic metabolic environments and changes in tumor cell metabolism, may contribute towards the onset and progression of different cancers.

We are also exploring the cellular and molecular mechanisms involved in cancer cell dissemination en route to forming metastases. This involves studying in detail the interactions between cancer cells and endothelial cells at primary tumors (for the exit/intravasation of the former) and at sites of metastatic dissemination (extravasation).

We also focus in the identification of the mechanisms involved in resistance to therapy in the metastatic setting, as well as in finding new therapeutic strategies to overcome such resistance. Currently our studies are mainly centered in the RANKL-RANK pathway and PLCg as mediators of resistance to therapy in breast and colorectal cancer, respectively. It is also our objective to interpret the dynamics of metastatic cancer progression by comprehensive analysis of clonal evolution and host immune and humoral response.

Sponsorship:

Research Team

Research Areas

• Bone metastases onset, progression and therapeutics
• Mechanisms of invasion and progression of colo-rectal cancer
• Mechanisms of resistance to therapy in the metastatic setting
• Comprehensive analysis of clonal evolution and host immune and humoral response by liquid biopsy

Ongoing Research Projects

2022-2024 FRONTAL. Coordinator: Luis Costa. Funding Agency: Roche.

2021-2023 IFN-mediated immune response in patients with metastatic breast cancer under CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET). Coordinator: Sandra Casimiro. Funding Agency: Pfizer.

2021-2023 Development of lupine and chickpea-based beverage as a functional food against colorectal cancer (PTDC/OCE-ETA/4836/2021): Coordinator: Ricardo Batista. Funding Agency: Fundação para a Ciência e para a Tecnologia.

2021-2023 A molecular and nano approach to target the RANK-TRAF6 interface for bone metastases treatment (PTDC/QUI-OUT/3854/2021): Coordinator: João Galamba. Funding Agency: Fundação para a Ciência e para a Tecnologia.

2021-2023 Multifunctional nano-immunotherapy for melanoma brain metastases treatment (PTDC/BTM-SAL/4350/2021). Coordinator: Helena Florindo. Funding Agency: Fundação para a Ciência e para a Tecnologia.

2021-2023 Multidimensional cartography of breast cancer micro- environment: identification of novel biomarkers predicting clinical outcome and uncover targets for therapeutic drugs. Coordinator: Karine Serre. Funding Agency: iMM- Laço Hub.

2020-2023 Sarcomas’ Metabolomics. Coordinator: Isabel Fernandes. Funding Agency: PharmaMar.

2020-2023 MCPP- Illumina. Coordinator: Luís Costa. Funding Agency: Illumina.

2020-2022 Estudo clinico-genómico retrospetivo - Otimização do valor em Saúde no follow-up das mulheres com cancro da mama em Portugal. Coordinator: Raquel Brás. Funding Agency: Roche.

2020-2022 MCPP - Multi-Cancer Profile Project Coordinator: Luis Costa. Funding Agency: Several

2020-2021 Regulation of Breast Cancer Intravasation. Coordinator: Ana Magalhães. Funding Agency: Fundo iMM-Laço.

2019-2023 WeGuide: Guia em saúde nos doentes com carcinoma colorretal – há um papel? Coordinator: Luis Costa. Funding Agency: Associação Terra dos Sonhos.

2018-2022 Inervação patológica em metástases ósseas: OSTEOCLASTOS, o que estão a fazer? Coordinator: Sandra Casimiro. Funding Agency: Fundação para a Ciência e para a Tecnologia.

2017-2023 ONCODYNAMICS. Coordinator: Luis Costa. Funding Agency: Several.

