Cancer genetics

  • Sanchez-Cespedes_Group_24_09_2019
Campus ICO-Germans Trias i Pujol

(+34) 93 557 2800 extn 4261

Josep Carreras Leukaemia Research Institute
Can Ruti Campus
Ctra de Can Ruti, Camí de les Escoles s/n
08916 Badalona, Barcelona



The complete genetic characterization of tumours is important to understand cancer development, to encourage the discovery of new drugs and to improve the selection of patients that may benefit from a given targeted cancer therapy. Our group is interested in the use of the latest high-throughput sequencing technologies to create profiles and catalogues of the recurrently altered genes in cancer. We are also deeply interested in understanding the mechanisms by which the abnormal function of these genes contributes to cancer development. Ultimately, our purpose is to define combinations of pathways according to the gene alteration profiles and the key molecule/s (Achilles’ heel/s) that need to be blocked to effectively reduce or abolish proliferation and inhibit invasion/metastasis. We hope that our work can help to improve the clinical management of cancer patients and to design novel therapeutic strategies.


For the last fifteen years, our group has provided information relevant to the understanding of lung cancer biology. We have discovered novel tumour suppressor genes and have contributed to the characterization of the molecular abnormalities of lung cancer.

My laboratory has been a pioneer in identifying genetic inactivation of BRG1 (the ATPase of the SWI/SNF complex) (Medina et al. 2010), now recognized as important tumour suppressor gene. In addition, we reported that SWI/SNF orchestrates the response to retinoid acid, glucocorticoids and histone deacetylase inhibitors, involving downregulation of MYC (Romero et al, 2012 & 2017).

Additionally, we unveiled inactivating mutations at the MYC-partner, MAX, in small cell lung cancer (Romero et al. 2014) and mutations in the polarity-related gene and PARD3 (Bonastre et al. 2015). In collaboration with European researchers, we observed the presence of recurrent mutations and of intragenic deletions at these genes, affecting 8-10% of the lung cancers. We also confirmed the ability of MAX and PARD3 to suppress cell growth and we have performed functional studies on the molecular effects associated with the inactivation of these genes.


More recently, and also with the contribution of various collaborators (at the European and Spanish level) we have performed whole exome and RNA sequencing of patient derived xenographs (PDX) and of patient derived cancer cells (PDCs) (Pereira et al. 2017; Pros et al. submitted). One of the genes found to be altered, was B2M, which codes for the small subunit of the HLA-class I complex, involved in immunosurveillance. We characterized these alterations, as well as others related to the response to interferon gamma, and proposed them as markers for predicting response to the current drugs based on inhibitors of PD-1 and PD-L1 (Pereira et al. 2017; Saigi et al. 2018 &2019).


Lines of Research

Derived from all our previous work, we have three important ongoing lines of research in the laboratory:

  • Determination of genetic profiles in cancer. We are interested in pursuing the use of exome and RNA sequencing to discover novel genes altered in lung cancer and the description of genetic profiles. We also undertake functional and mechanistic analysis for the dissection of pathways.
  • Study of the abnormalities at MYC/MAX/MGA and BRG1-(SWI/SNF) related pathways. Using high throughput technologies, including chromatin immunoprecipitation sequencing (ChIP-seq) and immunoprecipitation–mass Spectrometry (IP-MS), we aim to understand the functional connection between these pathways and how their abnormal function contributes to tumour development.Additionally, we are interested in identifying molecular vulnerabilities that can be used therapeutically.
  • Identification of markers that predict response to tyrosine kinase inhibitors (TKIs) and to immunocheckpoint inhibitors. Study of the mechanisms that underlie acquired resistance to tyrosine kinase inhibitors and to immunocheckpoint inhibitors in lung cancer.


Selected publications

Maria Saigi, Juan J Alburquerque-Bejar, Sanchez-Cespedes M

Determinants of immunological evasion and immunocheckpoint inhibition response in non-small cell lung cancer: the genetic front

Oncogene. 2019 Aug;38(31):5921-5932 , .
The incorporation into clinical practice of immune-checkpoint inhibitors (ICIs), such as those targeting the cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and the programmed cell death 1 (PD-1) and its ligand (PD-L1), has represented a major breakthrough in non-small cell lung cancer (NSCLC) treatment, especially in cases where the cancer has no druggable genetic alterations. Despite becoming the standard of care in certain clinical settings, either alone or in combination with chemotherapy, a proportion of patients do not respond while others actually progress during treatment. Therefore, there is a clinical need to identify accurate predictive biomarkers and to develop novel therapeutic strategies based on ICIs. Although they have limitations, the current markers evaluated to select which patients will undergo ICI treatment are the levels of PD-L1 and the tumor mutational burden. In this paper we describe what is currently known about the dynamic interaction between the cancer cell and the immune system during carcinogenesis, with a particular focus on the description of the functions and gene alterations that preclude the host immunoresponse in NSCLC. We emphasize the deleterious gene alterations in components of the major histocompatibility complex (HLA-I or B2M) and of the response to IFNγ (such as JAK2) which are mutually exclusive and can affect up to one fifth of the NSCLCs. The participation of other gene alterations, such as those of common oncogenes and tumor suppressors, and of the epigenetic alterations will also be discussed, in detail. Finally, we discuss the potential use of the tumor's genetic profile to predict sensitivity to ICIs.
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Garmendia I, Pajares MJ, Hermida-Prado F, Ajona D, Bértolo C, Sainz C, Lavín A, Remírez AB, Valencia K, Moreno H, Ferrer I, Behrens C, Cuadrado M, Paz-Ares L, Bustelo XR, Gil-Bazo I, Alameda D, Lecanda F, Calvo A, Felip E, Sanchez-Cespedes M, Wistuba II, Granda-Diaz R, Rodrigo JP, García-Pedrero JM, Pio R, Montuenga LM, Agorreta J

