Untitled

Funder

Organizational Unit

Publications

A systematic pan-cancer analysis of genetic heterogeneity reveals associations with epigenetic modifiers

Publication . Ramos De Matos, Mafalda; Posa, Ioana; Carvalho, Filipa; Morais, Vanessa A.; Grosso, Ana Rita; de Almeida, Sérgio F.

Intratumor genetic heterogeneity (ITH) is the main obstacle to effective cancer treatment and a major mechanism of drug resistance. It results from the continuous evolution of different clones of a tumor over time. However, the molecular features underlying the emergence of genetically-distinct subclonal cell populations remain elusive. Here, we conducted an exhaustive characterization of ITH across 2807 tumor samples from 16 cancer types. Integration of ITH scores and somatic variants detected in each tumor sample revealed that mutations in epigenetic modifier genes are associated with higher ITH levels. In particular, genes that regulate genome-wide histone and DNA methylation emerged as being determinant of high ITH. Indeed, the knockout of histone methyltransferase SETD2 or DNA methyltransferase DNMT3A using the CRISPR/Cas9 system on cancer cells led to significant expansion of genetically-distinct clones and culminated in highly heterogeneous cell populations. The ITH scores observed in knockout cells recapitulated the heterogeneity levels observed in patient tumor samples and correlated with a better mitochondrial bioenergetic performance under stress conditions. Our work provides new insights into tumor development, and discloses new drivers of ITH, which may be useful as either predictive biomarkers or therapeutic targets to improve cancer treatment.

2019Journal article

Open access

Genetic and microenvironmental intra-tumor heterogeneity impacts colorectal cancer evolution and metastatic development

Publication . Sobral, Daniel; Martins, Marta; Kaplan, Shannon; Golkaram, Mahdi; Salmans, Michael; Khan, Nafeesa; Vijayaraghavan, Raakhee; Casimiro, Sandra; Fernandes, Afonso; Borralho, Paula; Ferreira, Cristina; Pinto, Rui; Marques, Catarina; Costa, Ana Lúcia; Zhang, Shile; Pawlowski, Traci; Godsey, Jim; Mansinho, André; Macedo, Daniela; Lobo-Martins, Soraia; Filipe, Pedro; Esteves, Rui; Coutinho, Joao; Costa, Paulo M.; Ramires, Afonso; Aldeia, Fernando; Quintela, António; So, Alex; Liu, Li; Grosso, Ana Rita; Costa, Luis

Colorectal cancer (CRC) is a highly diverse disease, where different genomic instability pathways shape genetic clonal diversity and tumor microenvironment. Although intra-tumor heterogeneity has been characterized in primary tumors, its origin and consequences in CRC outcome is not fully understood. Therefore, we assessed intra- and inter-tumor heterogeneity of a prospective cohort of 136 CRC samples. We demonstrate that CRC diversity is forged by asynchronous forms of molecular alterations, where mutational and chromosomal instability collectively boost CRC genetic and microenvironment intra-tumor heterogeneity. We were able to depict predictor signatures of cancer-related genes that can foresee heterogeneity levels across the different tumor consensus molecular subtypes (CMS) and primary tumor location. Finally, we show that high genetic and microenvironment heterogeneity are associated with lower metastatic potential, whereas late-emerging copy number variations favor metastasis development and polyclonal seeding. This study provides an exhaustive portrait of the interplay between genetic and microenvironment intra-tumor heterogeneity across CMS subtypes, depicting molecular events with predictive value of CRC progression and metastasis development.

2022Journal article

Open access

Aerocyte specification and lung adaptation to breathing is dependent on alternative splicing changes

Publication . Fidalgo, Marta F; Fonseca, Catarina; Caldas, Paulo; Raposo, Alexandre; Balboni, Tania; Henao Mišíková, Lenka; Grosso, Ana R.; Vasconcelos, Francisca; Franco, Claudio

Adaptation to breathing is a critical step in lung function and it is crucial for organismal survival. Alveoli are the lung gas exchange units and their development, from late embryonic to early postnatal stages, requires feedbacks between multiple cell types. However, how the crosstalk between the alveolar cell types is modulated to anticipate lung adaptation to breathing is still unclear. Here, we uncovered a synchronous alternative splicing switch in multiple genes in the developing mouse lungs at the transition to birth, and we identified hnRNP A1, Cpeb4, and Elavl2/HuB as putative splicing regulators of this transition. Notably, we found that Vegfa switches from the Vegfa 164 isoform to the longer Vegfa 188 isoform exclusively in lung alveolar epithelial AT1 cells. Functional analysis revealed that VEGFA 188 (and not VEGFA 164) drives the specification of Car4-positive aerocytes, a subtype of alveolar endothelial cells specialized in gas exchanges. Our results reveal that the cell type-specific regulation of Vegfa alternative splicing just before birth modulates the epithelial-endothelial crosstalk in the developing alveoli to promote lung adaptation to breathing.

2022Journal article

Open access