Awards

2021 Sandra Casimiro, Pfizer Global Medical Grants - Metastatic Breast Cancer Research 2021

2021 Miguel Costa, Best Poster Presentation. iMed Conference 13.0 - Innovate Competition

2020 Laura Castro, Best Oral Presentation. GAPIC – Dia da Investigação 2020

2019 Guilherme Vilhais, Best Oral Presentation. GAPIC – Dia da Investigação 2019

2019 Inês Gomes, 1st year Best Oral Presentation. XIII Annual CAML PhD Students’ Meeting

2019 Raquel Duarte, 1st year Second Best Oral Presentation. XIII Annual CAML PhD Students’ Meeting

2017 Raquel Duarte, IMM Third Best Master Thesis Award 2016/2017

2017 Rita Bello e José Gomes, Best Oral Presentation. GAPIC – Dia da Investigação 2017

2018 Cecília Alvin, Rita Paiva, Raquel Brás, Isabel Fernandes, Leonor Ribeiro, Luis Costa, Prossyga’18. First Award – Prostate Cancer

2016 Marta Martins, Liga Portuguesa Contra o Cancro-NRS/Fundação Terry Fox Oncology Research Award

2016 Marta Martins, Grupo de Investigação em Cancro Digestivo/Bayer Award

2016 Inês Gomes, Breast Cancer Fellowship LPCC/Pfizer

2016 Sandra Casimiro, Fundo IMM/Laço Clinical Grant

2016 André Mansinho, Daniela Macedo, Rita Paiva, Isabel Fernandes, Luis Costa. Prossyga’16. Second Award – Prostate Cancer

2016 Arlindo Ferreira, YOuR Project – Metastatic Breast Cancer Research Grant from Sociedade Portuguesa de Oncologia

2014 Sandra Casimiro, Liga Portuguesa Contra o Cancro-NRS/Fundação Terry Fox Oncology Research Award

2008 Sandra Casimiro, Liga Portuguesa Contra o Cancro-NRS/Fundação Terry Fox Oncology Research Award

2008 Sandra Casimiro, EMBO Short Term Fellowship

Selected Publications

Raquel Cruz-Duarte, Cátia R. de Almeida, Magda Negrão, Afonso Fernandes, Paula Borralho, Daniel Sobral, Lina M. Gallego-Paez, Daniel Machado, João Gramaça, José Vílchez, Ana T. Xavier, Miguel Godinho Ferreira, Ana R. Miranda, Helder Mansinho, Maria J. Brito, Teresa R. Pacheco, Catarina Abreu, Ana Lucia-Costa, André Mansinho, Rita Fior, Luís Costa and Marta Martins (2022). Predictive and therapeutic implications of a novel PLCγ1/SHP2-driven mechanism of cetuximab resistance in metastatic colorectal cancer. Clinical Cancer Research. Published OnlineFirst on January 3, 2022; DOI: 10.1158/1078-0432.CCR-21-1992 (Original Research)

André Mansinho, Priscila Nejo, Tito Leitão, Sandra Casimiro, Luís Costa (2021) Management of bone metastases in renal cell carcinoma: Bone-targeted treatments, systemic therapies, and radiotherapy. J Cancer Metastasis Treat 2021;7:44 (Review)

Bjartell A, Lumen N, Maroto P, Paiss T, Gomez-Veiga F, Birtle A, Kramer G, Kalinka E, Spaëth D, Feyerabend S, Matveev V, Lefresne F, Lukac M, Wapenaar R, Costa L, Chowdhury S. (2021) Real-World Safety and Efficacy Outcomes with Abiraterone Acetate Plus Prednisone or Prednisolone as the First- or Second-Line Treatment for Metastatic Castration-Resistant Prostate Cancer: Data from the Prostate Cancer Registry. Target Oncol. 16(3):357-367. (Original Research)

Borges da Ponte C, Leitão TP, Miranda M, Polido J, Alvim C, Fernandes I, Braga T, Pena B, de Almeida JM, Costa L, Dos Reis JP. (2021) Prostate Ewing Sarcoma/PNET: A case of long survival in a highly aggressive malignancy. Urology. 16:S0090-4295(21)00396-4. (Case Report)

Joana Pinheiro Neto; Irina Alho; Luís Costa; Sandra Casimiro; Duarte Valério; Susana Vinga (2021). Dynamic modeling of bone remodeling, osteolytic metastasis and PK/PD therapy: introducing variable order derivatives as a simplification technique. J Math Biol. 83(4):39 (Original Research)

Leitão, T. P., Miranda, M., Polido, J., Morais, J., Corredeira, P., Alves, P., ... & Costa, L. (2021) Circulating tumor cell detection methods in renal cell carcinoma: A systematic review. Critical Reviews in Oncology/Hematology, 161, 103331. (Review)