YES1 Drives lung cancer growth and progression and predicts sensitivity to dasatinib

Am J Respir Crit Care Med. 2019 Oct 1;200(7):888-899 , .
The characterization of new genetic alterations is essential to assign effective personalized therapies in non-small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is essential for successful personalized therapies. Molecular alterations of YES1, a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found in a significant subset of patients with lung cancer.Objectives: To evaluate YES1 (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) genetic alteration as a therapeutic target and predictive biomarker of response to dasatinib in NSCLC.Methods: Functional significance was evaluated by in vivo models of NSCLC and metastasis and patient-derived xenografts. The efficacy of pharmacological and genetic (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 [CRISPR-associated protein 9]) YES1 abrogation was also evaluated. In vitro functional assays for signaling, survival, and invasion were also performed. The association between YES1 alterations and prognosis was evaluated in clinical samples.Measurements and Main Results: We demonstrated that YES1 is essential for NSCLC carcinogenesis. Furthermore, YES1 overexpression induced metastatic spread in preclinical in vivo models. YES1 genetic depletion by CRISPR/Cas9 technology significantly reduced tumor growth and metastasis. YES1 effects were mainly driven by mTOR (mammalian target of rapamycin) signaling. Interestingly, cell lines and patient-derived xenograft models with YES1 gene amplifications presented a high sensitivity to dasatinib, an SFK inhibitor, pointing out YES1 status as a stratification biomarker for dasatinib response. Moreover, high YES1 protein expression was an independent predictor for poor prognosis in patients with lung cancer.Conclusions: YES1 is a promising therapeutic target in lung cancer. Our results provide support for the clinical evaluation of dasatinib treatment in a selected subset of patients using YES1 status as predictive biomarker for therapy.
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Pros E, Saigi M, Alameda D, Gomez-Mariano G, Martinez-Delgado B, Alburquerque-Bejar JJ, Carretero J, Tonda R, Esteve-Codina A, Catala I, Palmero R, Jove M, Lazaro C, Patiño-Garcia A, Gil-Bazo I, Verdura S, Teulé A, Torres-Lanzas J, Sidransky D, Reguart N, Pio R, Juan-Vidal1 O, Nadal E, Felip E, Montuenga LM, Sanchez-Cespedes M

Genome-wide profiling of nonsmoking-related lung cancer cells reveals common RB1 rearrangements associated with histopathologic transformation in EGFR-mutant tumors

Ann Oncol Feb;31(2):274-282 8 (2020) , .
Background: The etiology and the molecular basis of lung adenocarcinomas (LuADs) in nonsmokers are currently unknown. Furthermore, the scarcity of available primary cultures continues to hamper our biological understanding of non-smoking-related lung adenocarcinomas (NSK-LuADs). Patients and methods: We established patient-derived cancer cell (PDC) cultures from metastatic NSK-LuADs, including two pairs of matched EGFR-mutant PDCs before and after resistance to tyrosine kinase inhibitors (TKIs), and then performed whole-exome and RNA sequencing to delineate their genomic architecture. For validation, we analyzed independent cohorts of primary LuADs. Results: In addition to known non-smoker-associated alterations (e.g. RET, ALK, EGFR, and ERBB2), we discovered novel fusions and recurrently mutated genes, including ATF7IP, a regulator of gene expression, that was inactivated in 5% of primary LuAD cases. We also found germline mutations at dominant familiar-cancer genes, highlighting the importance of genetic predisposition in the origin of a subset of NSK-LuADs. Furthermore, there was an over-representation of inactivating alterations at RB1, mostly through complex intragenic rearrangements, in treatment-naive EGFR-mutant LuADs. Three EGFR-mutant and one EGFR-wild-type tumors acquired resistance to EGFR-TKIs and chemotherapy, respectively, and histology on re-biopsies revealed the development of small-cell lung cancer/squamous cell carcinoma (SCLC/LuSCC) transformation. These features were consistent with RB1 inactivation and acquired EGFR-T790M mutation or FGFR3-TACC3 fusion in EGFR-mutant tumors. Conclusions: We found recurrent alterations in LuADs that deserve further exploration. Our work also demonstrates that a subset of NSK-LuADs arises within cancer-predisposition syndromes. The preferential occurrence of RB1 inactivation, via complex rearrangements, found in EGFR-mutant tumors appears to favor SCLC/LuSCC transformation under growth-inhibition pressures. Thus RB1 inactivation may predict the risk of LuAD transformation to a more aggressive type of lung cancer, and may need to be considered as a part of the clinical management of NSK-LuADs patients. Keywords: EGFR; RB1; lung adenocarcinoma; nonsmokers; tyrosine kinase inhibitors; whole-exome sequencing.
More information
Llabata P, Mitsuishi Y, Choi PS, Cai D, Francis JM, Torres-Diz M, Udeshi ND, Golomb L, Wu Z, Zhou J, Svinkina T, Aguilera-Jimenez E, Liu Y, Carr SA,, Sanchez-Cespedes M, Meyerson M, Zhang X.