Lopes, C., Piairo, P., Chícharo, A., Abalde-Cela, S., Pires, L. R., Corredeira, P., ... & Diéguez, L. (2021). HER2 Expression in Circulating Tumour Cells Isolated from Metastatic Breast Cancer Patients Using a Size-Based Microfluidic Device. Cancers, 13(17), 4446. (Original Research)

Mahdi Golkaram, Michael Salmans, Shannon Kaplan, Raakhee Vijayaraghavan, Marta Martins, Nafeesa Khan, Cassandra Garbutt, Aaron Wise, Joyee Yao, Sandra Casimiro, Catarina Abreu, Daniela Macedo, Ana Lúcia Costa, Cecília Alvim, André Mansinho, Pedro Filipe, Pedro Marques da Costa, Afonso Fernandes, Paula Borralho, Cristina Ferreira, Fernando Aldeia, João Malaquias, Jim Godsey, Alex So, Traci Pawlowski, Luis Costa, Shile Zhang, and Li Liu (2021) HERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcome. npj Genomic Medicine 6:13. (Original Research)

R Ferreira A, Ferreira S, Lambertini M, Maurer C, Martel S, Costa L, Ponde N, de Azambuja E. (2021) Association between pertuzumab-associated diarrhoea and rash and survival outcomes in patients with HER2-positive metastatic breast cancer: Exploratory analysis from the CLEOPATRA trial. Eur J Cancer. 144:351-359. (Original Research)

Coleman RE, Croucher PI, Padhani AR, Clézardin P, Chow E, Fallon M, Guise T, Colangeli S, Capanna R, Costa L (2020). Bone metastases. Nature Reviews Disease Primers 6(1):83. Review.

Gomes I, de Almeida BP, Dâmaso S, Mansinho A, Correia I, Henriques S, Cruz-Duarte R, Vilhais G, Félix P, Alves P, Corredeira P, Barbosa-Morais N, Costa L, Casimiro S (2020). Expression of receptor activator of NFkB (RANK) drives stemness and resistance to therapy in ER+HER2- breast cancer. Oncotarget 11 (19):1714-1728.

Ferreira AR, Ribeiro J, Miranda A, Mayer A, Passos-Coelho JL, Brito M, Fernandes J, Gouveia J, Costa L, Vaz-Luis I (2019). Effectiveness of Adjuvant Ovarian Function Suppression in Premenopausal Women With Early Breast Cancer: A Multicenter Cohort Study. Clinical Breast Cancer 19(5):e654-e667.

Willumsen N, Ali SM, Leitzel K, Drabick JJ, Yee N, Polimera HV, Nagabhairu V, Krecko L, Ali A, Maddukuri A, Moku P, Ali A, Poulose J, Menon H, Pancholy N, Costa L, Karsdal MA, Lipton A (2019). Collagen fragments quantified in serum as measures of desmoplasia associate with survival outcome in patients with advanced pancreatic cancer. Scientific Reports 9(1):19761.

Rodrigues NV, Correia DV, Mensurado S, Nóbrega-Pereira S, deBarros A, Kyle-Cezar F, Tutt A, Hayday AC, Norell H, Silva-Santos B, Dias S (2018). Low-Density Lipoprotein Uptake Inhibits the Activation and Antitumor Functions of Human Vγ9Vδ2 T Cells. Cancer Immunology Research 6(4):448-457.

Nóbrega-Pereira S, Caiado F, Carvalho T, Matias I, Graça G, Gonçalves LG, Silva-Santos B, Norell H, Dias S (2018). VEGFR-2-mediated reprogramming of mitochondrial metabolism regulates the sensitivity of acute myeloid leukemia to chemotherapy. Cancer Research 78(3):731-741.

Costa L, Ferreira AR (2017). Adjuvant zoledronic acid to treat breast cancer: not for all. Lancet Oncology 18(11):1437-1439.

Body JJ, Casimiro s, Costa L. Targeting bone metastases in prostate cancer: improving clinical outcome. Nature Reviews Urology, 12: 340–356. 2015. doi:10.1038/nrurol.2015.90

Ferreira A, Alho I, Casimiro S, Costa L. Bone remodeling markers and bone metastases: From cancer research to clinical implications. Bonekey Rep. 2015 Apr 22;4:668. doi: 10.1038/bonekey.2015.35. eCollection 2015. Review.

dos Santos CR, Domingues G, Matias I, Matos J, Fonseca I, de Almeida JM, Dias S (2014). LDL-cholesterol signaling induces breast cancer proliferation and invasion. Lipids in Health and Disease 13:16.

Costa L. Bisphosphonates in adjuvant setting for breast cancer: a review of the meta-analysis of bisphosphonates' effects on breast cancer recurrence presented in December 2013 at San Antonio Breast Conference. Curr Opin Support Palliat Care. 2014 Dec;8(4):414-9. doi: 10.1097/SPC.0000000000000101.

Casimiro S, Fernandes A, Oliveira AG, Franco M, Pires R, Peres M, Matias M, Tato-Costa J, Guerra N, Ramos M, Cruz J, Costa L. Metadherin expression and lung relapse in patients with colorectal carcinoma. Clin Exp Metastasis. 2014 Aug;31(6):689-96. doi: 10.1007/s10585-014-9659-0. Epub 2014 Jun 20.

Costa L, Casimiro S, Gupta S, Knapp S, Radhakrishna Pillai M, Toi M, Badwe R, Carmo-Fonseca M, and Rakesh Kumar (2014) The global cancer genomics consortium’s third anual symposium: from oncogenomics to cancer care. Genes & Cancer, 5(3-4): 64-70.

Fernandes C, Monteiro S, Mendes P, Gano L, Marques F, Casimiro S, Costa L, Correia, JGD, Santos, I Biological assessment of novel bisphosphonate-containing 99mTc/Re-organometallic complexes. Journal of Organometallic Chemistry. 2014 760:197-204.

Casimiro S, Alho I, Bettencourt M., Pires R, Lipton A, Costa L RANKL enhances the effect of an antagonist of inhibitor of apoptosis proteins (cIAPs) in RANK-positive breast cancer cells. Journal of Bone Oncology. 2(3): 116-122. 2013

Horvath A, Pakala SB, Mudvari P, Reddy SDN, Ohshiro K, Casimiro S, Pires R, 5. Fuqua SAW, Polyak K, Costa L, Toi M, Nair S, Sukumar S, Kumar R Novel Insights into Breast Cancer Genetic Variance through RNA Sequencing. Scientific Reports, 3:2256. 2013 Epub 2013 Jul 25

Costa L. Which bisphosphonate to treat bone metastases? Lancet Oncol. 2014 Jan;15(1):15-6. doi: 10.1016/S1470-2045(13)70583-7. Epub 2013 Dec 11.

Alho I, Costa L, Bicho M, Coelho C. Low molecular weight protein tyrosine phosphatase isoforms regulate breast cancer cells migration through a RhoA dependent mechanism. PLoS One. 2013 Sep 27;8(9):e76307. doi: 10.1371/journal.pone.0076307. eCollection 2013.

Casimiro S, Mohammad KS, Pires R, Tato-Costa J, Alho I, Teixeira R, Carvalho A, Ribeiro S, Lipton A, Guise TA, Costa L. RANKL/RANK/MMP-1 molecular triad contributes to the metastatic phenotype of breast and prostate cancer cells invitro. PLoS One. 2013 May 16;8(5):e63153. doi: 10.1371/journal.pone.0063153. Print 2013

Alho I, Costa L, Bicho M, Coelho C. Characterization of low molecular weight protein tyrosine phosphatase isoforms in human breast cancer epithelial cell lines. Anticancer Res. 2013 May;33(5):1983-7.

Suresh B. Pakala, Suresh K. Rayala, Rui-An Wang, Kazufumi Ohshiro, Prakriti Mudvari, Sirigiri Divijendra Natha Reddy, Yi Zheng, Ricardo Pires, Sandra Casimiro, M. Radhakrishna Pillai, Luis Costa, and Rakesh Kumar MTA1 Promotes STAT3 Transcription and Pulmonary Metastasis in Breast Cancer. Cancer Research, 73(12):3761-3770 2013, Epub 2013 Apr 11.