Multi-Omics analysis identifies MGA as a negative regulator of the MYC pathway in lung adenocarcinoma

Mol Cancer Res 2020 Apr;18(4):574-584 , .
Genomic analysis of lung adenocarcinomas has revealed that the MGA gene, which encodes a heterodimeric partner of the MYC-interacting protein MAX, is significantly mutated or deleted in lung adenocarcinomas. Most of the mutations are loss of function for MGA, suggesting that MGA may act as a tumor suppressor. Here, we characterize both the molecular and cellular role of MGA in lung adenocarcinomas and illustrate its functional relevance in the MYC pathway. Although MGA and MYC interact with the same binding partner, MAX, and recognize the same E-box DNA motif, we show that the molecular function of MGA appears to be antagonistic to that of MYC. Using mass spectrometry-based affinity proteomics, we demonstrate that MGA interacts with a noncanonical PCGF6-PRC1 complex containing MAX and E2F6 that is involved in gene repression, while MYC is not part of this MGA complex, in agreement with previous studies describing the interactomes of E2F6 and PCGF6. Chromatin immunoprecipitation-sequencing and RNA sequencing assays show that MGA binds to and represses genes that are bound and activated by MYC. In addition, we show that, as opposed to the MYC oncoprotein, MGA acts as a negative regulator for cancer cell proliferation. Our study defines a novel MYC/MAX/MGA pathway, in which MYC and MGA play opposite roles in protein interaction, transcriptional regulation, and cellular proliferation. IMPLICATIONS: This study expands the range of key cancer-associated genes whose dysregulation is functionally equivalent to MYC activation and places MYC within a linear pathway analogous to cell-cycle or receptor tyrosine kinase/RAS/RAF pathways in lung adenocarcinomas.
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Lafita-Navarro MC, Liaño-Pons J, Quintanilla A, Varela I, Blanco R, Ourique F, Bretones G, Aresti J, Molina E, Carroll P, Hurlin P, Romero OA,, Sanchez-Cespedes M, Eisenman RN, Delgado MD, León J.

The MNT transcription factor autoregulates its expression and supports proliferation in MYC-associated factor X (MAX)-deficient cells

J Biol Chem 2020 Feb 14;295(7):2001-2017. , .
The MAX network transcriptional repressor (MNT) is an MXD family transcription factor of the basic helix-loop-helix (bHLH) family. MNT dimerizes with another transcriptional regulator, MYC-associated factor X (MAX), and down-regulates genes by binding to E-boxes. MAX also dimerizes with MYC, an oncogenic bHLH transcription factor. Upon E-box binding, the MYC-MAX dimer activates gene expression. MNT also binds to the MAX dimerization protein MLX (MLX), and MNT-MLX and MNT-MAX dimers co-exist. However, all MNT functions have been attributed to MNT-MAX dimers, and no functions of the MNT-MLX dimer have been described. MNT's biological role has been linked to its function as a MYC oncogene modulator, but little is known about its regulation. We show here that MNT localizes to the nucleus of MAX-expressing cells and that MNT-MAX dimers bind and repress the MNT promoter, an effect that depends on one of the two E-boxes on this promoter. In MAX-deficient cells, MNT was overexpressed and redistributed to the cytoplasm. Interestingly, MNT was required for cell proliferation even in the absence of MAX. We show that in MAX-deficient cells, MNT binds to MLX, but also forms homodimers. RNA-sequencing experiments revealed that MNT regulates the expression of several genes even in the absence of MAX, with many of these genes being involved in cell cycle regulation and DNA repair. Of note, MNT-MNT homodimers regulated the transcription of some genes involved in cell proliferation. The tight regulation of MNT and its functionality even without MAX suggest a major role for MNT in cell proliferation. Keywords: MAX dimerization protein MLX; MAX network transcriptional repressor (MNT); MXD family; MYC-associated factor X (MAX); Myc (c-Myc); basic helix-loop-helix leucine zipper protein; gene regulation; proliferation; promoter; transcription.
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Current projects

Use of next-generation molecular strategies for the identification of new therapeutic targets and prognostic markers in poorly characterized types of lung carcinoma.

Project leader:Montse Sanchez-Cespedes
Start date:01/08/2019
End date:31/10/2020

CESAR Therapeutic Strategy (Cancer Epigenetic Short-circuit Adapted Response)

Project leader:Octavio Romero
Start date:01/12/2019
End date:30/11/2021