Alho I, Costa L, Bicho M, Coelho C. The role of low-molecular-weight protein tyrosine phosphatase (LMW-PTP ACP1) in oncogenesis. Tumour Biol. 2013 Aug;34(4):1979-89. doi: 10.1007/s13277-013-0784-1. Epub 2013 Apr 14. Review.

Fernandes I, Pacheco TR, Costa A, Santos AC, Fernandes AR, Santos M, Oliveira AG, Casimiro S, Quintela A, Fernandes A, Ramos M, Costa L. Prognostic significance of AKT/mTOR signaling in advanced neuroendocrine tumors treated with somatostatin analogs. Onco Targets Ther. 2012;5:409-16. doi: 10.2147/OTT.S36330. Epub 2012 Nov 28.

Global Cancer Genomics Consortium. The Global Cancer Genomics Consortium: interfacing genomics and cancer medicine. Cancer Res. 2012 Aug 1;72(15):3720-4. Epub 2012 May 24.

Clemons M, Russell K, Costa L, Addison CL. Adjuvant bisphosphonate treatment for breast cancer: why did something so elegant become so complicated? Breast Cancer Res Treat. 2012 Jul;134(2):453-7. doi: 10.1007/s10549-012-2077-6. Epub 2012 May 5. Review.

Lipton A, Costa L, Coleman RE. Bone turnover markers: tools for prognosis and monitoring response to bisphosphonates? Breast Dis. 2011;33(2):59-69. doi: 10.3233/BD-2010-0327.

Hadji P, Aapro M, Costa L, Gnant M. Antiresorptive treatment options and bone health in cancer patients-safety profiles and clinical considerations. Cancer Treat Rev. 2012 Oct;38(6):815-24. doi: 10.1016/j.ctrv.2012.03.002. Epub 2012 Apr 5. Review.

Casimiro S, Luis I, Fernandes A, Pires R, Pinto A, Gouveia AG, Francisco AF, Portela J, Correia L, Costa L. Analysis of a bone metastasis gene expression signature in patients with bone metastasis from solid tumors. Clin Exp Metastasis. 2012 Feb;29(2):155-64. doi: 10.1007/s10585-011-9438-0. Epub 2011 Nov 26.

David Henry, Luis Costa, Francois Goldwasser, Vera Hirsh, Vania Hungria, Jana Prausova, Giorgio Vittorio Scagliotti, Harm Sleeboom, Andrew Spencer, Saroj Vadhan-Raj, Roger von Moos, Wolfgang Willenbacher, Penella J Woll, Jianming Wang, Qi Jiang, Susie Jun, Roger Dansey, Howard Yeh.“ A Randomized, Double-blind Study of Denosumab Versus Zoledronic Acid in the Treatment of Bone Metastases in Patients With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma” J Clin Oncol (2011), Volume 29, nº 9, pages: 1125-1132

Ha NH, Nair VS, Reddy DN, Mudvari P, Ohshiro K, Ghanta KS, Pakala SB, Li DQ, Costa L, Lipton A, Badwe RA, Fuqua S, Wallon M, Prendergast GC, Kumar R.Lactoferrin-endothelin-1 axis contributes to the development and invasiveness of triple-negative breast cancer phenotypes. Cancer Res. 2011 Dec 1;71(23):7259-69. doi: 10.1158/0008-5472.CAN-11-1143. Epub 2011 Oct 17

Coleman R, Costa L, Saad F, Cook R, Hadji P, Terpos E, Garnero P, Brown J, Body JJ, Smith M, Lee KA, Major P, Dimopoulos M, Lipton A. Consensus on the utility of bone markers in the malignant bone disease setting. Crit Rev Oncol Hematol. 2011 Dec;80(3):411-32. doi: 10.1016/j.critrevonc.2011.02.005. Epub 2011 Mar 15. Review.

Costa L, Harper P, Coleman RE, Lipton A. Anticancer evidence for zoledronic acid across the cancer continuum. Crit Rev Oncol Hematol. 2011 Feb;77 Suppl 1:S31-7. doi: 10.1016/S1040-8428(11)70006-3. Review.

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